On 2013 Oct 31, John Cannell commented:

The authors stated that markers of oxidative stress are present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take

On 2013 Oct 31, John Cannell commented:

The authors found markers oxidative stress is present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take the Ameri

On 2013 Oct 31, John Cannell commented:

The authors stated that markers of oxidative stress are present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take

On 2013 Oct 31, John Cannell commented:

The authors stated that markers of oxidative stress are present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take

On 2016 Jan 08, Tom Kindlon commented:

This study uses the (so-called) empiric CFS criteria (Reeves et al., 2005)

Although they don't make it very clear, this study used the Reeves et al. (2005) criteria(1) for defining Chronic Fatigue Syndrome (CFS) (sometimes described by the CDC as an operationalization of the Fukuda et al. (1994) criteria (2)). This can be seen by examining the Reeves et al. (2007) paper on the Georgia cohort (2).

These (Reeves) criteria greatly increased the prevalence of CFS. The "empirical" definition gives a prevalence rate of 2.54% of the adult population(3) compared to 0.235% (95% confidence interval, 0.142%-0.327%) and 0.422% (95% confidence interval, 0.29%-0.56%) when the Fukuda definition (3) was used in previous population studies in the US(4,5).

The definition lacks specificity. For example, one research study(6) found that 38% of those with a diagnosis of a Major Depressive Disorder were misclassified as having CFS using the empirical/Reeves definition. A letter of mine discussed my concerns in more detail(7).

Due to the problems with the criteria, these criteria have not been used by researchers outside those contracted to analyse CDC data (apart from Leonard Jason's research team who studied it and showed problems with it (6)).

References:

1 Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic fatigue syndrome – a clinically empirical approach to its definition and study. BMC Med. 2005;3:19.

2 Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, Morrissey M, Devlin R. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr. 2007 Jun 8;5:5.

3 Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome; a comprehensive approach to its definition and study. Ann Int Med 1994, 121:953-959.

4 Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC: Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Int Med 2003, 163:1530-1536.

5 Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang CF, Plioplys S. A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999 Oct 11;159(18):2129-37.

6 Jason, LA, Najar N, Porter N, Reh C. Evaluating the Centers for Disease Control's empirical chronic fatigue syndrome case definition. Journal of Disability Policy Studies 2008, doi:10.1177/1044207308325995.

7 Kindlon T. Criteria used to define chronic fatigue syndrome questioned. Psychosom Med. 2010 Jun;72(5):506-7

On 2013 Dec 20, Raphael Stricker commented:

Fatal Clostridium Difficile Colitis Following Treatment for Lyme Disease: The Wrong Message.

Raphael B. Stricker, MD* and Lorraine Johnson, JD, MBA*

*International Lyme and Associated Diseases Society, P.O. Box 341461, Bethesda, MD 20827-1461. www.ILADS.org

Holzbauer and colleagues (1) describe a case of fatal Clostridium difficile colitis in a patient treated with ten weeks of oral antibiotics for chronic Lyme disease. Rather than focusing on patient-specific risk factors and prevention of antibiotic-related complications, the authors preach about the dangers of treating Lyme disease outside the controversial guidelines of the Infectious Diseases Society of America (IDSA), which were the subject of an antitrust investigation by the Connecticut Attorney General (2,3). In doing so, the authors exaggerate the risks of treating Lyme disease and ignore the risks of failing to treat an ongoing spirochetal infection that may cause disability equivalent to congestive heart failure, and even death (4,5). Consequently the emphasis of the case report is misguided and ultimately detrimental to patient care.

In the single case described here, no information is given about cellular or humoral immune dysfunction that may have contributed to the rapid demise of the 52-year-old patient. This rapid demise is unusual in patients less than 80 years old with C. difficile colitis (6) and suggests the presence of a hypervirulent C. difficile ribotype that might explain the clinical course. Furthermore, the authors fail to mention whether the patient received probiotic therapy during the extended oral antibiotic treatment. Probiotic therapy appears to be effective in avoiding antibiotic-induced complications, and evidence suggests that certain probiotics may neutralize C. difficile toxin (7,8). The lack of probiotic therapy may have been a significant factor in this patient’s demise.

As for the appropriateness of antibiotic therapy in a patient with clinical and laboratory evidence of chronic Lyme disease, two points should be considered. First, two approaches to treatment of this tickborne illness have been described in the medical literature. The approach promulgated by IDSA proscribes extended antibiotic therapy for persistent symptoms related to infection with Borrelia burgdorferi, the spirochetal agent of Lyme disease (2). In contrast, the competing approach of the International Lyme and Associated Diseases Society (ILADS) considers this therapy to be appropriate based on evidence of persistent spirochetal infection (4,9,10). Second, the patient described in the report received a course of oral antibiotics that is shorter than the antibiotic courses endorsed or accepted by IDSA for chronic conditions such as tuberculosis, leprosy, complicated actinomycosis, Whipple’s disease, Q fever endocarditis, alveolar echinococcosis, osteomyelitis and asplenia prophylaxis; the risks of prolonged antibiotic therapy are considered acceptable for these conditions (11-18). While several clinical studies have demonstrated the safety of extended oral and intravenous antibiotic therapy for patients diagnosed with Lyme disease (19-22), caution should always be exercised in administering extended antibiotic therapy to any patient with a chronic infectious disease.

References

1. Holzbauer SM, Kemperman MM, Lynfield R. Death due to community-associated Clostridium difficile in a woman receiving prolonged antibiotic therapy for suspected Lyme disease. Clin Infect Dis 2010;51:369-70.

2. Johnson L, Stricker RB. The Infectious Diseases Society of America Lyme guidelines: a cautionary tale about development of clinical practice guidelines. Philos Ethics Humanit Med 2010;5:9.

3. Johnson L, Stricker RB. Final report of the Lyme Disease Review Panel of the Infectious Diseases Society of America: A Pyrrhic victory? Clin Infect Dis 2010;51:1108-9.

4. Cameron DJ. Proof that chronic Lyme disease exists. Interdiscip Perspect Infect Dis 2010;2010:876450.

5. Centers for Disease Control and Prevention (CDC). Three sudden cardiac deaths associated with Lyme carditis - United States, November 2012-July 2013. MMWR Morb Mortal Wkly Rep. 2013;62:993-6.

6. Kotila SM, Virolainen A, Snellman M, Ibrahem S, Jalava J, Lyytikäinen O. Incidence, case fatality and genotypes causing Clostridium difficile infections, Finland, 2008. Clin Microbiol Infect 2011;17:888-93.

7. McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol 2006;101:812-22.

8. Castagliuolo I, Riegler MF, Valenick L, LaMont JT, Pothoulakis C. Saccharomyces boulardii protease inhibits the effects of Clostridium difficile toxins A and B in human colonic mucosa. Infect Immun 1999;67:302-7.

9. Stricker RB. Counterpoint: Long-term antibiotic therapy improves persistent symptoms associated with Lyme disease. Clin Infect Dis 2007;45:149-57.

10. Stricker RB, Johnson L. Lyme disease: The next decade. Infect Drug Resist 2011;4:1–9.

11. Small PM, Fujiwara PI. Management of tuberculosis in the United States. N Engl J Med 2001;345:189-200.

12. Cox H, Kebede Y, Allamuratova S, Ismailov G, Davletmuratova Z, Byrnes G, Stone C, Niemann S, Rüsch-Gerdes S, Blok L, Doshetov D. Tuberculosis recurrence and mortality after successful treatment: impact of drug resistance. PLoS Med 2006;3:e384.

13. Garner JP, Macdonald M, Kumar PK. Abdominal actinomycosis. Int J Surg 2007;5:441-8.

14. Freeman HJ. Tropheryma whipplei infection. World J Gastroenterol 2009;15:2078-80.

15. Liu YH, Wang XG, Gao JS, Qingyao Y, Horton J. Continuous albendazole therapy in alveolar echinococcosis: long-term follow-up observation of 20 cases. Trans R Soc Trop Med Hyg 2009;103:768-78.

16. Lazzarini L, Lipsky BA, Mader JT. Antibiotic treatment of osteomyelitis: what have we learned from 30 years of clinical trials? Int J Infect Dis 2005;9:127-38.

17. Price VE, Blanchette VS, Ford-Jones EL.The prevention and management of infections in children with asplenia or hyposplenia. Infect Dis Clin North Am 2007;21:697-710, viii-ix.

18. Beytout J, Tournilhac O, Laurichesse H. Antibiotic prophylaxis in splenectomized adults. Presse Med 2003;32(28 Suppl):S17-9.

19. Donta ST. Tetracycline therapy for chronic Lyme disease. Clin Infect Dis 1997;25 Suppl 1:S52-6.

20. Donta ST. Macrolide therapy of chronic Lyme disease. Med Sci Monit 2003;9:PI136-42.

21. Stricker RB, Green CL, Savely VR, Chamallas SN, Johnson L. Safety of intravenous antibiotic therapy in patients referred for treatment of neurologic Lyme disease. Minerva Med 2010; 101:1–7.

22. Stricker RB, Delong AK, Green CL, Savely VR, Chamallas SN, Johnson L. Benefit of intravenous antibiotic therapy in patients referred for treatment of neurologic Lyme disease. Int J Gen Med 2011;4:639-46.

Disclosure: RBS is a member of the International Lyme and Associated Diseases Society (ILADS) and a director of LymeDisease.org. He has no financial or other conflicts to declare.

On 2016 Sep 19, Morten Oksvold commented:

Please note that a rather extensive correction was published 7 December 2011: "The wrong images were mistakenly presented for day 3 for the wild-type and the racX ylmE double mutant in figure S4. The original and correct images are now shown. Also, the wrong image was presented for the mixture of L-amino acids in panel B of fig. S13 and has now been removed."

In 2013, the Losick group published results showing that D-amino acids inhibited bacterial growth and the expression of biofilm matrix genes and that the strain they originally used to study biofilm formation (B. subtilis) has a mutation in the D-tyrosyl-tRNA deacylase gene, an enzyme that prevents the misincorporation of D-amino acids into protein (Leiman et al., 2013). In a B. subtilis strain, which has a working copy of this gene, D–amino acids did not inhibit biofilm formation. The conclusion from their study was that "the susceptibility of B. subtilis to the biofilm-inhibitory effects of D-amino acids is largely, if not entirely, due to their toxic effects on protein synthesis.

Does that mean that they no longer see D-amino acids as a specific mechanism to disassemble biofilms in B. subtilis but rather as nonspecific inhibitors of growth in some genetic backgrounds?

Leiman et al. (2013) make no comment on the ability of D-amino acids to inhibit biofilm formation in staphylococcus aureus and Pseudomonas aeruginosa, as claimed in this article. The whole concept of biofilm dissasembly by D-amino acids therefore appears confusing.

It was recently published an article showing that D-amino acids do not inhibit biofilm formation in Staphylococcus aureus (Sarkar S and Pires MM, 2015).

On 2014 Jan 06, Tom Kindlon commented:

Why are we only given information on 3 out of the 8 SF-36 subscales?

Reading this paper, one could be forgiven for thinking that the SF-36 questionnaire only has 3 subscales: Physical Functioning, Mental Health and Social Functioning as that is all we are given information on. In fact, of course, the SF-36 questionnaire has 8 subscales: Physical function, Role physical, Bodily pain, General health, Vitality, Social function, Role emotional and Mental health[1]. The authors use the empiric definition for CFS[2] which requires at a minimum that the "role physical" and "role emotional" subscales also be measured. We also know that all 8 subscales were measured in this cohort[3]. So why was the information not given?

If one was not giving the authors the benefit of the doubt, one could speculate that it was because Table 4 would not look as good, as the Chi-squared calculations would not reach statistical significance for the missing data. But that would be speculation - there could be other reasons for the missing information.

Perhaps the authors could post the relevant data now.

I am not simply being mischievous - I would be interested in particular to see what are the scores for Classes 1 and 2 which include nearly all of the CFS patients (88/92, 95.7%).

References:

[1] Ware JE, Sherbourne CD: The MOS 36-item short form health survey (SF-36): conceptual framework and item selection. Med Care 1992, 30:473-483.

[2] Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C: Chronic fatigue syndrome--a clinically empirical approach to its definition and study. BMC Medicine 2005, 3:19.

[3] An evaluation of exclusionary medical/psychiatric conditions in the definition of chronic fatigue syndrome. Jones JF, Lin JM, Maloney EM, Boneva RS, Nater UM, Unger ER, Reeves WC. BMC Med. 2009 Oct 12;7(1):57. - see Tables 5 and 6.

On 2014 Jan 06, Tom Kindlon commented:

There has been criticism of how CFS is defined in this study

I thought it would be useful to point out that there is controversy [1,2] with regard to the criteria [3] used in this study to define Chronic Fatigue Syndrome (CFS).

For example, the criteria for CFS used in this study do not even require a patient to have fatigue. The authors say: “We used the Multidimensional Fatigue Inventory (MFI-20) [4] to measure characteristics of fatigue” but they do not give the thresholds. Given the MFI-20 has five subscales: (General fatigue, Physical fatigue, Mental fatigue, Activity reduction and Motivation reduction), one would probably suspect that a patient would have to score poorly on one of the headings which have fatigue in their title. But the actual criteria are: a patient needs to score >=13 on MFI general fatigue or >=10 on reduced activity. Note, one could score >=10 on the MFI reduced activity questions without necessarily being fatigued (one could be depressed or even lazy) (only current major depressive disorder with melancholic features (MDDm) is an exclusion for this definition of CFS).

This is despite the fact that in the current paper, the authors say: “Chronic fatigue syndrome (CFS) is a common, debilitating illness whose hallmark symptoms involve fatigue and fatigability”. Many other questions have been raised about the criteria for CFS that were used in this study. For example, the authors only considered current MDDm to be exclusionary for CFS while the International CFS Study group recommended that conditions (including MDDm) were considered exclusions unless they had been “resolved for more than 5 years before the onset of the current chronically fatiguing illness”[5].

Prevalence figures show that the criteria, that were used for this cohort, are selecting a broader group than previous criteria for CFS. Based on the figures derived from this cohort, the prevalence of CFS was estimated at 2.54% [6]. Other studies using similar methodology (but which did not operationalize the criteria [7] for the CFS in the same way as this study) estimated the prevalence of CFS to be 0.235% (95% confidence interval, 0.142%-0.327%) and 0.422% (95% confidence interval, 0.29%-0.56%) [8,9].

References:

[1]. Jason LA, & Richman JA. How science can stigmatize: The case of chronic fatigue syndrome. Journal of CFS 2007;14:85-103.

[2]. Jason LA, Najar N, Porter N, Reh C. Evaluating the Centers for Disease Control's empirical chronic fatigue syndrome case definition. Journal of Disability Policy Studies 2009;20;93.

[3]. Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C: Chronic fatigue syndrome--a clinically empirical approach to its definition and study. BMC Medicine 2005, 3:19.

[4]. Smets EM, Garssen B, Bonke B, De Haes JC. The multidimensional fatigue inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res 1995; 39: 315–25.

[5]. Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, Bleijenberg G, Evengard B, White PD, Nisenbaum R, Unger ER; International Chronic Fatigue Syndrome Study Group. Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res. 2003 Dec 31;3(1):25.

[6]. Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, Morrissey M, Devlin R. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr. 2007 Jun 8;5:5.

[7]. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome; a comprehensive approach to its definition and study. Ann Int Med 1994, 121:953-959.

[8]. Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC: Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Int Med 2003, 163:1530-1536.

[9]. Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang CF, Plioplys S. A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999 Oct 11;159(18):2129-37.

On 2014 Jan 06, Tom Kindlon commented:

A more detailed comparison would need to be made before one could say this replicates the previous study

Part of the aim of this study [1] appears to be to compare the classes that were drawn up with a previous cohort[2-4]. However it does not, to my mind, deal with this in a particularly rigorous fashion. The main quantitative comparisons are the percentages that fall in each class (Tables 6 and 7). However, the percentages will be influenced by the quantity and type of non-CFS controls used which are not the same in each cohort [to explain why this is important using an extreme example: if there were 1000 non-CFS cases for everyone one CFS case in one cohort, the percentages in each class would be different than if there was a 1:1 ratio of CFS to non-CFS cases in the other cohort].

The first study involved the following[5]: "This population-based case control study enrolled 227 adults identified from the population of Wichita with: (1) CFS (n = 58); (2) non-fatigued controls matched to CFS on sex, race, age and body mass index (n = 55); (3) persons with medically unexplained fatigue not CFS, which we term ISF (n = 59); (4) CFS accompanied by melancholic depression (n = 27); and (5) ISF plus melancholic depression (n = 28)." This was based on the classification in 1997-2000. These were then assessed during 2003. As one can see in Table 2, in 2003, 6 out of the original 58 CFS patients satisfied the CFS definition[6] as originally operationalized, along with 4 out of the controls. 6 more who had previously been excluded because of previous diagnosis of Major Depressive Disorder with melancholic features (MDDm) were also said to satisfy the original CFS diagnosis. The method for operationalizing the CFS definition[6] was then changed so there was then 43 individuals with CFS (see Table 5). Although the same method[5] of operationalizing the CFS definition[6] is used when comparing the Wichita and Georgia cohorts, it is a very different way to select patients and controls than the current study[1]. So it is questionable how interesting it is to compare the percentages in each class.

A comparison of the percentages of CFS in each class might have been interesting but that was not done.

Also, apart from the percentages, no tables with quantitative information are presented in the current paper to help the reader compare the class groups to see how valid the comparisons are. This is made more difficult because the original study gave much more detailed data on the six class solution rather than the five class solution [2]: "As the five- and six-class solutions produced practically identical classes, with the exception of the fifth group in the five-class solution being divided into the fifth and sixth classes in the six-class solution, only the six-class solution is presented in Table 2."

So in that paper, one has classes which have a median BMI of 32, 30 and 30 which are described in the current paper[1] as obese classes while class 5 would be a combination of classes 5 and 6 which have a median BMI of 26 and 27 are classed as non-obese. So numerical comparisons would have been of more use rather than looking at verbal descriptions - describing two groups which have a median BMI of 30 as obese (so approx 50% would have a BMI under 30, one threshold for obesity) and another group which has a median BMI of around 26.5 as non-obese, seems a bit unsatisfactory. There is a 5 class LCA solution in Figure 1 in one of the Wichita papers which gives some verbal descriptions[4]. As one can see, "obese" is only used to describe two of the five LCA groups: - Obese, hypnoea (27.93%) - Obese, hypnoea and stressed (15.32%) - Interoception (16.22%) - Interoception, depression (19.82%) - Well (20.72%)

However, this does not seem to be the same five class solution for the Wichita cohort as the one described in this paper as the percentages don't match up.

References:

[1]. Aslakson E, Vollmer-Conna U, Reeves WC, White PD. Replication of an empirical approach to delineate the heterogeneity of chronic unexplained fatigue. Popul Health Metr. 2009 Oct 5;7:17.

[2]. Vollmer-Conna U, Aslakson E, White PD: An empirical delineation of the heterogeneity of chronic unexplained fatigue in women. Pharmacogenomics 2006, 7(3):355-364.

[3]. Aslakson E, Vollmer-Conna U, White PD. The validity of an empirical delineation of heterogeneity in chronic unexplained fatigue. Pharmacogenomics. 2006 Apr;7(3):365-73.

[4]. Carmel L, Efroni S, White PD, Aslakson E, Vollmer-Conna U, Rajeevan MS. Gene expression profile of empirically delineated classes of unexplained chronic fatigue. Pharmacogenomics. 2006 Apr;7(3):375-86.

[5]. Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic fatigue syndrome--a clinically empirical approach to its definition and study. BMC Med. 2005 Dec 15;3:19.

[6]. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A: The chronic fatigue syndrome; a comprehensive approach to its definition and study. Ann Int Med 1994, 121:953-959.

On 2015 Oct 02, Simon Young commented:

This is an interesting review but omits some important manuscripts. For example, in the section on the effect of tryptophan loading on mood in healthy volunteers there is no mention of several relevant studies Leathwood PD, 1982, Charney DS, 1982, Greenwood MH, 1974, SMITH B, 1962. The same is true for studies on the effect of tryptophan on sleep Griffiths WJ, 1972, Hartmann E, 1977, Adam K, 1979. The statement in the section 4.1 that “there is little consensus in terms of Trp’s efficacy in treating depression” is not universally accepted. A Cochrane Database Systematic Review concluded that the available evidence suggests that tryptophan is better than placebo at alleviating depression Shaw K, 2002, and tryptophan has been available as a prescription drug for the treatment of depression in a number of countries. The Cochrane Database Systematic Review includes a number of studies not included in the article.

On 2013 Dec 06, Tom Kindlon commented:

Differences in medication usage in the Wichita and Georgia cohorts could be due to the different methods of operationalizing the Fukuda criteria that were used

Medication usage was not the same in the CFS populations found in the Wichita and Georgia populations.

The authors summarise the similarities and differences in the following paragraph:

“Our findings confirm those from a previous study of medication use in persons with CFS from Wichita, Kansas. Both studies found significantly higher usage of pain relievers, gastrointestinal drugs, antidepressants and benzodiazepines by persons with CFS compared to Well controls. Unlike the Wichita study, though, persons with CFS in Georgia were not significantly more likely than controls to use hormones and supplements but were significantly more likely than controls to use muscle relaxants and anti-allergy and cold/sinus medications. Overall, compared to persons with CFS from the Wichita study7, a smaller proportion of persons with CFS in Georgia used pain-relievers (65.5% in Georgia vs. 87.8% in Wichita), supplements/vitamins (44.3% vs. 62.2%), antidepressants (36.3% vs. 41.1%), antibiotics (7.1% vs. 16.7%), hormones (43.4% vs. 52.5%. among women only, 11.8% among all CFS), antihypertensive drugs (17.7% vs. 21.1%), muscle relaxants (8.9% vs. 12.2%), anti-asthma medications (7.1% vs. 12.2%), glucose-lowering drugs (0.9% vs. 4.4%.). Use of other prescription drug categories such as lipid-lowering drugs (11.5% vs.12.2%) and benzodiazepines (12.4%, vs. 11.1% respectively) was similar in Georgia and Wichita (Kansas). The relatively lower usage of most prescription drug medications by persons with CFS in Georgia compared to Wichita may reflect lower seeking of, or lower access to, health care.”

An alternative reason could be that the two sets of criteria for CFS used were not selecting the same type of patients.

The current study[1] uses the empiric definition for CFS[2]. As one can see from the paper that gives the criteria involved in the empiric definition, although it is also based on the Fukuda definition[3], a different number of patients satisfy the criteria [2] compared to how the authors used the definition in the initial study of the Wichita population.

This change looks more significant when one looks at the prevalence rates for CFS obtained in the two cohorts. In the Wichita study[4], the prevalence of CFS was 0.235% (95% confidence interval, 0.142%-0.327%). In the Georgia study[5], the prevalence of CFS was 2.54%, 10.8 times the prevalence in the Wichita study!

Concerns have been raised[6,7] about the newer method[2] of operationalizing the Fukuda definition[3] that were used in the current study[1]. In the only study[7] using the empiric criteria [2] that I am aware of that did not involve the CDC CFS team, 38% of those chosen as patients with Major Depressive Disorder but not CFS, were found to satisfy the new criteria[2] for CFS.

References

1] Boneva RS, Lin JM, Maloney EM, Jones JF, Reeves WC. Use of medications by people with chronic fatigue syndrome and healthy persons: a population-based study of fatiguing illness in Georgia. Health Qual Life Outcomes. 2009 Jul 20;7:67.

[2] Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic fatigue syndrome--a clinically empirical approach to its definition and study. BMC Med. 2005 Dec 15;3:19.

[3] Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome; a comprehensive approach to its definition and study. Ann Int Med 1994, 121:953-959.

[4] Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC: Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Int Med 2003, 163:1530-1536.

[5] Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, Morrissey M, Devlin R. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr. 2007 Jun 8;5:5.

[6] Jason LA, Richman JA. How science can stigmatize: The case of chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome 2008, 14, 85-103.

[7] Jason LA, Najar N, Porter N, Reh C. Evaluating the Centers for Disease Control’s empirical chronic fatigue syndrome case definition. Journal of Disability Policy Studies 2009, 20, 93-100. doi:10.1177/1044207308325995

On 2013 Oct 31, John Cannell commented:

The authors stated that markers of oxidative stress are present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take

On 2014 Jan 08, Tom Kindlon commented:

The references don't show that CFS "affects at least 4 million adults in the United States"

This is not necessarily a major point to do with the methodology. However given the paper involves CFS medical education, and gives few facts about CFS, one would think that the statements that are made are at least reasonably accurate.

However, this statement clearly isn't: "CFS affects at least 4 million adults in the United States [2-4]." The references given are the first three references below. The second study found a prevalence of 422 per 100,000 adults and the third study found a prevalence of 235 per 100,000 adults. These aren't even close to 4 million adults - the second one suggests a figure of at least 400,000 adults. This study involved one of the authors (William C Reeves). The other study[1], also involved Reeves, did find a prevalence of 2540 per 100,000 adults, which would equate to over 4 million adults. As can be seen, this is much higher than previous estimates of the prevalence of CFS in the US. The reason for the huge discrepancy is largely because it used a different method of defining CFS[4].

There has been some criticism of this new definition[5]. Unlike previous times when the CDC produced definitions for CFS[6,7], the definition used in this study is generally only being used by the CDC-funded CFS research team [the cohorts from the Wichita 2-day study in 2003 (not to be confused with the Reyes study) and the Georgia prevalence study[3]]. So it's far from clear that most people would accept that CFS "affects at least 4 million adults in the United States". But certainly two of the three studies given to back up this reference did not find anything close to such a prevalence.

References:

[1] Reeves WC, et al. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Population Health Metrics 2007, 5:5.

[2] Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huan CF, Plioplys S: A community-based study of chronic fatigue syndrome. Arch Int Med 1999, 159:2129-2137.

[3] Reyes M, Nisenbaum R, Hoaglin DC, Emmons C, Stewart G, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC: Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Intern Med 2003, 163:1530-1536.

[4] Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C: Chronic Fatigue Syndrome – A clinically empirical approach to its definition and study. BMC Medicine 2005, 3:19 (15 December 2005)

[5] Jason LA, Richman JA: How Science Can Stigmatize: The Case of Chronic Fatigue Syndrome. Journal of Chronic Fatigue Syndrome, Vol. 14(4), 2007

[6] Fukuda, K., Straus, S.E., Hickie, I., Sharpe, M.C., Dobbins, J.G., & Komaroff, A. (1994). The chronic fatigue syndrome: A comprehensive approach to its definition and study. Annals of Internal Medicine, 121 (12):953-959. http://www.annals.org/cgi/content/full/121/12/953

[7] Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med. 1988; 108:387-9.

On 2014 Aug 29, Massimo Ciccozzi commented:

I read with interest the paper by Santosh et al. HIV 2 infections were geographically restricted, affecting West African countries1, 2, whereas in Europe the prevalence of HIV-2 is high in those countries that have socioeconomic relationships with this African region 3-5 . However, increased migration from/to other countries and international travels might increase the risk of spreading of this virus worldwide. We recently published a phylogenetic analysis of HIV2 case series in Italy using sequences isolated from Indian patients try to connect this infection with other from different countries 6. This article is very interesting and give important information on HIV-2 using a complete genome analysis. In Indian country few papers have been written in Phylogenetic analysis and Santosh and coauthors have given a sort of thrust in this way. In my opinion I only suggest the use of Bayesian Methods to have more robust information about the origin of Indian epidemics, moreover I encourage all Indian researchers, that are able to make sequences, to do this. It is also important that the scientific community don't lower the watch and monitor this infection also because to study HIV 2 can be an opportunity to better understand the HIV disease pathogenesis, protein immunity and this have to be taken before it disappears.<br> References

1. Dougan S, Patel B, Tosswill JH, and Sinka K: Diagnoses of HIV-1 and HIV-2 in England, Wales, and Northern Ireland associated with west Africa. Sex Transm Infect 2005;81:338– 341.

2. Matheron S, Mendoza-Sassi G, Simon F, Olivares R, Coulaud JP, and Brun-Vezinet F: HIV-1 and HIV-2 AIDS in African patients living in Paris. AIDS 1997;11:934–936.3

3. Valadas E, Franc¸a L, Sousa S, and Antunes F: 20 years of HIV-2 infection in Portugal: Trends and changes in epidemiology. Clin Infect Dis 2009;48:1166–1167.

4. Barin F, Cazein F, Lot F, et al.: Prevalence of HIV-2 and HIV-1 group O infections among new HIV diagnoses in France: 2003– 2006. AIDS 2007;21:2351–2353.

5. Soriano V, Gomes P, Heneine W, et al.: Human immunodeficiency virus type 2 (HIV-2) in Portugal: Clinical spectrum, circulating subtypes, virus isolation, and plasma viral load. J Med Virol 2000;61:111–116.

6. D’Ettorre,G, Lo Presti A,Gori C, Cella E,Bertoli A,Vullo V,Perno CF, Ciotti M,. Foley Brian T, and Massimo Ciccozzi. An HIV Type 2 Case Series in Italy: A Phylogenetic Analysis.(2013) AIDS Res HUM Retroviruses

On 2014 Jan 08, Tom Kindlon commented:

Various comments

This paper refers to the use of a re-attribution programme. I thought I would highlight the results of a trial[1] published last year on the topic. It involved testing practice-based training of GPs in reattribution. The method to test the hypothesis was a "cluster randomised controlled trial in 16 practices, 74 GPs and 141 patients with medically unexplained symptoms of 6 hours of reattribution training v. treatment as usual." It found that "Practice-based training in reattribution changed doctor-patient communication without improving outcome of patients with medically unexplained symptoms". Hardly a ringing endorsement of the method.

There has been a lot of hype about the effectiveness of Cognitive Behavioural Therapy (CBT) for Chronic Fatigue Syndrome (CFS). However, a meta-analysis[2] of its efficacy of CBT for CFS published in 2008 might temper some of the enthusiasm. The studies involved a total of 1371 patients. This involved calculating the size of an effect measure, the Cohen's d value. They calculated d using the following method: "Separate mean effect sizes were calculated for each category of outcome variable (e.g., fatigue self-rating) and for each type of outcome variable (mental, physical, and mixed mental and physical). Studies generally included multiple outcome measures. For all analyses except those that compared different categories or types of outcome variables, we used the mean effect size of all the relevant outcome variables of the study."d was calculated to be 0.48. For anyone unfamiliar with Cohen's d values, they are not bounded by 1; also, the higher the score, the bigger the "effect size" i.e. the more "effective" a treatment was found to be. Cohen's d values are considered to be a small effect size at 0.2, a moderate effect size at 0.5, and a large effect size at 0.8[2].

There are now hundreds of studies that have found "physical" abnormalities of one sort or another in Chronic Fatigue Syndrome. Thus I question the placement of "Chronic Fatigue" (which many/most people would read as referring to Chronic Fatigue Syndrome as it is listed beside Fibromyalgia and Irritable Bowel Syndrome) in figure 1, "Hypothetical scatter plot of dysfunction versus pathology in primary care consultations" where "evidence of pathological change" is said to be "absent". The numerous abnormalities found raise questions about the placement on the scatter plot or else the limitations of the concept. Also how "reversible" the "abnormal functioning, either physiological or psychological" is, remains far from clear given the low recovery rates.

References:

[1] Morriss R, Dowrick C, Salmon P, Peters S, Dunn G, Rogers A, Lewis B, Charles-Jones H, Hogg J, Clifford R, Rigby C, Gask L. Cluster randomised controlled trial of training practices in reattribution for medically unexplained symptoms. Br J Psychiatry. 2007 Dec;191:536-42

[2] Malouff, J. M., et al., Efficacy of cognitive behavioral therapy for chronic fatigue syndrome: A meta-analysis. Clinical Psychology Review (2007), doi:10.1016/j.cpr.2007.10.004

[3] Cohen J: Statistical power analysis for the behavioural sciences. Edited by: 2. New Jersey: Lawrence Erlbaum; 1988.

On 2014 Jan 04, Tom Kindlon commented:

References:

[1] PD White, MC Sharpe, T Chalder, JC DeCesare, R Walwyn, for the PACE trial management group: Response to comments on "Protocol for the PACE trial" http://www.biomedcentral.com/1471-2377/7/6/comments#306608

[2] Goudsmit EM, Stouten B, Howes S: Fatigue in Myalgic Encephalomyelitis. Bulletin of the IACFS/ME - Volume 16, Issue 3. http://tinyurl.com/3zcgw8 i.e. http://www.iacfsme.org/BULLETINFALL2008/Fall08GoudsmitFatigueinMyalgicEnceph/tabid/292/Default.aspx

[3] Bazelmans E, Bleijenberg G, van der Meer JWM, Folgering H. Is physical deconditioning a perpetuating factor in chronic fatigue syndrome? A controlled study on maximal exercise performance and relations with fatigue, impairment and physical activity. Psychol Med 2001; 31: 107–14.

[4] Black CD, O’Connor PJ, McCully KK. Increased daily physical activity and fatigue symptoms in chronic fatigue syndrome. Dyn Med 2005; 4: 3.

[5] Sisto SA, Tapp WN, LaManca JJ et al. Physical activity before and after exercise in women with chronic fatigue syndrome. Q J Med 1998; 91:465–73.

[6] Vercoulen JHMM, Bazelmans E, Swanink CMA et al. Physical activity in chronic fatigue syndrome assessment and its role in fatigue. J Psych Res 1997; 31: 661–73.

[7] Van der Werf SP, Prins JB, Vercoulen JHM, van der Meer JWM, Bleijenberg G. Identifying physical activity patterns in chronic fatigue syndrome using actigraphic assessment. J Psychosom Res 2000; 49: 373–79.

[8] Nijs J, Almond F, De Becker P, Truijen S, Paul L. Can exercise limits prevent post-exertional malaise in chronic fatigue syndrome? An uncontrolled clinical trial. Clin Rehabil. 2008 May;22(5):426-35.

[9] Clapp LL, Richardson MT, Smith JF, Wang M, Clapp AJ, Pieroni RE. Acute effects of thirty minutes of light-intensity, intermittent exercise on patients with chronic fatigue syndrome. Phys Ther 1999; 79: 749-56.

[10] Lapp, C (1997). Exercise limits in chronic fatigue syndrome. Am J Med, 103: 83-84.

[11] DL Arnold et al. Excessive intracellular acidosis of skeletal muscles on exercise in the post viral exhaustion / fatigue syndrome: a 31P-NMR Study. Proceedings of third Annual Meeting of the Society for Magnetic Resonance in Medicine, New York, 1984, 12-13.

[12] Jammes Y, Steinberg JG, Mambrini O, Bregeon F, Delliaux S: Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. Journal: J Intern Med., 2005 Mar;257(3):299-310.

[13] Black CD, McCully KK: Time course of exercise induced alterations in daily activity in chronic fatigue syndrome. Dyn Med. 2005 Oct 28;4:10.

On 2014 Jan 08, Tom Kindlon commented:

New or "Unusual" definition for CFS used in this study

(This was originally posted on the journal's website here: http://www.biomedcentral.com/1471-2377/6/41/comments. However, the formatting has been removed meaning few may read it there)

People reading this study need to be aware that it uses a new or "unusual" definition of Chronic Fatigue Syndrome (CFS)[1] so the results may not apply to CFS cohorts as usually defined[2].This definition selects a group covering 2.54% of the adult population[3]. This is much higher than previous estimates of the prevalence of CFS. For example, members of the team in this study have previously estimated the prevalence as 0.235%[4] i.e. the prevalence rate using this definition is 10.8 times the rate found using the more usual CFS definition[2].

There has been some criticism of this new definition[5]. Unlike previous times when the CDC produced definitions for CFS[2,6], the definition used in this study is generally only being used by the CDC-funded CFS research team.

References:

[1] Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C: Chronic Fatigue Syndrome – A clinically empirical approach to its definition and study. BMC Medicine 2005, 3:19 (15 December 2005)

[2] Fukuda, K., Straus, S.E., Hickie, I., Sharpe, M.C., Dobbins, J.G., & Komaroff, A. (1994). The chronic fatigue syndrome: A comprehensive approach to its definition and study. Annals of Internal Medicine, 121 (12):953-959. http://www.annals.org/cgi/content/full/121/12/953

[3] Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, Morrissey M, Devlin RPrevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Population Health Metrics 2007, 5:5 (8 June 2007)

[4] Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC: Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Int Med 2003, 163:1530-1536.

[5] Jason Leonard: Issues with CDC Empirical Case Definition and Prevalence of CFS. IACFS website http://tinyurl.com/2qdgu4 i.e. http://www.iacfsme.org/IssueswithCDCEmpiricalCaseDefinitionandPrev/tabid/105/Default.aspx

[6] Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med. 1988; 108:387-9.

On 2014 Jan 09, Tom Kindlon commented:

(contd.)

There are numerous pre-existing instruments out there that measure other symptoms associated with CFS. Off the top of my head, two that come to mind are the Chronic Fatigue Syndrome Symptom List and the CFS CDC Symptom Inventory. It encompasses the 19 most frequently reported symptoms in a sample of 1578 chronic fatigue syndrome patients[8]. In order to assess the severity of the symptoms included in the Chronic Fatigue Syndrome Symptom List, visual analogue scales (100 mm) are used. The Symptom Inventory "collects information about the presence, frequency, and intensity of 19 fatigue and illness-related symptoms" including the 8 CDC criteria symptoms. Perceived frequency of each symptom is rated on a four-point scale (1=a little of the time, 2=some of the time, 3=most of time, 4=all of the time), and severity or intensity of symptoms was measured on a three-point scale (1=mild, 2=moderate, 3=severe). To summarize the degree of distress associated with each symptom, individual symptom scores were calculated by multiplying the frequency score by the intensity score. The scoring would not have to be done like this - for example in the same paper I quoted from for the method of scoring above, the CDC team[8] used the following method: they "transformed the intensity scores into equidistant scores before multiplication (i.e., 0 = symptom not reported 1 = mild, 2.5 = moderate, 4 = severe) resulting in range 0–16 for each symptom." A total score for each person can be calculated by summing the 19 individual symptom scores (possible range from 0 to 304). A Case Definition score can be calculated as the sum of the 8 individual CFS case-definition symptom scores and an Other Symptoms score by considering only the 11 non-CFS symptoms.Calculating levels of various symptoms like this would have given a better overall idea of the health of the patients and how badly affected they were by "CFS/ME".

They could also have been used before and after the exercise testing.

In most management strategies these days, whether they're based on a graded exercise/activity model or a pacing model, patients are discouraged from "boom and bust" i.e. doing too much or pushing themselves and then crashing with lots of symptoms. Faced with the exercise testing, a patient who is good at avoiding "booming and busting" may not push themselves as hard as another patient. That does not mean they are not as well or do not manage their illness as well as another patient. One way of measuring whether this occurred with the exercise testing was if measures were used before and after the exercise testing. Given the post-exertional nature of many of the symptoms of "CFS/ME", it can be good not to restrict testing just to the day of exercise testing.

There are some examples in the literature of patients being followed up after exercise testing. For example, Nijs[10] performed a gentle walking exercise on patients where they walked on average 558m(+/-340) (range: 120-1620) at a speed of 0.9m/s (+/-0.2) (range: 0.6-1.1). This resulted in a statistically significant (p<0.05) worsening of scores in the following areas when comparing pre-exercise, post-exercise and 24 hour post-exercise scores using ANOVA: VAS fatigue, VAS musculoskeletal pain, VAS sore throat, SF-36 bodily pain and SF-36 general health perception. 14 out of 24 subjects experienced a clinically meaningful change (worsening) in bodily pain (i.e. a minimum change of the SF-36 bodily pain subscale score of at least 10).In another study, Lapp [11] reported on the effects of 31 patients to his practice who were asked to monitor their symptoms three weeks before to 12 days after a maximal exercise test. 74% of the patients experienced worsening fatigue and 26% stayed the same. None improved. The average relapse lasted 8.82 days although 22% were still in relapse when the study ended at 12 days. There were similar changes with exercise in lymph pain, depression, abdominal pain, sleep quality, joint and muscle pain and sore throat.

Actometers could also have been used in the period before and after testing to see whether there was "booming and busting" and so to see whether the exercise testing alone is useful or not.

I am unsure whether much of what I've written can be used at this stage for this study but it may be useful for people interpreting the results as well as for others designing further trials.* When quoting from the paper's text, I have changed the reference numbers of papers to ones I've used.

Publications

1 Whiting P, Bagnall A-M, Sowden A, Cornell J, Mulrow C, Ramirez G: Interventions for the treatment and management of chronic fatigue syndrome. A systematic review. JAMA 2001, 286:1360-1368.

2 Friedberg, F. Does graded activity increase activity? A case study of chronic fatigue syndrome. Journal of Behavior Therapy and Experimental Psychiatry, 2002, 33, 3-4, 203-215

3 Prins JB, Bleijenberg G, Bazelmans E, et al. Cognitive behaviour therapy for chronic fatigue syndrome: a multicentre randomised controlled trial. Lancet 2001; 357: 841-47.

4 Van Essen, M and de Winter, LJM. Cognitieve gedragstherapie by het vermoeidheidssyndroom cognitive behaviour therapy for chronic fatigue syndrome). Report from the College voor Zorgverzekeringen. Amstelveen: Holland. June 27th, 2002. Bijlage B. Table 2.

5 O'Dowd, H., Gladwell, P., Rogers, CA., Hollinghurst, S and Gregory, A. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme. Health Technology Assessment, 2006, 10, 37, 1-140.

6 Roberts AD, Papadopoulos AS, Wessely S, Chalder T, Cleare AJ. Salivary cortisol output before and after cognitive behavioural therapy for chronic fatigue syndrome. J Affect Disord. 2008 Oct 18.

7 Priebe S, Fakhoury WK, Henningsen P. Functional incapacity and physical and psychological symptoms: how they interconnect in chronic fatigue syndrome. Psychopathology. 2008;41(6):339-45.

8 De Becker P, McGregor N, De Meirleir K. A definition-based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome. J Intern Med 2001; 250: 234–40.

9 Wagner D, Nisenbaum R, Heim C, Jones JF, Unger ER, Reeves WC. Psychometric properties of the CDC Symptom Inventory for assessment of chronic fatigue syndrome. Popul Health Metr. 2005 Jul 22;3:8.

10 Nijs J, Almond F, De Becker P, Truijen S, Paul L. Can exercise limits prevent post-exertional malaise in chronic fatigue syndrome? An uncontrolled clinical trial. Clin Rehabil. 2008 May;22(5):426-35.

11 Lapp, C (1997). Exercise limits in chronic fatigue syndrome. Am J Med, 103: 83-84.

On 2014 Feb 02, Tom Kindlon commented:

More symptoms could be added to a CFS Symptom Inventory

(This was originally posted here: http://www.pophealthmetrics.com/content/3/1/8/comments but the formatting has been removed and some people may not read the paper there either).

Many would feel that the 8 symptoms used in the CDC '94 definition [1] were chosen in a somewhat arbitrary fashion; so it is to be welcomed that the CDC itself has started to look beyond these symptoms with the CDC CFS Symptom Inventory. The idea of a Short Form of the CDC Symptom Inventory is also interesting.

However, it is not clear to me where the extra symptoms that are on the CDC CFS Symptom Inventory came from. For example, I didn't see some of the symptoms listed in Reeves et al [2].

In 2001, De Becker et al [3] published data on the symptoms found in over 2500 patients. They tried to improve on the 1988 [4] and 1994 CDC criteria. They suggested a list of symptoms that could be used to strengthen the ability to select ME/CFS patients. Many of the symptoms they mentioned are not in the CDC CFS Symptom Inventory.

So to claim that the "CDC Symptom Inventory assesses the full range of CFS associated symptoms" seems questionable. It would be interesting if in future these symptoms (that De Becker et al were suggesting) were added before statistical analyses are performed. The fatigue criteria and functional impairment criteria have become much less restrictive [5]. For example, to satisfy the fatigue criteria, the fatigue is required to be greater than or equal to the medians of the MFI general fatigue (≥ 13) or reduced activity (≥ 10) scales. So it now seems particularly important that the symptom criteria have good sensitivity and specificity or one is going to end up with a definition that leads to very heterogeneous samples.

References:

[1] Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A: The chronic fatigue syndrome; a comprehensive approach to its definition and study.Ann Int Med 1994, 121:953-959.

[2] Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, Bleijenberg G, Evengard B, White PD, Nisenbaum R, Unger ER, International Chronic Fatigue Syndrome Study Group: Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution.BMC Health Services Research 2003, 3:25.http://dx.doi.org/10.1186/1472-6963-3-25

[3] A definition-based analysis of symptoms in a large cohort of patients withchronic fatigue syndrome, P. De Becker, N. McGregor, and K. De Meirleir.Journal of Internal Medicine 2001;250:234-240

[4] Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, et al.: Chronic fatigue syndrome: a working case definition. Ann Intern Med 1988, 108:387-389.

[5] Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA,Unger ER, Vernon SD, Heim C: Chronic fatigue syndrome — a clinically empirical approachto its definition and study. BMC Medicine 2005, 3:16.

On 2014 Jul 04, Tom Kindlon commented:

References:

1. Collings AD, Newton D. Re: What causes chronic fatigue syndrome? BMJ 2014 (18 June).

2. Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon SD, Reeves WC, Lloyd A; Dubbo Infection Outcomes Study Group. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. 2006 Sep 16;333(7568):575.

3. Bavinton J, Darbishire L, White PD -on behalf of the PACE trial management group. Graded Exercise Therapy for CFS/ME (Therapist manual): http://www.pacetrial.org/docs/get-therapist-manual.pdf (Accessed: June 25, 2014)

4. Burgess M, Chalder T. PACE manual for therapists. Cognitive behaviour therapy for CFS/ME.http://www.pacetrial.org/docs/cbt-therapist-manual.pdf (Accessed: June 25, 2014)

5. Twisk FNM, Maes M. A review on Cognitive Behavorial Therapy (CBT) and Graded Exercise Therapy (GET) in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS. Neuro Endocrinol Lett. 2009;30:284-299.

6. Kindlon T. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Bulletin of the IACFS/ME. 2011;19(2):59-111http://www.iacfsme.org/BULLETINFALL2011/Fall2011KindlonHarmsPaperABSTRACT/tabid/501/Default.aspx

7. Rapport d’évaluation (2002-2004) portant sur l’exécution des conventions de rééducation entre le Comité de l’assurance soins de santé (INAMI) et les Centres de référence pour le Syndrome de fatigue chronique (SFC). 2006. http://www.inami.fgov.be/care/fr/re...mation/studies/study-sfc-cvs/pdf/rapport.pdf . (French language edition) (Accessed: June 25, 2014)

8. Evaluatierapport (2002-2004) met betrekking tot de uitvoering van de revalidatieovereenkomsten tussen het Comité van de verzekering voor geneeskundige verzorging (ingesteld bij het Rijksinstituut voor Ziekte- en invaliditeitsverzekering) en de Referentiecentra voor het Chronisch vermoeidheidssyndroom (CVS). 2006. Available online: http://www.inami.fgov.be/care/nl/re...mation/studies/study-sfc-cvs/pdf/rapport.pdf Accessed September 16, 2011 (Dutch language version) (Accessed: June 25, 2014)

9. Stordeur S, Thiry N, Eyssen M. Chronisch Vermoeidheidssyndroom: diagnose, behandeling en zorgorganisatie. Health Services Research (HSR). Brussel: Federaal Kenniscentrum voor de Gezondheidszorg (KCE); 2008. KCE reports 88A (D/2008/10.273/58)https://kce.fgov.be/sites/default/files/page_documents/d20081027358.pdf (Accessed: June 25, 2014)

10. Crawley E, Collin SM, White PD, Rimes K, Sterne JA, May MT; CFS/ME National Outcomes Database. Treatment outcome in adults with chronic fatigue syndrome: a prospective study in England based on the CFS/ME National Outcomes Database. QJM. 2013 Jun;106(6):555-65

11. "How we can help ME sufferers in north Essex" http://www.gazette-news.co.uk/search/4453571.How_we_can_help_ME_sufferers_in_north_Essex/

12. Walwyn R, Potts L, McCrone P, Johnson AL, DeCesare JC, Baber H, Goldsmith K, Sharpe M, Chalder T, White PD. A randomised trial of adaptive pacing therapy, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome (PACE): statistical analysis plan. Trials. 2013 Nov 13;14:386.

13. White PD, Goldsmith KA, Johnson AL, et al; PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36.

14. McCrone P, Sharpe M, Chalder T, Knapp M, Johnson AL, Goldsmith KA, White PD. Adaptive pacing, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome: a cost-effectiveness analysis. PLoS One. 2012;7(8):e40808.

15. Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychol Med. 2010 Aug;40(8):1281-7.

16. White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; PACE trial group. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol. 2007 Mar 8;7:6.

17. White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013 Oct;43(10):2227-35.

18. Adamowicz JL, Caikauskaite I, Friedberg F. Defining recovery in chronic fatigue syndrome: a critical review. Qual Life Res. 2014 May 3.

19. Shepherd C. Letter to the editor: comments on 'Recovery from chronic fatigue syndrome after treatments given in the PACE trial'. Psychol Med. 2013 Aug;43(8):1790-1.

20. Maryhew C. Letter to the editor: comments on 'Recovery from chronic fatigue syndrome after treatments given in the PACE trial'. Psychol Med. 2013 Aug;43(8):1789-90.

21. Cox D. Letter to the editor: 'Recovery from chronic fatigue syndrome after treatments given in the PACE trial': data on the recovery groups as a whole would be useful. Psychol Med. 2013 Aug;43(8):1789.

22. Courtney R. Letter to the editor: 'Recovery from chronic fatigue syndrome after treatments given in the PACE trial': an appropriate threshold for a recovery? Psychol Med. 2013 Aug;43(8):1788-9.

23. Carter S. Letter to the editor: 'Recovery from chronic fatigue syndrome after treatments given in the PACE trial': recovery or remission? Psychol Med. 2013 Aug;43(8):1787-8.

24. Agardy S. Letter to the editor: comments on 'Recovery from chronic fatigue syndrome after treatments given in the PACE trial'. Psychol Med. 2013 Aug;43(8):1787.

25. Kindlon T. Author's response: Criticisms of the PACE Trial were justified. BMJ. October 16, 2013http://www.bmj.com/content/347/bmj.f5963/rr/667107

26. Kindlon T. PACE trial: Simply giving a reason why an outcome measure was changed is not necessarily sufficient. BMJ November 2013 http://www.bmj.com/content/347/bmj.f5963/rr/670755.

27. Clarke D. It is wrong to prevent patients from making informed decisions about their medical care. BMJ November 26, 2013. http://www.bmj.com/content/347/bmj.f5963/rr/674255

28. McPhee G. A fundamental misuse of statistics. BMJ November 21, 2013http://www.bmj.com/content/347/bmj.f5963/rr/673572

29. Baldwin A. PACE trial steering group fail to spot error in reasons for protocol changes. BMJ November 21, 2013 http://www.bmj.com/content/347/bmj.f5963/rr/673502

30. Matthees A. Did PACE make major unapproved protocol changes after seeing outcomes data? BMJ November 29, 2013 http://www.bmj.com/content/347/bmj.f5963/rr/674770

31. Carter S. Published protocols exist to protect patients. BMJ December 2, 2013http://www.bmj.com/content/347/bmj.f5963/rr/675525

32. Clifford Couch I. SF-36 Scale for Normal Physical Function, Age Matters. BMJ December 2, 2013http://www.bmj.com/content/347/bmj.f5963/rr/675527

33. Kirby SBM. Re: PACE trial authors’ reply to letter by Kindlon. BMJ February 1, 2014http://www.bmj.com/content/347/bmj.f5963/rr/684828

34. "Selected data on PACE Trial participants" request:https://www.whatdotheyknow.com/request/selected_data_on_pace_trial_part

On 2014 Feb 05, Tom Kindlon commented:

A CFS study which raises questions about the use of the Role Emotional (RE) subscale of the SF-36 to define CFS

(This was originally posted here: http://www.biomedcentral.com/1472-6963/3/25/comments but the formatting has been lost and some people may read the paper on PubMed Central)

As I mentioned in the previous comment, this paper recommends, amongst other questionnaires, the use of the SF-36 questionnaire but does not specify which subscales should be used.

One group of researchers[1] have decided to use the physical function, role physical, social function and role emotional subscales of the SF-36 to define disability, with a low score on just one of these subscales being sufficient to satisfy the criteria (i.e. there didn't need to be more than one low scores).

Since then, this definition has gone on to be used in numerous papers (such as [2-5]) as the CDC are using it as the definition they're using for their CFS studies in the US, and they probably have the largest CFS research program in the world. It was used to give the prevalence rate of 2.54% for CFS in the adult population[6]. Most recently, it was used to investigate the prevalence of the reporting of childhoold trauma in this cohort[7].

A study by Fulcher and White (2000)[8] raises questions about the use of the Role Emotional (RE) subscale of the SF-36 to select patients with CFS. The study involved 66 patients with CFS without a current psychiatric disorder, 30 healthy but sedentary controls, and 15 patients with a current major depressive disorder.

It found, amongst other things, that "the two patient groups were significantly more incapacitated than the sedentary controls on all SF-36 measures (p<0.001), except that the patients with CFS were not significantly different in emotional or mental function." Also, "the depressed subjects were significantly more incapacitated in emotional and mental functioning than the patients with CFS p<0.001)."

These results suggest that low scores on the emotional and mental functioning subscales of the SF-36 do not seem to be an intrinsic part of CFS (if they're found, they could be related to comorbid psychiatric issues). They also points out the risks of using the RE subscale alone [especially given CFS shares some characteristics with depression and so some people with depression (but not CFS) could potentially score the required 25 points on the Symptom Inventory] i.e. one could inadvertently include some people who have depression but not CFS, as CFS patients.

References

[1] Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic Fatigue Syndrome – A clinically empirical approach to its definition and study. BMC Medicine 2005, 3:19<br><br>

[2] Raison CL, Lin JM, Reeves WC. Association of peripheral inflammatory markers with chronic fatigue in a population-based sample. Brain Behav Immun. 2008 Dec 11.

[3] Welberg LA, Capuron L, Miller AH, Pagnoni G, Reeves WC. Neuropsychological performance in persons with chronic fatigue syndrome: results from a population-based study.Majer M, Psychosom Med. 2008 Sep;70(7):829-36.

[4] Nater UM, Youngblood LS, Jones JF, Unger ER, Miller AH, Reeves WC, Heim C. Alterations in diurnal salivary cortisol rhythm in a population-based sample of cases with chronic fatigue syndrome. Psychosom Med. 2008 Apr;70(3):298-305.

[5] Nater UM, Maloney E, Boneva RS, Gurbaxani BM, Lin JM, Jones JF, Reeves WC, Heim C. Attenuated morning salivary cortisol concentrations in a population-based study of persons with chronic fatigue syndrome and well controls. J Clin Endocrinol Metab. 2008 Mar;93(3):703-9.

[6] Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, Morrissey M, Devlin R. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr. 2007 Jun 8;5:5.

[7] Heim C, Nater UM, Maloney E, Boneva R, Jones JF, Reeves WC. Childhood trauma and risk for chronic fatigue syndrome: association with neuroendocrine dysfunction. Arch Gen Psychiatry. 2009 Jan;66(1):72-80.

[8] Fulcher KY, White PD. Strength and physiological response to exercise in patients with chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 2000 Sep;69(3):302-7.

On 2014 Feb 03, Tom Kindlon commented:

Which subscales of the SF-36 should be used? Results from a study in Fibromyalgia patients

(This was originally posted here: http://www.biomedcentral.com/1472-6963/3/25/comments but the formatting has been lost and some people may read the paper on PubMed Central)

This paper recommends, amongst other questionnaires, the use of the SF-36 questionnaire. But which subscales should be used? One group of researchers[1] decided to use the physical function, role physical, social function and role emotional subscales of the SF-36 to define disability, with a low score on just one of these subscales being sufficient to satisfy the criteria (i.e. there didn't need to be more than one low scores). Since then, this definition[1] has gone on to be used in numerous papers (for example, 2-5).

But is this a good way of using the SF-36 given the Fukuda definition for CFS[6] requires that there be a "substantial reduction in previous levels of occupational, educational, social, or personal activities".

Fibromyalgia patients share many similarities with CFS patients and many researchers use CFS and FMS patients together in their studies (for example [7-10]).

One study[11] recently assessed Fibromyalgia Syndrome (FS) patients using the SF-36 questionnaire. It found that patients could be broken down into two groups using the SF-36 subscales looking at mental well-being (social functioning, role limitation due to emotional health problems, and mental health). "One group demonstrated psychological dysfunction, whereas the other showed normal psychological scores. Physical well-being scores (physical functioning, role limitation due to physical health problems, bodily pain, general health, and vitality) did not differ between FS patients but were altogether below the normal range."

If this was found to be the same in other populations, it would suggest that perhaps including patients who solely have low scores on subscales assessing mental well-being such as the role emotional and social functioning subscales of SF-36, which is all the CFS definition prepared by Reeves[1] requires, would select a group of people with psychological dysfunction but not necessarily greater physical disability.

References:

[1] Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic Fatigue Syndrome – A clinically empirical approach to its definition and study. BMC Medicine 2005, 3:19

[2] Reeves WC, Heim C, Maloney EM, Youngblood LS, Unger ER, Decker MJ, Jones JF, Rye DB. Sleep characteristics of persons with chronic fatigue syndrome and non-fatigued controls: results from a population-based study. BMC Neurology 2006, 6:41

[3] Majer M, Jones JF, Unger ER, Youngblood LS, Decker MJ, Gurbaxani B, Heim C, Reeves WC. Perception versus polysomnographic assessment of sleep in CFS and non-fatigued control subjects: results from a population-based study. BMC Neurology 2007, 7:40

[4] Jones JF, Maloney EM, Boneva RS, Jones AB, Reeves WC. Complementary and alternative medical therapy utilization by people with chronic fatiguing illnesses in the United States. BMC Complementary and Alternative Medicine 2007, 7:12

[5] Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, Morrissey M, Devlin R.Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr. 2007 Jun 8;5:5.

[6] Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A: The chronic fatigue syndrome; a comprehensive approach to its definition and study. Ann Int Med 1994, 121:953-959.

[7] Teitelbaum JE, Johnson C, St Cyr J. The use of D-ribose in chronic fatigue syndrome and fibromyalgia: a pilot study. J Altern Complement Med. 2006 Nov;12(9):857-62.

[8] Glass JM. Cognitive dysfunction in fibromyalgia and chronic fatigue syndrome: new trends and future directions. Curr Rheumatol Rep. 2006 Dec;8(6):425-9.

[9] Zachrisson O, Regland B, Jahreskog M, Jonsson M, Kron M, Gottfries CG. Treatment with staphylococcus toxoid in fibromyalgia/chronic fatigue syndrome--a randomised controlled trial. Eur J Pain. 2002;6(6):455-66.

[10] Zachrisson O, Regland B, Jahreskog M, Kron M, Gottfries CG. A rating scale for fibromyalgia and chronic fatigue syndrome (the FibroFatigue scale). J Psychosom Res. 2002 Jun;52(6):501-9.

[11] Oswald J, Salemi S, Michel BA, Sprott H. Use of the Short-Form-36 Health Survey to detect a subgroup of fibromyalgia patients with psychological dysfunction. Clin Rheumatol. 2008 Apr 1

What questions am I left with? What would I like to know more about?

There are a two questions that immediately spring to mind upon engaging with this article: First, I wonder, do engineers understand quite how deep the problem goes? Second, while I believe the solution to the problem is really quite simple, I am curious whether most Engineers would be willing to embrace it. I will now address each of these questions in turn.

Do Engineers understand quite how deep the problem goes?

There is now an overwhelming body of evidence which indicates that evolution engineered the brain to put analytic and empathic thinking into tension. Scientific and mechanical reasoning, along with calculation (math) and logic, are prototypical types of analytic thinking. When we engage in these types of thinking, we shut down the brain areas we need to understand the perspective of others (Anticevic et al., 2012; Jack et al., 2012) – an absolutely crucial component of ethical awareness and deliberation (Friedman & Jack, 2017; Jack, Dawson, & Norr, 2013).

My main critique of this discussion article relates to the fact that the authors only touch on the surface of the large body of evidence which not only supports this view of the brain, but which also indicates that it impacts human behavior. First, the authors appear to have overlooked other work from my laboratory which is supportive of this view (e.g. a follow up study of the neural basis of dehumanizing (Jack et al., 2013)My laboratory has focused on this issue and its behavioral consequences for many years now. However, it would be very concerning if such claims about the function of the brain were wholly dependent on work from a single laboratory! Happily, this is not the case. The fact that attention demanding analytic tasks, such as mechanical reasoning, tend to deactivate brain regions essential for social, emotional and moral cognition might be fairly characterized as one of the most clearly established findings in cognitive neuroscience (Anticevic et al., 2012; Buckner, Andrews-Hanna, & Schacter, 2008; Shulman et al., 1997)]. This work is broken down in greater detail in many of my more recent articles. In addition, there are behavioral studies by researchers with no interest in the brain which clearly show that analytic thinking negatively impacts ethical thinking and behavior (Small, Loewenstein, & Slovic, 2007; Wang, Zhong, & Murnighan, 2014; Zhong, 2011)

These studies provide powerful convergent evidence, since they were in no way motivated or informed by neuroscience – they are observations about patterns of human behavior made by behavioral economists and psychologists without reference to the underlying neural mechanism which explains why they occur. Since the authors do not appear to be aware of much of this literature, large parts of the article are quite tentative in tone. Nonetheless, in the section titled “Reflections on the implications for learning engineering”, the authors provide an excellent and incisive summary of exactly why our understanding of the brain should be a serious cause for concern for those who are concerned about educating ethical engineers.

In this regard, it is worth mentioning how an emphasis on analytic thinking might increase one’s ability to ‘rationalize away’ the ethical consequences of one’s decision(s). The sorts of problem solving skills that engineers learn might then be applied to social and ethical dilemmas, which in turn removes the social and ethical significance.

The authors do an excellent job of discussing why an engineering education is likely to reinforce students into predominately relying upon analytic thinking in preference to empathic thinking. They do this using the model shown in Figure 4, which illustrates how doing/behavior (i.e. practice at particular types of task) enables changes in structure (neural network function), and also vice-versa: changes in structure enable changes in doing/behavior. This creates a cycle of reinforcement. As the authors nicely put it: “the ‘doing’ that activates the Physical Stance [i.e. an engineering education] gives rise to the Physical stance as a preferred, low activation cognitive pathway….condition[ing] people to unconsciously apply mechanical reasoning to situations where social or moral reasoning would be a better fit for the purpose.” I believe the authors are exactly on point with this model. In my laboratory we have extended our neuroscience work by also measuring individual tendencies to think analytically and empathically with simple behavioral tests and self-report questionnaires. One way in which we measure analytic thinking is using the Intuitive Physics Test developed by Simon Baron-Cohen and colleagues, which can be easily found online for those who are interested and which is a good measure of everyday aptitude for mechanical thinking (Baron-Cohen, Wheelwright, Spong, Scahill, & Lawson, 2001)

In these purely behavioral tests, we consistently find evidence for a small trade-off between these two ways of thinking (Friedman & Jack, 2017). That is, individuals who score higher on analytic thinking tend to score very slightly lower on empathic thinking. Some of these findings are reported incidentally in (Jack, Friedman, Boyatzis, & Taylor, 2016). We are currently preparing a manuscript which collates a much larger set of studies and focuses solely on this issue. The small trade-off between empathic and analytic thinking becomes accentuated for cases where it is less clear which way of thinking is best suited to the matter of hand. For instance, we have now performed a number of studies of religious belief. Supernatural claims, such as that God or a universal spirit exists, seem clearly incorrect from a purely mechanical way of thinking. However, we posited that they would seem correct from an empathic way of thinking. Correspondingly, we found that analytic thinking ability is associated with decreased religious belief, whereas empathic thinking is associated with increased religious belief (Jack et al., 2016). Other unpublished work in progress shows an even more robust association between these two ways of thinking and how much individuals care about dehumanized outgroups. Unsurprisingly, people higher in empathy care more about dehumanized outgroups than people lower in empathy. More remarkably, people who score higher on the Intuitive Physics Test care less about dehumanized outgroups than people who score lower on that measure of analytic thinking. I am comfortable informally reporting this finding since we have now replicated it. We aim to extend it with a further study before publication. The important point which emerges from this work is that individuals who have strongly reinforced one way of thinking without seeking to balance that out with another way of thinking show a clear tendency to default to (or prefer) one cognitive strategy over another when faced with any situation which is even remotely ambiguous. In other words, those whose training has focused predominantly on analytic thinking, such as engineers, will tend to overlook the more human perspective. This observation was made anecdotally long before cognitive neuroscience emerged as a discipline, or psychology developed the instruments to assess it quantitatively. The famous Oxford philosopher, P.F. Strawson, wrote in his groundbreaking article on the philosophy of free will “But what is above all interesting is the tension there is, in us, …between our humanity and our intelligence” (Strawson 1962, p.10).

In the next part of their section titled “Reflections on the implications for learning engineering,” the authors make another insightful and important point. They observe that as we overdevelop one way of thinking, we may distort our whole picture of the world to fit with that way of thinking. They make this point by reference to Lakoff’s notion of frames, which is certainly a useful tool for thinking about how we think. However, I would suggest the basic point is perhaps more simply and more powerfully made by the well-known aphorism they aptly mention: “If one only has a hammer, everything looks like a nail.”

The distortion of the world to fit with a purely scientific or analytic way of thinking is something I find I am obliged to wrestle with frequently. One label for this phenomenon is ‘scientism’. Since I teach at university dominated by the hard sciences and Engineering, such scientistic attitudes are quite common. They are also quite common in neuroscience and in some branches of psychology. An amusing example of this is a recent book by the very analytically smart psychologist Paul Bloom, who has written many warmly received popular science books. However, he recently published a book titled “Against Empathy” to resounding condemnation from virtually all intellectually informed readers, in particular other psychologists, philosophers, sociologists and anthropologists. In essence, Paul Bloom’s lack of connection to empathy motivated him to form a completely distorted picture of it, and motivated him to write a book which attacks empathy in ridiculous and contrived ways, such that it is barely coherent from an analytic (either scientific or logical) point of view. Such poor judgment is remarkable for such a smart and accomplished individual, both as a scientist and as a popular science author.

Since the discussion article highlights the tension between mechanistic reasoning and ethics, it is important to note that ethics itself can be split into perspectives that are predominantly analytic (utilitarianism), versus more empathic perspectives that focus more on humanity. This is in itself a topic of some study in cognitive neuroscience. My own published view is that competent ethical thinking requires us to balance analytic and empathic perspectives on a situation (Friedman, Jack, Rochford, & Boyatzis, 2015; Friedman & Jack, 2017; Rochford, Jack, Boyatzis, & French, 2016). In general, the error that is most often made in current society is to tend towards emphasizing an analytic approach and excluding an empathic approach. That a purely analytic way of thinking ethically is problematic is illustrated by the fact it motivates actions without regard for human rights, including acts which would be categorized under current law as unjustified killing. Many of the recent ethical scandals that have plagued major corporations appear to have stemmed from an overemphasis on an analytic way seeing issues. An analytic, performance oriented way of thinking, especially in organizations, can have more subtle ethical consequences, such that those individuals are less likely to engage in helpful behaviors that bolster the social atmosphere at that organization (Bergeron, 2007; Bergeron, Shipp, Rosen, & Furst, 2011).

While a solution may be straightforward, would most engineers be willing to embrace such a solution?

There is one way in which the problem may not be quite so bad as the authors fear. They suggest that a focus on mechanical reasoning may actively weaken our social and ethical thinking skills. This is one way of reading what the neuroscience tells us, however I would suggest another way of understanding it. The fact that social, emotional and moral cognition areas are suppressed during mechanical reasoning need not mean they are being weakened. Another way of looking at this suppression is that it is protective – it gets those brain areas out of the way. In any case, there is no reason to suppose the suppression actively weakens the function of those brain areas. It merely fails to develop them. This is a problem which, I suggest, can be overcome by two strategies: (1) training to ensure the empathic, as opposed to the analytic brain network, is deployed during social and ethical decision making and (2) training to develop the empathic brain network. Neither of these strategies need impugn the intention to predominantly train engineering students in mechanical reasoning. They merely require engineering schools to embrace and positively require a modest number of courses which can help stem one side of their students brains’ from withering away. Training of the empathic network may be accomplished by classes on empathic listening, social skills for leadership, art appreciation, history, literature, as well as philosophy classes on happiness and ethics. Such classes are likely to greatly help students to possess more balanced brains and live more balanced lives. As a result they are likely to improve student performance, rather than detract from their engineering skills. My concern, however, is that many professional engineers are likely to be so unfamiliar with these forms of understanding, that they will find it hard to endorse including them in the curriculum. Indeed, some engineering faculty may be so unfamiliar with the value of these types of thinking that they find them threatening, and so react by being dismissive and actively fighting their introduction in the curriculum. In other words, they might be ‘blind’ to the value of such social, ethical and moral insights because they lack they the cognitive ability to perceive them, let alone appreciate them. Hence, while there may be many enlightened Engineering faculty, such as those who have written this discussion piece, I suspect a different voice will triumph in faculty meetings. If psychology has taught us anything, it is that human decision making is rarely guided by passion for the truth as much as by other emotions, especially emotions associated with a sense of threat to self. Hence, while it may be that no reasonable person could deny the brain has been engineered by evolution such that it needs to be educated in different modalities, I rather doubt this truth will guide engineering faculty.

I'd like to acknowledge Jared Friedman for thoughtful input to the reflections that I offer here.

Anticevic, A., Cole, M. W., Murray, J. D., Corlett, P. R., Wang, X. J., & Krystal, J. H. (2012). The role of default network deactivation in cognition and disease. Trends Cogn Sci, 16(12), 584-592. doi:10.1016/j.tics.2012.10.008 S1364-6613(12)00244-6 [pii]

Baron-Cohen, S., Wheelwright, S., Spong, A., Scahill, V., & Lawson, J. (2001). Are intuitive physics and intuitive psychology independent? A test with children with Asperger Syndrome. Journal of Developmental and Learning Disorders, 5(1), 47-78.

Bergeron, D. M. (2007). The potential paradox of organizational citizenship behavior: Good citizens at what cost? Academy of Management Review, 32(4), 1078-1095. Bergeron, D. M., Shipp, A. J., Rosen, B., & Furst, S. A. (2011). Organizational citizenship behavior and career outcomes the cost of being a good citizen. Journal of Management, 0149206311407508.

Buckner, R. L., Andrews-Hanna, J. R., & Schacter, D. L. (2008). The Brain's Default Network: Anatomy, Function, and Relevance to Disease. Annals of the New York Academy of Sciences, 1124(1), 1-38. doi:10.1196/annals.1440.011 Cech, E. A. (2014). Culture of disengagement in engineering education? Science, Technology, & Human Values, 39(1), 42-72.

Friedman, J., Jack, A. I., Rochford, K., & Boyatzis, R. (2015). Antagonistic Neural Networks Underlying Organizational Behavior. Organizational Neuroscience (Monographs in Leadership and Management, Volume 7) Emerald Group Publishing Limited, 7, 115-141.

Friedman, J. P., & Jack, A. I. (2017). Mapping cognitive structure onto the landscape of philosophical debate: An empirical framework with relevance to problems of consciousness, free will and ethics. Review of Philosophy and Psychology.

Jack, Dawson, A. J., Begany, K. L., Leckie, R. L., Barry, K. P., Ciccia, A. H., & Snyder, A. Z. (2012). fMRI reveals reciprocal inhibition between social and physical cognitive domains. Neuroimage, 66C, 385-401. doi:S1053-8119(12)01064-6 [pii] 10.1016/j.neuroimage.2012.10.061

Jack, Dawson, A. J., & Norr, M. E. (2013). Seeing human: distinct and overlapping neural signatures associated with two forms of dehumanization. Neuroimage, 79, 313-328. Jack, A. I., Friedman, J. P., Boyatzis, R. E., & Taylor, S. N. (2016). Why do you believe in God? Relationships between religious belief, analytic thinking, mentalizing and moral concern. PloS one, 11(3), e0149989.

Rochford, K. C., Jack, A. I., Boyatzis, R. E., & French, S. E. (2016). Ethical leadership as a balance between opposing neural networks. Journal of Business Ethics, 1-16.

Shulman, G. L., Fiez, J. A., Corbetta, M., Buckner, R. L., Miezin, F. M., Raichle, M. E., & Petersen, S. E. (1997). Common Blood Flow Changes across Visual Tasks: II. Decreases in Cerebral Cortex. J Cogn Neurosci, 9(5), 648-663. doi:10.1162/jocn.1997.9.5.648

Small, D. A., Loewenstein, G., & Slovic, P. (2007). Sympathy and callousness: The impact of deliberative thought on donations to identifiable and statistical victims. Organizational Behavior and Human Decision Processes, 102(2), 143-153. doi:10.1016/j.obhdp.2006.01.005

Wang, L., Zhong, C.-B., & Murnighan, J. K. (2014). The social and ethical consequences of a calculative mindset. Organizational Behavior and Human Decision Processes, 125(1), 39-49.

Zhong, C.-B. (2011). The ethical dangers of deliberative decision making. Administrative Science Quarterly, 56(1), 1-25.

Bagnato investigates the agonists of the endothelin B receptor (ET(B)R), endothelin-1 (ET-1) and ET-3 and the role that they play in tumorigenesis.

Bagnato states that (ET(B)R) is a marker for tumor progression. This study supported the role of ET-1 and ET-3 to impede the usual interactions between hosts and tumors.

The ligands also promote development of cutaneous melanoma. Melanoma is a cancer in melanin-producing cells. Cutaneous melanoma is melanoma that occurs on skin.

no entiendo lo que quieres decir con podría perdidas

Corbit et al. were interested in how control can be reestablished after drug abuse.

The authors assessed whether chronic drug use shifts behavior from a goal-oriented process to a habit learning process, and studied the physiological implications of those changes. In addition, they tested whether N-acetylcystine, a treatment previously shown to prevent relapse into cocaine use, could prevent the rapid formation of habits after drug exposure.

This report describes the data set obtained by the Simons Genome Diversity Project (SGDP), which contains genome data from 300 individuals from 142 diverse populations, and reveals more features of human genetic variation. The SGDP focused on smaller populations than the 1000 Genomes Project.

Teng et al. describe a database they have curated called 4DGenome. They have collected published data related to how chromatin interacts with itself and make it available through a database that other researchers can use as a centralized location for chromatin interaction data.

I wonder what this would be today?

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Analytic note: AIDS-related stigma and discrimination remains a pervasive problem in health care institutions worldwide. Previous studies have demonstrated that AIDS-related stigma is a common phenomenon worldwide that occurs in a variety of contexts, including the family, community, workplace, and health care settings. This article discusses the effectiveness of a stigma-reduction intervention, with the goals of reducing discriminatory practices and improving quality of care for people living with HIV/AIDS in India. A mixed-method research is used and the study findings highlight issues peculiar to the health care sector in limited-resource settings. Strikingly, these findings mirrored in our study, done in a resource-rich context, confirm that HIV/AIDS-related stigma and discrimination in healthcare settings persist, despite progress made with various stigma-reduction interventions.

Source excerpt: The health care setting is a particularly conspicuous context for HIV/AIDS-related stigma and discrimination. In this context people living with HIV or AIDS (PLWHA) often discover their status, and it is where people living with HIV have the potential to gather information about how to care for themselves and prevent transmission to others, as well as get treatment and care. Because of stigma, there have been various reports of HIV positive people receiving inferior care or being denied care altogether (Ogden & Nyblade, 2005). For example, health care workers are influenced by the attitudes of the greater society, and prevailing negative attitudes can result in discrimination. In India, a country with an estimated HIV/AIDS. While AIDS-related stigma in health facilities has become better understood over the years, it is only recently that responses are moving beyond documenting negative experiences to implementing interventions. The findings reported on in this paper highlight that stigmatizing attitudes and discriminatory behaviors towards people living with HIV/AIDS are big challenges in hospitals in India, and that there are particular issues in this limited resource setting that are often not taken into account in global discussions about HIV-related stigma in the health care sector.

Full Citation: Mahendra, V. S., Gilborn, L., Bharat, S., Mudoi, R., Gupta, I., George, B. et al. (2007) Understanding and measuring AIDS-related stigma in health care settings: a developing country perspective. SAHARA Journal 4(2), 616–625. https://doi.org/10.1080/17290376.2007.9724883

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Analytic Note (Source 1): Stigma is still perceived as a major limiting factor in HIV/AIDS prevention and care. HIV/AIDS stigma and discrimination continue to influence people living with and affected by HIV disease as well as their health care providers, wherever they live. This review article discusses HIV/AIDS stigma, the impact of AIDS stigma and how healthcare providers can help to manage HIV/AIDS stigma in South Africa. In defining stigma, authors look into different definitions of stigma by various authors and make particular allusion to Goffman’s definition of stigma as ‘an attribute that is deeply discrediting within a particular social interaction’, as a ‘spoiled social identity’ and ‘a deviation from the attributes considered normal and acceptable by society. On the impact of AIDS stigma, the article gives an insight into the fear of, and the stigma associated with, HIV were significantly related to the HIV-affected person’s decision to not seek timely healthcare services. This article provided a base for our study.

Analytic Note (Source 2): According to the late Jonathan Mann, the former WHO Head of Global Program on AIDS recognized stigma, discrimination, blame, and denial as potentially the most difficult aspects of HIV/AIDS to address. This article summarizes the key contributions of the Horizons stigma research portfolio to describing the drivers of stigma, identifying effective interventions and approaches for reducing stigma in different settings, and improving methods for measuring stigma. Horizons developed and implemented a wide range of activities in collaboration with numerous local and international partners in Africa, Asia, and Latin America. This article is cited to corroborate the existence of stigma and discrimination in different settings including healthcare.

Analytic Note (Source 3): This article reflects on the progress over the last 30 years with respect to older and more emergent forms of education concerning HIV and AIDS. This education includes treatment education, HIV prevention education, and education to encourage positive and supportive community response. The article emphasizes on the careful analysis of different forms of HIV-related education, the consequences, effects and identifying specific effectivity of HIV-related education in order to achieve positive outcomes. The article also discusses new ways of seeing and understanding the need to support processes that “think” ahead of the epidemic. This article does not discuss HIV educational strategies that may reduce stigma and discrimination in healthcare settings in the globalized world. However, this article is relevant, though not the basis of our research, because it highlights the difficulty to provide HIV education to stigmatized and discriminated groups after more than 30 years since the start of the epidemic. Giving the negative social responses to HIV and AIDS, education is vital in contributing to a positive response. Individual and community empowerment are the necessary mechanisms by which social inclusion can be promoted.

Source Excerpt (Source 1): Other researchers have reported that health care personnel knew very little about the potential for HIV contamination in the workplace. In Kuwait, some family doctors knew less than they should have about HIV and looked upon AIDS patients negatively, even in the third decade of the AIDS pandemic. Similarly, AIDS stigma and discrimination continue to influence people living with and affected by HIV disease as well as their health care providers, particularly in southern Africa where the burden of AIDS is so significant. Stigma is perceived as a major limiting factor in primary and secondary HIV/AIDS prevention and care. Similar to the findings of Adebajo, Bamgbala and Oyediran (2003) in Nigeria, the results in Kuwait showed that nurses and laboratory technicians also had negative attitudes toward AIDS patients. Health care workers’ poor attitudes and inadequate care in these anecdotal reports could be related to stigma. This argument was reaffirmed in our study.

Source Excerpt (Source 2): Horizons and partners recognized from the outset that to improve the environment for people with HIV in health-care settings, it was important for management and health providers to acknowledge that stigma exists in their facilities. They found that a participatory approach that included ongoing sharing of data about levels and types of stigma in institutions helped build staff and management support for stigma-reduction activities

Source Excerpt (Source 3): “As we approach the 30th anniversary of the date on which AIDS was first identified, it is salutary to reflect on progress made in tackling the epidemic. This is especially so in relation to education and HIV, a field that is laden with possibilities but one that has in many ways eluded its potential. Despite these difficulties, education in a variety of forms holds the potential to arrest and turn back the three epidemics (Mann, 1987) to which HIV has given rise: (a) the epidemic of AIDS, which has caused untold harm through serious illness and death; (b) the epidemic of HIV, in many ways silent, unseen, and often unknown; and (c) the epidemic of fear, shame and denial that has led people living with HIV to be stigmatized, ostracized, discriminated against, and denied their human rights”.

Full Citation (Source 1): Holzemer, W. L. & Uys, L. R. (2004) Managing AIDS stigma. SAHARA Journal 1(3), 165–174. doi/pdf/10.1080/17290376.2004.9724839

Full Citation (Source 2): Pulerwitz, J., Michaelis, A., Weiss, E., Brown, L. & Mahendra, V. (2010) Reducing HIV-related stigma: lessons learned from Horizons research and programs. Public Health Reports 125(2), 272–281. doi: 10.1177/003335491012500218

Full Citation (Source 3): Aggleton, P., Yankah, E. & Crewe, M. (2011) Education and HIV/AIDS-30 years on. AIDS Education and Prevention 23(6), 495–507DOI: 10.1521/aeap.2011.23.6.495

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Analytic Note (Source 1): Stigma and discrimination in healthcare remains a pervasive problem. This review paper argues that stigma has a far more insidious influence, going well beyond the individual and potentially impacting on all sectors of society. As in our study, this article underlines how stigma undermines a person's identity and capacity to cope with the disease at an individual level.

Analytic Note (Source 2): The study examines internalized AIDS stigmas among people living with HIV/AIDS in Cape Town, South Africa. It demonstrates that discrimination experiences are common and internalized AIDS stigmas were prevalent among people living with HIV/AIDS. Our article confirms the persistence of social stigmas and discrimination and internalized stigma.

Analytic Note (Source 3): HIV/AIDS has evolved but stigma and discrimination persists. This article measures the frequency of discrimination and assesses its correlates among people living with HIV in France. The survey uses data from a national representative survey, the ANRS-Vespa2 study, conducted in France in 2011 among 3022 male and female HIV-positive patients followed at hospitals. The most striking finding relates to women from sub-Saharan Africa reporting the highest levels of discrimination, whereas heterosexual non-African men reporting the lowest. In this study, HIV-related stigma and gender intertwine. We cited this article because it demonstrates that people living with HIV are exposed to stigma not only because of their HIV-positive status but also because they are blacks or belong to a minority population in France, as is the case in Belgium and most European Union countries.

Source Excerpt (Source 1): Discrimination has significant impacts on diagnosis and treatment. For the individual it can delay diagnosis and therefore also delay entry into treatment and adoption of a healthy lifestyle. There is no motivation to be tested, as the person sees no benefit when the diagnosis of HV is seen as equivalent to death, and they are likely to experience discrimination.

Source Excerpt (Source 2): Discrimination experiences were common and internalized AIDS stigmas were prevalent among people living with HIV/AIDS in Cape Town.

Source Excerpt (Source 3): Since the advent of AIDS, discrimination has remained at the core of the experience of people living with HIV (PLHIV). PLHIV who belong to minority groups are exposed to discrimination not only on the grounds of their HIV infection but also because of rejecting attitudes towards drug users, homosexuals and black people.

Full Citation (Source 1): Skinner, D. & Mfecane, S. (2004) Stigma, discrimination and the implications for people living with HIV/AIDS in South Africa. SAHARA Journal 1(3), 157–164. DOI: 10.1080/17290376.2004.9724838

Full Citation (Source 2): Simbayi, L. C., Kalichman, S., Strebel, A., Cloete, A., Henda, N. & Mqeketo, A. (2007) Internalized stigma, discrimination, and depression among men and women living with HIV/AIDS in Cape Town, South Africa. Social Science & Medicine 64(9), 1823–1831. DOI:10.1016/j.socscimed.2007.01.006

Full Citation (Source 3): Marsicano, E., Dray-Spira, R., Lert, F., Aubriere, C., Spire, B. & Hamelin, C. (2014) Multiple discriminations experienced by people living with HIV in France: results from the ANRS-Vespa2 study. AIDS Care 26 (Supplement 1), S97–S106. DOI: 10.1080/09540121.2014.907385

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Analytic Note (Source 1): Stigma and discrimination has public health implications worldwide. This essay discusses five interrelated components of stigma namely labelling, stereotyping, grouping, discrimination and loss of status and self-esteem and the exercise of power. It also discusses direct, structural, and insidious (labelling) as major forms of discrimination. This essay is vital as it forms a base for our research, whereby stigma and discrimination is experienced by women living with HIV/AIDS.

Analytic Note (Source 2): HIV-related stigma and discrimination goes beyond borders and culture. This study discusses factors that are associated with the level of empathy among healthcare service providers in China. The authors hypothesize that providers’ empathy levels would be associated with a lower level of avoidance attitudes to PLWHA at work. However, the study finds empathy, as well as stigma and discrimination among healthcare providers towards people living with HIV/AIDS in China, similar to what we found in our study.

Source Excerpt (Source 1): Stigma processes have a dramatic and probably under recognized effect on the distribution of life chances such as employment opportunities, housing, and access to medical care. We believe that under recognition occurs because attempts to measure the impact of stigma have generally restricted analysis to one circumstance (e.g., AIDS, obesity, race, or mental illness) and examined only one outcome (e.g., earnings, self- esteem, housing, or social interactions). If all stigmatized conditions were considered together and all outcomes examined we believe that stigma would be shown to have an enormous impact on people’s lives. To exemplify one part of this point we analyzed nationally representative data from the USA, in which multiple stigmatizing factors were taken into consideration in relation to self-esteem, and found that stigma could explain a full 20% of the variance beyond the effects of age, sex, and years of education.

Source Excerpt (Source 2): HIV-related stigma is prevalent worldwide and greatly undermines public health efforts to combat the epidemic. Perceived stigma is associated with stress, depression, and lower perceived quality of life among people living with HIV/AIDS (PLWHA). More directly, health service providers’ stigmatizing attitudes and avoidance behaviours toward PLWHA discourage people from seeking HIV testing and counselling, participating in prevention programs, accessing HIV treatment, and adhering to antiretroviral therapies. To start to address HIV-related stigma in health care settings, researchers have made efforts to understand its multiple origins. Factors contributing to stigmatizing and discriminatory responses among service providers include a lack of appropriate knowledge and training; the perception that HIV/AIDS is incurable; insufficient institutional support and perceived societal discrimination against HIV; lack of knowledge and supply of universal precautions and post exposure prophylaxis and legislative or policy gaps including health controls, quarantine, compulsory internment, and/or segregation in hospital etc.

Full Citation (Source 1): Link, B. G. & Phelan, J. C. (2006) Stigma and its public health implications. Lancet 367(9509), 528–529. DOI:10.1016/S0140-6736(06)68184-1

Full Citation (Source 2): Lin, C., Li, L., Wan, D., Wu, Z. & Yan, Z. (2012) Empathy and avoidance in treating patients living with HIV/AIDS (PLWHA) among service providers in China. AIDS Care 24(11), 1341–1348. doi: 10.1080/09540121.2011.648602

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Analytic Note: Stigma is pervasive and a fundamental cause of health and social inequalities. This article discusses the persistence of inequality because of certain characteristics of the fundamental causes. It examines how fundamental social cause influences multiple disease outcomes through multiple risk factors among a substantial number of people. It also indicates that fundamental social cause involves access to resources such as knowledge, money, power, prestige, and beneficial social connections. This article was useful in our research as we described the causes of stigma in healthcare settings. Our findings confirmed the existing HIV stigma.

Source Excerpt: Bodies of research pertaining to specific stigmatized statuses have typically developed in separate domains and have focused on single outcomes at 1 level of analysis, thereby obscuring the full significance of stigma as a fundamental driver of population health. Here we provide illustrative evidence on the health consequences of stigma and present a conceptual framework describing the psychological and structural pathways through which stigma influences health. Because of its pervasiveness, its disruption of multiple life domains (e.g., resources, social relationships, and coping behaviors), and its corrosive impact on the health of populations, stigma should be considered alongside the other major organizing concepts for research on social determinants of population health.

Full Citation: Hatzenbuehler, M. L., Phelan, J. C. & Link, B. G. (2013) Stigma as a fundamental cause of population health inequalities. American Journal of Public Health 103(5), 813–821. doi: 10.2105/AJPH.2012.301069

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Analytic note: The claim that officials provide little to no governance is surprising, and one that I initially met with skepticism. However, the number of confirming accounts, from a wide range of source (cited here, but also a large literature), provide confidence in the claim. More generally, as one observes the shockingly low quality of official governance in many Latin American prisons, the case in Bolivia becomes less unusual and more plausible.

Full Citations: Baltimore, B., A. Bastien van der Meer, M. Brennan, M. Burton, M. Castillo, L. Cavise, A. Davis, J. Friedman-Rudovsky, A. Mendoza, D. Oliveira, J. Somberg,V. Spinazola, K. Staskawicz, L. Stern, and L. Tockman, et al. 2007. Report of Delegation to Bolivia. New York: National Lawyers Guild.

Organization of American States. 2007. Access to Justice and Social Inclusion: The Road Towards Strengthening Democracy in Bolivia. Washington, DC: Inter-American Commission on Human Rights.

Research is needed to further this discussion. Evaluate sources and explore further off of ProQuest.

Discussing the importance of being specific when typing questions into a search engine reminds me of http://www.bristol.ac.uk/library/support/findinginfo/search-engines/ which goes into detail about how to make the best out of a search engine. https://video.search.yahoo.com/video/play;_ylt=AwrC5pk5VtZaEHoABTg0nIlQ;_ylu=X3oDMTByZWc0dGJtBHNlYwNzcgRzbGsDdmlkBHZ0aWQDBGdwb3MDMQ--?p=how+to+use+a+search+engine+effectively&vid=9bf0d5d37d4dc51cd871e871b3a39b28&turl=https%3A%2F%2Ftse4.mm.bing.net%2Fth%3Fid%3DOVP.61buA0jkcYnUo5UPzPB40wEsDS%26pid%3D15.1%26h%3D210%26w%3D300%26c%3D7%26rs%3D1&rurl=https%3A%2F%2Fwww.youtube.com%2Fwatch%3Fv%3DL6mvnMW_nnY&tit=How+to+use+the+Google+Search+Engine+more+Effectively.&c=0&h=210&w=300&l=434&sigr=11bdiha8i&sigt=11lisflue&sigi=12r61em25&age=1260459057&fr2=p%3As%2Cv%3Av&fr=yhs-arh-001&hsimp=yhs-001&hspart=arh&type=zxy_5e685049fc1e67cf88&tt=b

This YouTube video also, specifically using Google search, gives similar tips to this article on how to search effectively and get the answers you're looking for.

British government officials of a wide range of positions, such as William Adam, were often sent to the British colonies to report on the status, progress, and areas of improvement of their communities. This excerpt by William Adam, The Third Report on The State of Education in Bengal; Including Some Account of The State of Education in Behar, and A Consideration of The Means Adapted to The Improvement and Extension of Public Instruction in Both Provinces, outlines and contextualizes the ideas in which the British government was approaching education in India. It establishes their commonly thought ideas surrounding the natives, their communities, and how they believe their education is lacking. It is also of importance because it shows how imperialism finds its way in to education and how the British want to perpetuate their colonial and imperialist ideologies through education and teaching the english language. With this we can see commonly held British government sentiment towards education in India.

APA no alfabético.

Bueno

Ejemplo para poder empezar con las condiciones del cultivo

by this I mean, all teachers are leaders - though I didn't assign it as a text, I'll be referencing the book: Levin, Barbara B. & Schrum L (2016). Every Teacher a Leader.Corwin.

I wanted to do this test on Genius, but it was just too much.

In a rare departure from the normal format for the rules publications, the 1945 edition included significant minor league representation, from the National Association president to minor league presidents.

Dick Butler, president of the South Atlantic minor league, and Vincent McNamara, president of the New York-Penn minor league, were the only minor league representatives on the rules committee.

Vincent McNamara, president of the New York-Penn minor league, was the only minor league representative on the rules committee.

Dick Butler, president of the South Atlantic minor league, and Vincent McNamara, president of the New York-Penn minor league, were the only minor league representatices on the rules committee.

In what sense did it work and what were the limits within which it worked?

Cardinale reviews the roles of "primary producer" biodiversity with respect to ecological processes critical to the functionality and health of terrestrial and marine ecosystems.

Byrne's review focuses on the impacts of assemblage diversity on ecosystem functions.

This study acknowledges the impact of diversity on resource utilization and thus productivity, however the focus is on the characterization of multi-functionality.

Barnosky discusses the events known as mass extinctions and compares the rates of extinction for these events to modern rates of extinction.

Has the Earth's sixth mass extinction already arrived? A. D. Barnosky, N. Matzke, S. Tomiya, G. O. U. Wogan, B. Swartz, T. B. Quental, C. Marshall, J. L. McGuire, E. L. Lindsey, K. C. Maguire, B. Mersey, E. A. Ferrer

This article suggests that the current rate of species extinction is higher than what has been expected in the past (compared against fossil records). The authors propose that this elevated rate of extinction may possibly be the beginning of the 6th known mass extinction event on earth.

This extinction would drastically lower biodiversity by killing off many species that would otherwise function as carbon sinks. The release of such massive amounts of carbon might have dramatic effects upon the environment.

On 2014 Feb 03, Tom Kindlon commented:

Which subscales of the SF-36 should be used? Results from a study in Fibromyalgia patients

(This was originally posted here: http://www.biomedcentral.com/1472-6963/3/25/comments but the formatting has been lost and some people may read the paper on PubMed Central)

This paper recommends, amongst other questionnaires, the use of the SF-36 questionnaire. But which subscales should be used? One group of researchers[1] decided to use the physical function, role physical, social function and role emotional subscales of the SF-36 to define disability, with a low score on just one of these subscales being sufficient to satisfy the criteria (i.e. there didn't need to be more than one low scores). Since then, this definition[1] has gone on to be used in numerous papers (for example, 2-5).

But is this a good way of using the SF-36 given the Fukuda definition for CFS[6] requires that there be a "substantial reduction in previous levels of occupational, educational, social, or personal activities".

Fibromyalgia patients share many similarities with CFS patients and many researchers use CFS and FMS patients together in their studies (for example [7-10]).

One study[11] recently assessed Fibromyalgia Syndrome (FS) patients using the SF-36 questionnaire. It found that patients could be broken down into two groups using the SF-36 subscales looking at mental well-being (social functioning, role limitation due to emotional health problems, and mental health). "One group demonstrated psychological dysfunction, whereas the other showed normal psychological scores. Physical well-being scores (physical functioning, role limitation due to physical health problems, bodily pain, general health, and vitality) did not differ between FS patients but were altogether below the normal range."

If this was found to be the same in other populations, it would suggest that perhaps including patients who solely have low scores on subscales assessing mental well-being such as the role emotional and social functioning subscales of SF-36, which is all the CFS definition prepared by Reeves[1] requires, would select a group of people with psychological dysfunction but not necessarily greater physical disability.

References:

[1] Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic Fatigue Syndrome – A clinically empirical approach to its definition and study. BMC Medicine 2005, 3:19

[2] Reeves WC, Heim C, Maloney EM, Youngblood LS, Unger ER, Decker MJ, Jones JF, Rye DB. Sleep characteristics of persons with chronic fatigue syndrome and non-fatigued controls: results from a population-based study. BMC Neurology 2006, 6:41

[3] Majer M, Jones JF, Unger ER, Youngblood LS, Decker MJ, Gurbaxani B, Heim C, Reeves WC. Perception versus polysomnographic assessment of sleep in CFS and non-fatigued control subjects: results from a population-based study. BMC Neurology 2007, 7:40

[4] Jones JF, Maloney EM, Boneva RS, Jones AB, Reeves WC. Complementary and alternative medical therapy utilization by people with chronic fatiguing illnesses in the United States. BMC Complementary and Alternative Medicine 2007, 7:12

[5] Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, Morrissey M, Devlin R.Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr. 2007 Jun 8;5:5.

[6] Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A: The chronic fatigue syndrome; a comprehensive approach to its definition and study. Ann Int Med 1994, 121:953-959.

[7] Teitelbaum JE, Johnson C, St Cyr J. The use of D-ribose in chronic fatigue syndrome and fibromyalgia: a pilot study. J Altern Complement Med. 2006 Nov;12(9):857-62.

[8] Glass JM. Cognitive dysfunction in fibromyalgia and chronic fatigue syndrome: new trends and future directions. Curr Rheumatol Rep. 2006 Dec;8(6):425-9.

[9] Zachrisson O, Regland B, Jahreskog M, Jonsson M, Kron M, Gottfries CG. Treatment with staphylococcus toxoid in fibromyalgia/chronic fatigue syndrome--a randomised controlled trial. Eur J Pain. 2002;6(6):455-66.

[10] Zachrisson O, Regland B, Jahreskog M, Kron M, Gottfries CG. A rating scale for fibromyalgia and chronic fatigue syndrome (the FibroFatigue scale). J Psychosom Res. 2002 Jun;52(6):501-9.

[11] Oswald J, Salemi S, Michel BA, Sprott H. Use of the Short-Form-36 Health Survey to detect a subgroup of fibromyalgia patients with psychological dysfunction. Clin Rheumatol. 2008 Apr 1

On 2014 Feb 05, Tom Kindlon commented:

A CFS study which raises questions about the use of the Role Emotional (RE) subscale of the SF-36 to define CFS

(This was originally posted here: http://www.biomedcentral.com/1472-6963/3/25/comments but the formatting has been lost and some people may read the paper on PubMed Central)

As I mentioned in the previous comment, this paper recommends, amongst other questionnaires, the use of the SF-36 questionnaire but does not specify which subscales should be used.

One group of researchers[1] have decided to use the physical function, role physical, social function and role emotional subscales of the SF-36 to define disability, with a low score on just one of these subscales being sufficient to satisfy the criteria (i.e. there didn't need to be more than one low scores).

Since then, this definition has gone on to be used in numerous papers (such as [2-5]) as the CDC are using it as the definition they're using for their CFS studies in the US, and they probably have the largest CFS research program in the world. It was used to give the prevalence rate of 2.54% for CFS in the adult population[6]. Most recently, it was used to investigate the prevalence of the reporting of childhoold trauma in this cohort[7].

A study by Fulcher and White (2000)[8] raises questions about the use of the Role Emotional (RE) subscale of the SF-36 to select patients with CFS. The study involved 66 patients with CFS without a current psychiatric disorder, 30 healthy but sedentary controls, and 15 patients with a current major depressive disorder.

It found, amongst other things, that "the two patient groups were significantly more incapacitated than the sedentary controls on all SF-36 measures (p<0.001), except that the patients with CFS were not significantly different in emotional or mental function." Also, "the depressed subjects were significantly more incapacitated in emotional and mental functioning than the patients with CFS p<0.001)."

These results suggest that low scores on the emotional and mental functioning subscales of the SF-36 do not seem to be an intrinsic part of CFS (if they're found, they could be related to comorbid psychiatric issues). They also points out the risks of using the RE subscale alone [especially given CFS shares some characteristics with depression and so some people with depression (but not CFS) could potentially score the required 25 points on the Symptom Inventory] i.e. one could inadvertently include some people who have depression but not CFS, as CFS patients.

References

[1] Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic Fatigue Syndrome – A clinically empirical approach to its definition and study. BMC Medicine 2005, 3:19<br><br>

[2] Raison CL, Lin JM, Reeves WC. Association of peripheral inflammatory markers with chronic fatigue in a population-based sample. Brain Behav Immun. 2008 Dec 11.

[3] Welberg LA, Capuron L, Miller AH, Pagnoni G, Reeves WC. Neuropsychological performance in persons with chronic fatigue syndrome: results from a population-based study.Majer M, Psychosom Med. 2008 Sep;70(7):829-36.

[4] Nater UM, Youngblood LS, Jones JF, Unger ER, Miller AH, Reeves WC, Heim C. Alterations in diurnal salivary cortisol rhythm in a population-based sample of cases with chronic fatigue syndrome. Psychosom Med. 2008 Apr;70(3):298-305.

[5] Nater UM, Maloney E, Boneva RS, Gurbaxani BM, Lin JM, Jones JF, Reeves WC, Heim C. Attenuated morning salivary cortisol concentrations in a population-based study of persons with chronic fatigue syndrome and well controls. J Clin Endocrinol Metab. 2008 Mar;93(3):703-9.

[6] Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, Morrissey M, Devlin R. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr. 2007 Jun 8;5:5.

[7] Heim C, Nater UM, Maloney E, Boneva R, Jones JF, Reeves WC. Childhood trauma and risk for chronic fatigue syndrome: association with neuroendocrine dysfunction. Arch Gen Psychiatry. 2009 Jan;66(1):72-80.

[8] Fulcher KY, White PD. Strength and physiological response to exercise in patients with chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 2000 Sep;69(3):302-7.

On 2014 Feb 02, Tom Kindlon commented:

More symptoms could be added to a CFS Symptom Inventory

(This was originally posted here: http://www.pophealthmetrics.com/content/3/1/8/comments but the formatting has been removed and some people may not read the paper there either).

Many would feel that the 8 symptoms used in the CDC '94 definition [1] were chosen in a somewhat arbitrary fashion; so it is to be welcomed that the CDC itself has started to look beyond these symptoms with the CDC CFS Symptom Inventory. The idea of a Short Form of the CDC Symptom Inventory is also interesting.

However, it is not clear to me where the extra symptoms that are on the CDC CFS Symptom Inventory came from. For example, I didn't see some of the symptoms listed in Reeves et al [2].

In 2001, De Becker et al [3] published data on the symptoms found in over 2500 patients. They tried to improve on the 1988 [4] and 1994 CDC criteria. They suggested a list of symptoms that could be used to strengthen the ability to select ME/CFS patients. Many of the symptoms they mentioned are not in the CDC CFS Symptom Inventory.

So to claim that the "CDC Symptom Inventory assesses the full range of CFS associated symptoms" seems questionable. It would be interesting if in future these symptoms (that De Becker et al were suggesting) were added before statistical analyses are performed. The fatigue criteria and functional impairment criteria have become much less restrictive [5]. For example, to satisfy the fatigue criteria, the fatigue is required to be greater than or equal to the medians of the MFI general fatigue (≥ 13) or reduced activity (≥ 10) scales. So it now seems particularly important that the symptom criteria have good sensitivity and specificity or one is going to end up with a definition that leads to very heterogeneous samples.

References:

[1] Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A: The chronic fatigue syndrome; a comprehensive approach to its definition and study.Ann Int Med 1994, 121:953-959.

[2] Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, Bleijenberg G, Evengard B, White PD, Nisenbaum R, Unger ER, International Chronic Fatigue Syndrome Study Group: Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution.BMC Health Services Research 2003, 3:25.http://dx.doi.org/10.1186/1472-6963-3-25

[3] A definition-based analysis of symptoms in a large cohort of patients withchronic fatigue syndrome, P. De Becker, N. McGregor, and K. De Meirleir.Journal of Internal Medicine 2001;250:234-240

[4] Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, et al.: Chronic fatigue syndrome: a working case definition. Ann Intern Med 1988, 108:387-389.

[5] Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA,Unger ER, Vernon SD, Heim C: Chronic fatigue syndrome — a clinically empirical approachto its definition and study. BMC Medicine 2005, 3:16.

On 2014 Jan 08, Tom Kindlon commented:

New or "Unusual" definition for CFS used in this study

(This was originally posted on the journal's website here: http://www.biomedcentral.com/1471-2377/6/41/comments. However, the formatting has been removed meaning few may read it there)

People reading this study need to be aware that it uses a new or "unusual" definition of Chronic Fatigue Syndrome (CFS)[1] so the results may not apply to CFS cohorts as usually defined[2].This definition selects a group covering 2.54% of the adult population[3]. This is much higher than previous estimates of the prevalence of CFS. For example, members of the team in this study have previously estimated the prevalence as 0.235%[4] i.e. the prevalence rate using this definition is 10.8 times the rate found using the more usual CFS definition[2].

There has been some criticism of this new definition[5]. Unlike previous times when the CDC produced definitions for CFS[2,6], the definition used in this study is generally only being used by the CDC-funded CFS research team.

References:

[1] Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C: Chronic Fatigue Syndrome – A clinically empirical approach to its definition and study. BMC Medicine 2005, 3:19 (15 December 2005)

[2] Fukuda, K., Straus, S.E., Hickie, I., Sharpe, M.C., Dobbins, J.G., & Komaroff, A. (1994). The chronic fatigue syndrome: A comprehensive approach to its definition and study. Annals of Internal Medicine, 121 (12):953-959. http://www.annals.org/cgi/content/full/121/12/953

[3] Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, Morrissey M, Devlin RPrevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Population Health Metrics 2007, 5:5 (8 June 2007)

[4] Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC: Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Int Med 2003, 163:1530-1536.

[5] Jason Leonard: Issues with CDC Empirical Case Definition and Prevalence of CFS. IACFS website http://tinyurl.com/2qdgu4 i.e. http://www.iacfsme.org/IssueswithCDCEmpiricalCaseDefinitionandPrev/tabid/105/Default.aspx

[6] Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med. 1988; 108:387-9.

On 2014 Jan 08, Tom Kindlon commented:

Various comments

This paper refers to the use of a re-attribution programme. I thought I would highlight the results of a trial[1] published last year on the topic. It involved testing practice-based training of GPs in reattribution. The method to test the hypothesis was a "cluster randomised controlled trial in 16 practices, 74 GPs and 141 patients with medically unexplained symptoms of 6 hours of reattribution training v. treatment as usual." It found that "Practice-based training in reattribution changed doctor-patient communication without improving outcome of patients with medically unexplained symptoms". Hardly a ringing endorsement of the method.

There has been a lot of hype about the effectiveness of Cognitive Behavioural Therapy (CBT) for Chronic Fatigue Syndrome (CFS). However, a meta-analysis[2] of its efficacy of CBT for CFS published in 2008 might temper some of the enthusiasm. The studies involved a total of 1371 patients. This involved calculating the size of an effect measure, the Cohen's d value. They calculated d using the following method: "Separate mean effect sizes were calculated for each category of outcome variable (e.g., fatigue self-rating) and for each type of outcome variable (mental, physical, and mixed mental and physical). Studies generally included multiple outcome measures. For all analyses except those that compared different categories or types of outcome variables, we used the mean effect size of all the relevant outcome variables of the study."d was calculated to be 0.48. For anyone unfamiliar with Cohen's d values, they are not bounded by 1; also, the higher the score, the bigger the "effect size" i.e. the more "effective" a treatment was found to be. Cohen's d values are considered to be a small effect size at 0.2, a moderate effect size at 0.5, and a large effect size at 0.8[2].

There are now hundreds of studies that have found "physical" abnormalities of one sort or another in Chronic Fatigue Syndrome. Thus I question the placement of "Chronic Fatigue" (which many/most people would read as referring to Chronic Fatigue Syndrome as it is listed beside Fibromyalgia and Irritable Bowel Syndrome) in figure 1, "Hypothetical scatter plot of dysfunction versus pathology in primary care consultations" where "evidence of pathological change" is said to be "absent". The numerous abnormalities found raise questions about the placement on the scatter plot or else the limitations of the concept. Also how "reversible" the "abnormal functioning, either physiological or psychological" is, remains far from clear given the low recovery rates.

References:

[1] Morriss R, Dowrick C, Salmon P, Peters S, Dunn G, Rogers A, Lewis B, Charles-Jones H, Hogg J, Clifford R, Rigby C, Gask L. Cluster randomised controlled trial of training practices in reattribution for medically unexplained symptoms. Br J Psychiatry. 2007 Dec;191:536-42

[2] Malouff, J. M., et al., Efficacy of cognitive behavioral therapy for chronic fatigue syndrome: A meta-analysis. Clinical Psychology Review (2007), doi:10.1016/j.cpr.2007.10.004

[3] Cohen J: Statistical power analysis for the behavioural sciences. Edited by: 2. New Jersey: Lawrence Erlbaum; 1988.

On 2014 Aug 29, Massimo Ciccozzi commented:

I read with interest the paper by Santosh et al. HIV 2 infections were geographically restricted, affecting West African countries1, 2, whereas in Europe the prevalence of HIV-2 is high in those countries that have socioeconomic relationships with this African region 3-5 . However, increased migration from/to other countries and international travels might increase the risk of spreading of this virus worldwide. We recently published a phylogenetic analysis of HIV2 case series in Italy using sequences isolated from Indian patients try to connect this infection with other from different countries 6. This article is very interesting and give important information on HIV-2 using a complete genome analysis. In Indian country few papers have been written in Phylogenetic analysis and Santosh and coauthors have given a sort of thrust in this way. In my opinion I only suggest the use of Bayesian Methods to have more robust information about the origin of Indian epidemics, moreover I encourage all Indian researchers, that are able to make sequences, to do this. It is also important that the scientific community don't lower the watch and monitor this infection also because to study HIV 2 can be an opportunity to better understand the HIV disease pathogenesis, protein immunity and this have to be taken before it disappears.<br> References

1. Dougan S, Patel B, Tosswill JH, and Sinka K: Diagnoses of HIV-1 and HIV-2 in England, Wales, and Northern Ireland associated with west Africa. Sex Transm Infect 2005;81:338– 341.

2. Matheron S, Mendoza-Sassi G, Simon F, Olivares R, Coulaud JP, and Brun-Vezinet F: HIV-1 and HIV-2 AIDS in African patients living in Paris. AIDS 1997;11:934–936.3

3. Valadas E, Franc¸a L, Sousa S, and Antunes F: 20 years of HIV-2 infection in Portugal: Trends and changes in epidemiology. Clin Infect Dis 2009;48:1166–1167.

4. Barin F, Cazein F, Lot F, et al.: Prevalence of HIV-2 and HIV-1 group O infections among new HIV diagnoses in France: 2003– 2006. AIDS 2007;21:2351–2353.

5. Soriano V, Gomes P, Heneine W, et al.: Human immunodeficiency virus type 2 (HIV-2) in Portugal: Clinical spectrum, circulating subtypes, virus isolation, and plasma viral load. J Med Virol 2000;61:111–116.

6. D’Ettorre,G, Lo Presti A,Gori C, Cella E,Bertoli A,Vullo V,Perno CF, Ciotti M,. Foley Brian T, and Massimo Ciccozzi. An HIV Type 2 Case Series in Italy: A Phylogenetic Analysis.(2013) AIDS Res HUM Retroviruses

On 2014 Jan 08, Tom Kindlon commented:

The references don't show that CFS "affects at least 4 million adults in the United States"

This is not necessarily a major point to do with the methodology. However given the paper involves CFS medical education, and gives few facts about CFS, one would think that the statements that are made are at least reasonably accurate.

However, this statement clearly isn't: "CFS affects at least 4 million adults in the United States [2-4]." The references given are the first three references below. The second study found a prevalence of 422 per 100,000 adults and the third study found a prevalence of 235 per 100,000 adults. These aren't even close to 4 million adults - the second one suggests a figure of at least 400,000 adults. This study involved one of the authors (William C Reeves). The other study[1], also involved Reeves, did find a prevalence of 2540 per 100,000 adults, which would equate to over 4 million adults. As can be seen, this is much higher than previous estimates of the prevalence of CFS in the US. The reason for the huge discrepancy is largely because it used a different method of defining CFS[4].

There has been some criticism of this new definition[5]. Unlike previous times when the CDC produced definitions for CFS[6,7], the definition used in this study is generally only being used by the CDC-funded CFS research team [the cohorts from the Wichita 2-day study in 2003 (not to be confused with the Reyes study) and the Georgia prevalence study[3]]. So it's far from clear that most people would accept that CFS "affects at least 4 million adults in the United States". But certainly two of the three studies given to back up this reference did not find anything close to such a prevalence.

References:

[1] Reeves WC, et al. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Population Health Metrics 2007, 5:5.

[2] Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huan CF, Plioplys S: A community-based study of chronic fatigue syndrome. Arch Int Med 1999, 159:2129-2137.

[3] Reyes M, Nisenbaum R, Hoaglin DC, Emmons C, Stewart G, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC: Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Intern Med 2003, 163:1530-1536.

[4] Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C: Chronic Fatigue Syndrome – A clinically empirical approach to its definition and study. BMC Medicine 2005, 3:19 (15 December 2005)

[5] Jason LA, Richman JA: How Science Can Stigmatize: The Case of Chronic Fatigue Syndrome. Journal of Chronic Fatigue Syndrome, Vol. 14(4), 2007

[6] Fukuda, K., Straus, S.E., Hickie, I., Sharpe, M.C., Dobbins, J.G., & Komaroff, A. (1994). The chronic fatigue syndrome: A comprehensive approach to its definition and study. Annals of Internal Medicine, 121 (12):953-959. http://www.annals.org/cgi/content/full/121/12/953

[7] Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med. 1988; 108:387-9.

On 2013 Oct 31, John Cannell commented:

The authors stated that markers of oxidative stress are present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take

On 2013 Dec 06, Tom Kindlon commented:

Differences in medication usage in the Wichita and Georgia cohorts could be due to the different methods of operationalizing the Fukuda criteria that were used

Medication usage was not the same in the CFS populations found in the Wichita and Georgia populations.

The authors summarise the similarities and differences in the following paragraph:

“Our findings confirm those from a previous study of medication use in persons with CFS from Wichita, Kansas. Both studies found significantly higher usage of pain relievers, gastrointestinal drugs, antidepressants and benzodiazepines by persons with CFS compared to Well controls. Unlike the Wichita study, though, persons with CFS in Georgia were not significantly more likely than controls to use hormones and supplements but were significantly more likely than controls to use muscle relaxants and anti-allergy and cold/sinus medications. Overall, compared to persons with CFS from the Wichita study7, a smaller proportion of persons with CFS in Georgia used pain-relievers (65.5% in Georgia vs. 87.8% in Wichita), supplements/vitamins (44.3% vs. 62.2%), antidepressants (36.3% vs. 41.1%), antibiotics (7.1% vs. 16.7%), hormones (43.4% vs. 52.5%. among women only, 11.8% among all CFS), antihypertensive drugs (17.7% vs. 21.1%), muscle relaxants (8.9% vs. 12.2%), anti-asthma medications (7.1% vs. 12.2%), glucose-lowering drugs (0.9% vs. 4.4%.). Use of other prescription drug categories such as lipid-lowering drugs (11.5% vs.12.2%) and benzodiazepines (12.4%, vs. 11.1% respectively) was similar in Georgia and Wichita (Kansas). The relatively lower usage of most prescription drug medications by persons with CFS in Georgia compared to Wichita may reflect lower seeking of, or lower access to, health care.”

An alternative reason could be that the two sets of criteria for CFS used were not selecting the same type of patients.

The current study[1] uses the empiric definition for CFS[2]. As one can see from the paper that gives the criteria involved in the empiric definition, although it is also based on the Fukuda definition[3], a different number of patients satisfy the criteria [2] compared to how the authors used the definition in the initial study of the Wichita population.

This change looks more significant when one looks at the prevalence rates for CFS obtained in the two cohorts. In the Wichita study[4], the prevalence of CFS was 0.235% (95% confidence interval, 0.142%-0.327%). In the Georgia study[5], the prevalence of CFS was 2.54%, 10.8 times the prevalence in the Wichita study!

Concerns have been raised[6,7] about the newer method[2] of operationalizing the Fukuda definition[3] that were used in the current study[1]. In the only study[7] using the empiric criteria [2] that I am aware of that did not involve the CDC CFS team, 38% of those chosen as patients with Major Depressive Disorder but not CFS, were found to satisfy the new criteria[2] for CFS.

References

1] Boneva RS, Lin JM, Maloney EM, Jones JF, Reeves WC. Use of medications by people with chronic fatigue syndrome and healthy persons: a population-based study of fatiguing illness in Georgia. Health Qual Life Outcomes. 2009 Jul 20;7:67.

[2] Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic fatigue syndrome--a clinically empirical approach to its definition and study. BMC Med. 2005 Dec 15;3:19.

[3] Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome; a comprehensive approach to its definition and study. Ann Int Med 1994, 121:953-959.

[4] Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC: Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Int Med 2003, 163:1530-1536.

[5] Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, Morrissey M, Devlin R. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr. 2007 Jun 8;5:5.

[6] Jason LA, Richman JA. How science can stigmatize: The case of chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome 2008, 14, 85-103.

[7] Jason LA, Najar N, Porter N, Reh C. Evaluating the Centers for Disease Control’s empirical chronic fatigue syndrome case definition. Journal of Disability Policy Studies 2009, 20, 93-100. doi:10.1177/1044207308325995

On 2015 Oct 02, Simon Young commented:

This is an interesting review but omits some important manuscripts. For example, in the section on the effect of tryptophan loading on mood in healthy volunteers there is no mention of several relevant studies Leathwood PD, 1982, Charney DS, 1982, Greenwood MH, 1974, SMITH B, 1962. The same is true for studies on the effect of tryptophan on sleep Griffiths WJ, 1972, Hartmann E, 1977, Adam K, 1979. The statement in the section 4.1 that “there is little consensus in terms of Trp’s efficacy in treating depression” is not universally accepted. A Cochrane Database Systematic Review concluded that the available evidence suggests that tryptophan is better than placebo at alleviating depression Shaw K, 2002, and tryptophan has been available as a prescription drug for the treatment of depression in a number of countries. The Cochrane Database Systematic Review includes a number of studies not included in the article.

On 2014 Jan 06, Tom Kindlon commented:

A more detailed comparison would need to be made before one could say this replicates the previous study

Part of the aim of this study [1] appears to be to compare the classes that were drawn up with a previous cohort[2-4]. However it does not, to my mind, deal with this in a particularly rigorous fashion. The main quantitative comparisons are the percentages that fall in each class (Tables 6 and 7). However, the percentages will be influenced by the quantity and type of non-CFS controls used which are not the same in each cohort [to explain why this is important using an extreme example: if there were 1000 non-CFS cases for everyone one CFS case in one cohort, the percentages in each class would be different than if there was a 1:1 ratio of CFS to non-CFS cases in the other cohort].

The first study involved the following[5]: "This population-based case control study enrolled 227 adults identified from the population of Wichita with: (1) CFS (n = 58); (2) non-fatigued controls matched to CFS on sex, race, age and body mass index (n = 55); (3) persons with medically unexplained fatigue not CFS, which we term ISF (n = 59); (4) CFS accompanied by melancholic depression (n = 27); and (5) ISF plus melancholic depression (n = 28)." This was based on the classification in 1997-2000. These were then assessed during 2003. As one can see in Table 2, in 2003, 6 out of the original 58 CFS patients satisfied the CFS definition[6] as originally operationalized, along with 4 out of the controls. 6 more who had previously been excluded because of previous diagnosis of Major Depressive Disorder with melancholic features (MDDm) were also said to satisfy the original CFS diagnosis. The method for operationalizing the CFS definition[6] was then changed so there was then 43 individuals with CFS (see Table 5). Although the same method[5] of operationalizing the CFS definition[6] is used when comparing the Wichita and Georgia cohorts, it is a very different way to select patients and controls than the current study[1]. So it is questionable how interesting it is to compare the percentages in each class.

A comparison of the percentages of CFS in each class might have been interesting but that was not done.

Also, apart from the percentages, no tables with quantitative information are presented in the current paper to help the reader compare the class groups to see how valid the comparisons are. This is made more difficult because the original study gave much more detailed data on the six class solution rather than the five class solution [2]: "As the five- and six-class solutions produced practically identical classes, with the exception of the fifth group in the five-class solution being divided into the fifth and sixth classes in the six-class solution, only the six-class solution is presented in Table 2."

So in that paper, one has classes which have a median BMI of 32, 30 and 30 which are described in the current paper[1] as obese classes while class 5 would be a combination of classes 5 and 6 which have a median BMI of 26 and 27 are classed as non-obese. So numerical comparisons would have been of more use rather than looking at verbal descriptions - describing two groups which have a median BMI of 30 as obese (so approx 50% would have a BMI under 30, one threshold for obesity) and another group which has a median BMI of around 26.5 as non-obese, seems a bit unsatisfactory. There is a 5 class LCA solution in Figure 1 in one of the Wichita papers which gives some verbal descriptions[4]. As one can see, "obese" is only used to describe two of the five LCA groups: - Obese, hypnoea (27.93%) - Obese, hypnoea and stressed (15.32%) - Interoception (16.22%) - Interoception, depression (19.82%) - Well (20.72%)

However, this does not seem to be the same five class solution for the Wichita cohort as the one described in this paper as the percentages don't match up.

References:

[1]. Aslakson E, Vollmer-Conna U, Reeves WC, White PD. Replication of an empirical approach to delineate the heterogeneity of chronic unexplained fatigue. Popul Health Metr. 2009 Oct 5;7:17.

[2]. Vollmer-Conna U, Aslakson E, White PD: An empirical delineation of the heterogeneity of chronic unexplained fatigue in women. Pharmacogenomics 2006, 7(3):355-364.

[3]. Aslakson E, Vollmer-Conna U, White PD. The validity of an empirical delineation of heterogeneity in chronic unexplained fatigue. Pharmacogenomics. 2006 Apr;7(3):365-73.

[4]. Carmel L, Efroni S, White PD, Aslakson E, Vollmer-Conna U, Rajeevan MS. Gene expression profile of empirically delineated classes of unexplained chronic fatigue. Pharmacogenomics. 2006 Apr;7(3):375-86.

[5]. Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic fatigue syndrome--a clinically empirical approach to its definition and study. BMC Med. 2005 Dec 15;3:19.

[6]. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A: The chronic fatigue syndrome; a comprehensive approach to its definition and study. Ann Int Med 1994, 121:953-959.

On 2014 Jan 06, Tom Kindlon commented:

There has been criticism of how CFS is defined in this study

I thought it would be useful to point out that there is controversy [1,2] with regard to the criteria [3] used in this study to define Chronic Fatigue Syndrome (CFS).

For example, the criteria for CFS used in this study do not even require a patient to have fatigue. The authors say: “We used the Multidimensional Fatigue Inventory (MFI-20) [4] to measure characteristics of fatigue” but they do not give the thresholds. Given the MFI-20 has five subscales: (General fatigue, Physical fatigue, Mental fatigue, Activity reduction and Motivation reduction), one would probably suspect that a patient would have to score poorly on one of the headings which have fatigue in their title. But the actual criteria are: a patient needs to score >=13 on MFI general fatigue or >=10 on reduced activity. Note, one could score >=10 on the MFI reduced activity questions without necessarily being fatigued (one could be depressed or even lazy) (only current major depressive disorder with melancholic features (MDDm) is an exclusion for this definition of CFS).

This is despite the fact that in the current paper, the authors say: “Chronic fatigue syndrome (CFS) is a common, debilitating illness whose hallmark symptoms involve fatigue and fatigability”. Many other questions have been raised about the criteria for CFS that were used in this study. For example, the authors only considered current MDDm to be exclusionary for CFS while the International CFS Study group recommended that conditions (including MDDm) were considered exclusions unless they had been “resolved for more than 5 years before the onset of the current chronically fatiguing illness”[5].

Prevalence figures show that the criteria, that were used for this cohort, are selecting a broader group than previous criteria for CFS. Based on the figures derived from this cohort, the prevalence of CFS was estimated at 2.54% [6]. Other studies using similar methodology (but which did not operationalize the criteria [7] for the CFS in the same way as this study) estimated the prevalence of CFS to be 0.235% (95% confidence interval, 0.142%-0.327%) and 0.422% (95% confidence interval, 0.29%-0.56%) [8,9].

References:

[1]. Jason LA, & Richman JA. How science can stigmatize: The case of chronic fatigue syndrome. Journal of CFS 2007;14:85-103.

[2]. Jason LA, Najar N, Porter N, Reh C. Evaluating the Centers for Disease Control's empirical chronic fatigue syndrome case definition. Journal of Disability Policy Studies 2009;20;93.

[3]. Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C: Chronic fatigue syndrome--a clinically empirical approach to its definition and study. BMC Medicine 2005, 3:19.

[4]. Smets EM, Garssen B, Bonke B, De Haes JC. The multidimensional fatigue inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res 1995; 39: 315–25.

[5]. Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, Bleijenberg G, Evengard B, White PD, Nisenbaum R, Unger ER; International Chronic Fatigue Syndrome Study Group. Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res. 2003 Dec 31;3(1):25.

[6]. Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, Morrissey M, Devlin R. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr. 2007 Jun 8;5:5.

[7]. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome; a comprehensive approach to its definition and study. Ann Int Med 1994, 121:953-959.

[8]. Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC: Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Int Med 2003, 163:1530-1536.

[9]. Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang CF, Plioplys S. A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999 Oct 11;159(18):2129-37.

On 2014 Jan 06, Tom Kindlon commented:

Why are we only given information on 3 out of the 8 SF-36 subscales?

Reading this paper, one could be forgiven for thinking that the SF-36 questionnaire only has 3 subscales: Physical Functioning, Mental Health and Social Functioning as that is all we are given information on. In fact, of course, the SF-36 questionnaire has 8 subscales: Physical function, Role physical, Bodily pain, General health, Vitality, Social function, Role emotional and Mental health[1]. The authors use the empiric definition for CFS[2] which requires at a minimum that the "role physical" and "role emotional" subscales also be measured. We also know that all 8 subscales were measured in this cohort[3]. So why was the information not given?

If one was not giving the authors the benefit of the doubt, one could speculate that it was because Table 4 would not look as good, as the Chi-squared calculations would not reach statistical significance for the missing data. But that would be speculation - there could be other reasons for the missing information.

Perhaps the authors could post the relevant data now.

I am not simply being mischievous - I would be interested in particular to see what are the scores for Classes 1 and 2 which include nearly all of the CFS patients (88/92, 95.7%).

References:

[1] Ware JE, Sherbourne CD: The MOS 36-item short form health survey (SF-36): conceptual framework and item selection. Med Care 1992, 30:473-483.

[2] Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C: Chronic fatigue syndrome--a clinically empirical approach to its definition and study. BMC Medicine 2005, 3:19.

[3] An evaluation of exclusionary medical/psychiatric conditions in the definition of chronic fatigue syndrome. Jones JF, Lin JM, Maloney EM, Boneva RS, Nater UM, Unger ER, Reeves WC. BMC Med. 2009 Oct 12;7(1):57. - see Tables 5 and 6.

On 2016 Sep 19, Morten Oksvold commented:

Please note that a rather extensive correction was published 7 December 2011: "The wrong images were mistakenly presented for day 3 for the wild-type and the racX ylmE double mutant in figure S4. The original and correct images are now shown. Also, the wrong image was presented for the mixture of L-amino acids in panel B of fig. S13 and has now been removed."

In 2013, the Losick group published results showing that D-amino acids inhibited bacterial growth and the expression of biofilm matrix genes and that the strain they originally used to study biofilm formation (B. subtilis) has a mutation in the D-tyrosyl-tRNA deacylase gene, an enzyme that prevents the misincorporation of D-amino acids into protein (Leiman et al., 2013). In a B. subtilis strain, which has a working copy of this gene, D–amino acids did not inhibit biofilm formation. The conclusion from their study was that "the susceptibility of B. subtilis to the biofilm-inhibitory effects of D-amino acids is largely, if not entirely, due to their toxic effects on protein synthesis.

Does that mean that they no longer see D-amino acids as a specific mechanism to disassemble biofilms in B. subtilis but rather as nonspecific inhibitors of growth in some genetic backgrounds?

Leiman et al. (2013) make no comment on the ability of D-amino acids to inhibit biofilm formation in staphylococcus aureus and Pseudomonas aeruginosa, as claimed in this article. The whole concept of biofilm dissasembly by D-amino acids therefore appears confusing.

It was recently published an article showing that D-amino acids do not inhibit biofilm formation in Staphylococcus aureus (Sarkar S and Pires MM, 2015).

On 2013 Dec 20, Raphael Stricker commented:

Fatal Clostridium Difficile Colitis Following Treatment for Lyme Disease: The Wrong Message.

Raphael B. Stricker, MD* and Lorraine Johnson, JD, MBA*

*International Lyme and Associated Diseases Society, P.O. Box 341461, Bethesda, MD 20827-1461. www.ILADS.org

Holzbauer and colleagues (1) describe a case of fatal Clostridium difficile colitis in a patient treated with ten weeks of oral antibiotics for chronic Lyme disease. Rather than focusing on patient-specific risk factors and prevention of antibiotic-related complications, the authors preach about the dangers of treating Lyme disease outside the controversial guidelines of the Infectious Diseases Society of America (IDSA), which were the subject of an antitrust investigation by the Connecticut Attorney General (2,3). In doing so, the authors exaggerate the risks of treating Lyme disease and ignore the risks of failing to treat an ongoing spirochetal infection that may cause disability equivalent to congestive heart failure, and even death (4,5). Consequently the emphasis of the case report is misguided and ultimately detrimental to patient care.

In the single case described here, no information is given about cellular or humoral immune dysfunction that may have contributed to the rapid demise of the 52-year-old patient. This rapid demise is unusual in patients less than 80 years old with C. difficile colitis (6) and suggests the presence of a hypervirulent C. difficile ribotype that might explain the clinical course. Furthermore, the authors fail to mention whether the patient received probiotic therapy during the extended oral antibiotic treatment. Probiotic therapy appears to be effective in avoiding antibiotic-induced complications, and evidence suggests that certain probiotics may neutralize C. difficile toxin (7,8). The lack of probiotic therapy may have been a significant factor in this patient’s demise.

As for the appropriateness of antibiotic therapy in a patient with clinical and laboratory evidence of chronic Lyme disease, two points should be considered. First, two approaches to treatment of this tickborne illness have been described in the medical literature. The approach promulgated by IDSA proscribes extended antibiotic therapy for persistent symptoms related to infection with Borrelia burgdorferi, the spirochetal agent of Lyme disease (2). In contrast, the competing approach of the International Lyme and Associated Diseases Society (ILADS) considers this therapy to be appropriate based on evidence of persistent spirochetal infection (4,9,10). Second, the patient described in the report received a course of oral antibiotics that is shorter than the antibiotic courses endorsed or accepted by IDSA for chronic conditions such as tuberculosis, leprosy, complicated actinomycosis, Whipple’s disease, Q fever endocarditis, alveolar echinococcosis, osteomyelitis and asplenia prophylaxis; the risks of prolonged antibiotic therapy are considered acceptable for these conditions (11-18). While several clinical studies have demonstrated the safety of extended oral and intravenous antibiotic therapy for patients diagnosed with Lyme disease (19-22), caution should always be exercised in administering extended antibiotic therapy to any patient with a chronic infectious disease.

References

1. Holzbauer SM, Kemperman MM, Lynfield R. Death due to community-associated Clostridium difficile in a woman receiving prolonged antibiotic therapy for suspected Lyme disease. Clin Infect Dis 2010;51:369-70.

2. Johnson L, Stricker RB. The Infectious Diseases Society of America Lyme guidelines: a cautionary tale about development of clinical practice guidelines. Philos Ethics Humanit Med 2010;5:9.

3. Johnson L, Stricker RB. Final report of the Lyme Disease Review Panel of the Infectious Diseases Society of America: A Pyrrhic victory? Clin Infect Dis 2010;51:1108-9.

4. Cameron DJ. Proof that chronic Lyme disease exists. Interdiscip Perspect Infect Dis 2010;2010:876450.

5. Centers for Disease Control and Prevention (CDC). Three sudden cardiac deaths associated with Lyme carditis - United States, November 2012-July 2013. MMWR Morb Mortal Wkly Rep. 2013;62:993-6.

6. Kotila SM, Virolainen A, Snellman M, Ibrahem S, Jalava J, Lyytikäinen O. Incidence, case fatality and genotypes causing Clostridium difficile infections, Finland, 2008. Clin Microbiol Infect 2011;17:888-93.

7. McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol 2006;101:812-22.

8. Castagliuolo I, Riegler MF, Valenick L, LaMont JT, Pothoulakis C. Saccharomyces boulardii protease inhibits the effects of Clostridium difficile toxins A and B in human colonic mucosa. Infect Immun 1999;67:302-7.

9. Stricker RB. Counterpoint: Long-term antibiotic therapy improves persistent symptoms associated with Lyme disease. Clin Infect Dis 2007;45:149-57.

10. Stricker RB, Johnson L. Lyme disease: The next decade. Infect Drug Resist 2011;4:1–9.

11. Small PM, Fujiwara PI. Management of tuberculosis in the United States. N Engl J Med 2001;345:189-200.

12. Cox H, Kebede Y, Allamuratova S, Ismailov G, Davletmuratova Z, Byrnes G, Stone C, Niemann S, Rüsch-Gerdes S, Blok L, Doshetov D. Tuberculosis recurrence and mortality after successful treatment: impact of drug resistance. PLoS Med 2006;3:e384.

13. Garner JP, Macdonald M, Kumar PK. Abdominal actinomycosis. Int J Surg 2007;5:441-8.

14. Freeman HJ. Tropheryma whipplei infection. World J Gastroenterol 2009;15:2078-80.

15. Liu YH, Wang XG, Gao JS, Qingyao Y, Horton J. Continuous albendazole therapy in alveolar echinococcosis: long-term follow-up observation of 20 cases. Trans R Soc Trop Med Hyg 2009;103:768-78.

16. Lazzarini L, Lipsky BA, Mader JT. Antibiotic treatment of osteomyelitis: what have we learned from 30 years of clinical trials? Int J Infect Dis 2005;9:127-38.

17. Price VE, Blanchette VS, Ford-Jones EL.The prevention and management of infections in children with asplenia or hyposplenia. Infect Dis Clin North Am 2007;21:697-710, viii-ix.

18. Beytout J, Tournilhac O, Laurichesse H. Antibiotic prophylaxis in splenectomized adults. Presse Med 2003;32(28 Suppl):S17-9.

19. Donta ST. Tetracycline therapy for chronic Lyme disease. Clin Infect Dis 1997;25 Suppl 1:S52-6.

20. Donta ST. Macrolide therapy of chronic Lyme disease. Med Sci Monit 2003;9:PI136-42.

21. Stricker RB, Green CL, Savely VR, Chamallas SN, Johnson L. Safety of intravenous antibiotic therapy in patients referred for treatment of neurologic Lyme disease. Minerva Med 2010; 101:1–7.

22. Stricker RB, Delong AK, Green CL, Savely VR, Chamallas SN, Johnson L. Benefit of intravenous antibiotic therapy in patients referred for treatment of neurologic Lyme disease. Int J Gen Med 2011;4:639-46.

Disclosure: RBS is a member of the International Lyme and Associated Diseases Society (ILADS) and a director of LymeDisease.org. He has no financial or other conflicts to declare.

On 2016 Jan 08, Tom Kindlon commented:

This study uses the (so-called) empiric CFS criteria (Reeves et al., 2005)

Although they don't make it very clear, this study used the Reeves et al. (2005) criteria(1) for defining Chronic Fatigue Syndrome (CFS) (sometimes described by the CDC as an operationalization of the Fukuda et al. (1994) criteria (2)). This can be seen by examining the Reeves et al. (2007) paper on the Georgia cohort (2).

These (Reeves) criteria greatly increased the prevalence of CFS. The "empirical" definition gives a prevalence rate of 2.54% of the adult population(3) compared to 0.235% (95% confidence interval, 0.142%-0.327%) and 0.422% (95% confidence interval, 0.29%-0.56%) when the Fukuda definition (3) was used in previous population studies in the US(4,5).

The definition lacks specificity. For example, one research study(6) found that 38% of those with a diagnosis of a Major Depressive Disorder were misclassified as having CFS using the empirical/Reeves definition. A letter of mine discussed my concerns in more detail(7).

Due to the problems with the criteria, these criteria have not been used by researchers outside those contracted to analyse CDC data (apart from Leonard Jason's research team who studied it and showed problems with it (6)).

References:

1 Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic fatigue syndrome – a clinically empirical approach to its definition and study. BMC Med. 2005;3:19.

2 Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, Morrissey M, Devlin R. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr. 2007 Jun 8;5:5.

3 Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome; a comprehensive approach to its definition and study. Ann Int Med 1994, 121:953-959.

4 Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC: Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Int Med 2003, 163:1530-1536.

5 Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang CF, Plioplys S. A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999 Oct 11;159(18):2129-37.

6 Jason, LA, Najar N, Porter N, Reh C. Evaluating the Centers for Disease Control's empirical chronic fatigue syndrome case definition. Journal of Disability Policy Studies 2008, doi:10.1177/1044207308325995.

7 Kindlon T. Criteria used to define chronic fatigue syndrome questioned. Psychosom Med. 2010 Jun;72(5):506-7

On 2013 Oct 31, John Cannell commented:

The authors stated that markers of oxidative stress are present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take

On 2013 Oct 31, John Cannell commented:

The authors stated that markers of oxidative stress are present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take

On 2013 Oct 31, John Cannell commented:

The authors found markers oxidative stress is present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take the Ameri

On 2013 Oct 31, John Cannell commented:

The authors stated that markers of oxidative stress are present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take

On 2015 Aug 12, Tom Kindlon commented:

This study uses the (so-called) empiric CFS criteria (Reeves et al., 2005)

This study used the Reeves et al. (2005) criteria(1) for defining Chronic Fatigue Syndrome (CFS) (sometimes described by the CDC as an operationalization of the Fukuda et al. (1994) criteria (2)).

These (Reeves) criteria greatly increased the prevalence of CFS. The "empirical" definition gives a prevalence rate of 2.54% of the adult population(3) compared to 0.235% (95% confidence interval, 0.142%-0.327%) and 0.422% (95% confidence interval, 0.29%-0.56%) when the Fukuda definition was used in previous population studies in the US(4,5).

The definition lacks specificity. For example, one research study(6) found that 38% of those with a diagnosis of a Major Depressive Disorder were misclassified as having CFS using the empirical/Reeves definition. A letter of mine discussed my concerns in more detail(7).

Due to the problems with the criteria, these criteria have not been used by researchers outside those contracted to analyse CDC data (apart from Leonard Jason's research team who studied it and showed problems with it (6)).

References:

1 Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic fatigue syndrome – a clinically empirical approach to its definition and study. BMC Med. 2005;3:19.

2 Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome; a comprehensive approach to its definition and study. Ann Int Med 1994, 121:953-959.

3 Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, Morrissey M, Devlin R. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr. 2007 Jun 8;5:5.

4 Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC: Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Int Med 2003, 163:1530-1536.

5 Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang CF, Plioplys S. A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999 Oct 11;159(18):2129-37.

6 Jason, LA, Najar N, Porter N, Reh C. Evaluating the Centers for Disease Control's empirical chronic fatigue syndrome case definition. Journal of Disability Policy Studies 2008, doi:10.1177/1044207308325995.

7 Kindlon T. Criteria used to define chronic fatigue syndrome questioned. Psychosom Med. 2010 Jun;72(5):506-7

On 2016 Sep 27, Alem Matthees commented:

The 'normal range' was not a strict criterion for recovery nor was it based on healthy scores

The editorial by Bleijenberg & Knoop (2011) contains a misleading statement: “PACE used a strict criterion for recovery: a score on both fatigue and physical function within the range of the mean plus (or minus) one standard deviation of a healthy person’s score. In accordance with this criterion, the recovery rate of cognitive behavioural and graded exercise therapy was about 30%—although not very high, the rate is significantly higher than that with both other interventions.” [1]

However, the PACE publication did not report on "recovery" [2] and the PACE authors issued a statement to that effect [3] despite previously approving the editorial before it was published [4,5]. The normal range overlapped with trial eligibility criteria for severe disabling fatigue [2]. The largest overlap was with SF-36 physical function, where 13% of participants simultaneously met the normal range on this measure and the entry criteria for "significant disability" [6]. The individual participant data recently released from the PACE trial reveals that 45% (60/134) of those within the normal range at 52-week follow-up still met Oxford CFS criteria [7].

It is disappointing that the Lancet and Bleijenberg & Knoop stand by the comment on recovery despite being alerted of the problems [5]. The Press Complaints Commission ruled that the editorial was misleading [4,5]. Oddly enough, both Bleijenberg & Knoop have previously co-authored papers where a score of 60 (the threshold for normal physical function) was regarded as severe impairment [8-11].

The normal range was not based on healthy people of working age only. For example, the normal range for physical function was based on a general population that included the elderly and chronically disabled [3]. If the normal range was based on a healthy population as asserted, the threshold for normal physical function would be 85 points or more, not 60 or more [6]. A preliminary re-analysis of recovery in the PACE trial, based on the protocol-specified recovery criteria, shows that the recovery rates in the CBT and GET groups were 6.8% and 4.4% respectively, and not significantly higher than with specialist medical care alone [7].

References

1) Bleijenberg G, Knoop H. Chronic fatigue syndrome: where to PACE from here? Lancet. 2011 Mar 5;377(9768):786-8. doi: 10.1016/S0140-6736(11)60172-4. Epub 2011 Feb 18. PMID: 21334060. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60172-4/fulltext

2) White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36. doi: 10.1016/S0140-6736(11)60096-2. Epub 2011 Feb 18. PMID: 21334061. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065633/

3) White PD, Goldsmith KA, Johnson AL, Walwyn R, Baber HL, Chalder T, Sharpe M, [on behalf of the coauthors]. The PACE trial in chronic fatigue syndrome — Authors' reply. The Lancet, Volume 377, Issue 9780, Pages 1834 - 1835, 28 May 2011 (Published Online: 17 May 2011). doi:10.1016/S0140-6736(11)60651-X http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60651-X/fulltext

4) http://www.pcc.org.uk/cases/adjudicated.html?article=ODQwOQ

5) Continuing Correspondence Between Countess of Mar and Professor Peter White and Professor Sir Simon Wessely. 26 January 2013. http://forums.phoenixrising.me/index.php?threads/continuing-correspondence-countess-of-mar-and-prof-white-and-prof-sir-s-wessely.21545/

6) Matthees A. Re: Tackling fears about exercise is important for ME treatment, analysis indicates. BMJ Rapid Response. 21 January 2015. http://www.bmj.com/content/350/bmj.h227/rr-16

7) Matthees A, Kindlon T, Maryhew C, Stark P, Levin B. A preliminary analysis of ‘recovery’ from chronic fatigue syndrome in the PACE trial using individual participant data. Virology Blog. 21 September 2016. http://www.virology.ws/wp-content/uploads/2016/09/preliminary-analysis.pdf

8) van't Leven M, Zielhuis GA, van der Meer JW, Verbeek AL, Bleijenberg G. Fatigue and chronic fatigue syndrome-like complaints in the general population. Eur J Public Health. 2010 Jun;20(3):251-7. Epub 2009 Aug 18. PMID: 19689970. http://eurpub.oxfordjournals.org/content/20/3/251.long

9) Tummers M, Knoop H, van Dam A, Bleijenberg G. Implementing a minimal intervention for chronic fatigue syndrome in a mental health centre: a randomized controlled trial. Psychol Med. 2012 Oct;42(10):2205-15. doi: 10.1017/S0033291712000232. Epub 2012 Feb 21. PMID: 22354999. http://www.ncbi.nlm.nih.gov/pubmed/22354999

10) Stulemeijer M, de Jong LW, Fiselier TJ, Hoogveld SW, Bleijenberg G. Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial. BMJ. 2005 Jan 1;330(7481):14. Epub 2004 Dec 7. doi: 10.1136/bmj.38301.587106.63. PMID: 15585538. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC539840

11) Heins M, Knoop H, Nijs J, Feskens R, Meeus M, Moorkens G, Bleijenberg G. Influence of symptom expectancies on stair-climbing performance in chronic fatigue syndrome: effect of study context. Int J Behav Med. 2013 Jun;20(2):213-8. doi: 10.1007/s12529-012-9253-2. PMID: 22865100. http://www.ncbi.nlm.nih.gov/pubmed/22865100

On 2016 Sep 27, Alem Matthees commented:

Post-hoc outcome switching inflated clinical response rates by several times

The primary outcomes as pre-specified in the published PACE trial protocol [1] were abandoned after the trial was over but before the unmasking of data [2] (although the trial was already open-label). While the new primary outcomes are useful, they were group-level and therefore not a direct replacement of the original primary outcomes, which were individual-level i.e. the proportion of participants meeting thresholds for fatigue and physical function.

The thresholds for individual-level improvement on the measures of fatigue and physical function were eventually replaced with post-hoc analyses after the unmasking of data [3], and it is unclear whether these changes were independently approved. The new thresholds have been criticised for being too lax, much less stringent than the pre-specified version, poorly calculated, and a possible example of "outcome reporting bias" [4,5].

On 8 September 2016, Queen Mary University of London (QMUL) released the PACE trial primary outcome results as defined in the published trial protocol [6]. This happened one day before the deadline to appeal the Information Tribunal’s ruling that QMUL must disclose a selection of de-identified participant-level data under the Freedom of Information Act (see EA/2015/0269).

Here is a comparison of the different rates: the clinically useful difference in both fatigue and physical function (Lancet 2011) [3] was 45% for SMC, 59% for CBT, and 61% for GET; the overall improvers or positive outcomes for both fatigue and physical function (QMUL 2016) [6] were 10% for SMC, 20% for CBT, and 21% for GET.

Without going into the issues with the nature and generalisability of the reported benefits, these new results provide a more realistic estimation of the clinical response rates of CBT and GET. However it also indicates that post-hoc outcome switching had inflated the estimated response rates in the PACE trial by several times. This exaggeration allowed proponents of CBT and GET to claim that 60% improved after these therapies (often without mentioning the SMC control rate of 45%). Outcome switching is recognised as a major problem in the research community [7].

There is also evidence that the PACE trial investigators changed the primary outcome measures in the trial registration entry (ISRCTN54285094 [8]). Using web.archive.org shows that an earlier version dated May 2005 [9] describes the primary outcomes with details about the pre-specified thresholds for improvement, but the current version only describes the primary hypotheses being tested or general objectives, without those additional details, allowing the investigators to change their primary outcomes without appearing to be deviating from the trial registration details.

References

1) White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; PACE trial group. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol. 2007 Mar 8;7:6. PMID: 17397525. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2147058/

2) Walwyn R, Potts L, McCrone P, Johnson AL, DeCesare JC, Baber H, Goldsmith K, Sharpe M, Chalder T, White PD. A randomised trial of adaptive pacing therapy, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome (PACE): statistical analysis plan. Trials. 2013 Nov 13;14:386. doi: 10.1186/1745-6215-14-386. PMID: 24225069. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226009/

3) White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36. doi: 10.1016/S0140-6736(11)60096-2. Epub 2011 Feb 18. PMID: 21334061. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065633/

4) Giakoumakis J. The PACE trial in chronic fatigue syndrome. Lancet. 2011 May 28;377(9780):1831; author reply 1834-5. doi: 10.1016/S0140-6736(11)60689-2. Epub 2011 May 16. PMID: 21592554. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60689-2/fulltext

5) Stouten B, Goudsmit EM, Riley N. The PACE trial in chronic fatigue syndrome. Lancet. 2011 May 28;377(9780):1832-3; author reply 1834-5. doi: 10.1016/S0140-6736(11)60685-5. Epub 2011 May 16. PMID: 21592558. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60685-5/fulltext

6) Goldsmith KA, White PD, Chalder T, Johnson AL, Sharpe M. The PACE trial: analysis of primary outcomes using composite measures of improvement. 8 September 2016. http://www.wolfson.qmul.ac.uk/images/pdfs/pace/PACE_published_protocol_based_analysis_final_8th_Sept_2016.pdf

7) http://compare-trials.org/

8) http://www.controlled-trials.com/ISRCTN54285094

9) <http://web.archive.org/web/20050524130106/http://www.controlled-trials.com/mrct/trial/CHRONIC FATIGUE SYNDROME/1042/40645.html>

On 2014 Feb 06, Anastasia L Bodnar commented:

This comment focuses on the claim by Aris and Leblanc that CryAb1 toxin was detected. In short, they used an incorrect method and an incorrect standard.

The ELISA kit used by Aris and Leblanc to detect Bt was made by a company called Agdia (as described in section 2.4. of the paper). The kit was created and tested to detect Bt in plant tissues (Agdia doesn’t make any kits for animal tissues). This is potentially a problem because a kit that is not tested on mammalian tissues might cross-react with proteins found in mammals that aren’t found in plants, giving a false positive result. ELISA methods have been developed for Cry proteins in mammalian blood, but these methods have had varying success.

German researchers developed an ELISA method for cows’ blood, which was able to detect Cry proteins in blood that was spiked with the protein. They did not find any significant difference between cows that had been fed Bt and conventional maize for a two month period, and all values detected in all cows’ blood were less than 1.5 ng/mL. Paul V, 2008

Aris and Leblanc did cite a paper that showed fragments and intact Bt protein could be detected with ELISA in the gastrointestinal tract (not in blood). Aris and Leblanc did not mention that the researchers found that Bt was probably digested in cattle, and suggested that a different method besides ELISA should be used to confirm presence of Cry protein. Lutz B, 2005

Aris and Leblanc also cited a paper that used ELISA to detect Cry protein in pigs. ELISA, immunochromatography, and immunoblot were sucessful in detecting Cry protein fragments in the gastrointestinal tract. Aris and Leblanc did not mention that the researchers did not detect any Cry protein in blood with any of these methods. Chowdhury EH, 2003

In addition to using an incorrect method to detect Cry proteins in blood, Aris and Leblanc also used an incorrect standard. Aris and LeBlanc created Cry protein solutions of 0.1 to 10 ng/mL. In Table 2, they report that a a range of 0 to 1.50 ng/mL was detected in maternal blood and 0 to 0.14 was detected in fetal cord blood. The mean and SD for maternal was 0.19 ng/mL ± 0.30 and for fetal was 0.04 ± 0.04 ng/mL. Ideally, test values will be in the middle of a standard curve. Any values outside or at the edges of of the standard curve may be false positives. Aris and Leblanc could have confirmed their results with a Western blot or any number of other methods, but they did not.

On 2016 Dec 20, Alessandro Rasman commented:

Anatomical stenosis of the internal jugular veins : supportive evidence of chronic cerebrospinal venous insufficiency ?

Andrea Baiocchini, MD Raffaele Toscano, Wilfredo von Lorch and Franca Del Nonno National Institute for Infectious Diseases "L. Spallanzani", Via Portuense 292, 00149 Rome, Italy, +390655170277, Fax +390655170430

We write in relation to the editorial commentary from Khan et Tselis (1) who rightly suggest caution to consider chronic cerebrospinal venous insufficiency (CCSVI) as a pathological entity and cast serious doubt on its relevance to multiple sclerosis (MS); they forecast properly designed studies to investigate the relevance of CCSVI to MS, in order to carry out interventional procedures.

The absence of extracranial venous stenosis at the earliest stage of MS makes it an unlikely cause of the disease (2). The idea of venous congestion as a possible contributor to the pathogenesis of MS has been discussed for the past 40 years, but remained widely unappreciated by the scientific community.

In contrast with other authors, Zamboni et al (3) defined CCSVI as a vascular condition associated with MS; it is characterized by multiple intraluminal stenosing malformations of the principal pathways of extracranial venous drainage, particularly in the internal jugular veins (IJVs) and the azygous vein (AZY), that restrict the normal outflow of blood from the brain. In the study of Zamboni et al there was significant extracranial venous stenosis localised at the principal level of the cerebrospinal venous segments as detected by selective venography and anomalies of venous outflow at color Doppler high resolution examination. The pathological consequences of CCSVI have been hypothesised to emanate from chronic venous reflux and hypertension leading to increased iron deposition in the brain and subsequent MS pathology, including inflammation and neurodegeneration.

Other recent reports found no differences in cerebrospinal venous drainage using transcranial and extracranial Doppler imaging (4-5). The discrepancies in the results may be explained with the absence of standardized internationally accepted criteria for normal Doppler venous flow parameters (2).

We performed complete post-mortem examination of two patients with MS, died for different causes. One patient, a 74 year-old-woman, was hospitalized for acute respiratory illness and died because of bacterial pneumonia; the other one, a 35 year-old-woman, died for otogenic bacterial meningitis complicated with internal jugular thrombosis as demonstrated on MR venography.

Postmortem examination demonstrated in both patients a marked stenosis of left internal jugular vein at the apex of the angle formed by the two heads of the sternocleidomastoid muscle where the IJV overlie the carotid artery with ectasia and congestion of the intracranial veins. Venous flow slowing, caused by the stenosis, had predisposed to IJV thrombosis, histologically demonstrated in the second case.

Severe inflammatory disease may be a risk factor for deep venous thrombosis but also chronic cerebrospinal venous insufficiency. We demonstrate, for the first time as far as we are aware, the presence of anatomical alteration in the veins of the neck with impaired venous drainage from the central nervous system in two patients with multiple sclerosis who died from other causes.

We do not know the exact implications in MS pathology and certainly there is no doubt that this area warrants a great deal more study. Clinical trials for evaluating new therapeutic agents and other clinical experimental protocols may be required.

References: 1. Khan O, Tselis A. Chronic cerebrospinal venous insufficiency and multiple sclerosis: science or science fiction? J Neurol Neurosurg Psychiatry 2011;82:355. 2. Yamout B, Herlopian A, Issa Z Extracranial venous stenosis is an unlikely cause of multiple sclerosis Mult Scler 2010 16: 1341-9 3. Zamboni P, Galeotti R, Menegatti E, et al Chronic cerebrospinal venous insuffiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2009;80:392-9. 4. Doepp F, Paul F, Valdueza JM, et al No cerebrocervical venous congestion in patients with multiple sclerosis. Ann Neurol 2010, 68:173-183. 5. Sundstrom P, Wahlin A, Ambarki K, et al Venous and cerebrospinal fluid flow in multiple sclerosis: a case-control study. Ann Neurol 2010, 68:255-259.

Conflict of Interest: None declared

Published 28 April 2011

On 2013 Oct 31, John Cannell commented:

The authors stated that markers of oxidative stress are present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take

On 2015 Sep 17, Tom Kindlon commented:

This study uses the (so-called) empiric CFS criteria (Reeves et al., 2005)

Although they don't make it very clear, this study used the Reeves et al. (2005) criteria(1) for defining Chronic Fatigue Syndrome (CFS) (sometimes described by the CDC as an operationalization of the Fukuda et al. (1994) criteria (2)). This can be seen by examining the Reeves et al. (2005) paper which shows that 43 people from the two-day study satisfied the Reeves et al. (2005) operationalization of the criteria which the number satisfying how they operationalized the Fukuda et al. criteria was considering less(1,2).

These (Reeves) criteria greatly increased the prevalence of CFS. The "empirical" definition gives a prevalence rate of 2.54% of the adult population(3) compared to 0.235% (95% confidence interval, 0.142%-0.327%) and 0.422% (95% confidence interval, 0.29%-0.56%) when the Fukuda definition was used in previous population studies in the US(4,5).

The definition lacks specificity. For example, one research study(6) found that 38% of those with a diagnosis of a Major Depressive Disorder were misclassified as having CFS using the empirical/Reeves definition. A letter of mine discussed my concerns in more detail(7).

Due to the problems with the criteria, these criteria have not been used by researchers outside those contracted to analyse CDC data (apart from Leonard Jason's research team who studied it and showed problems with it (6)).

References:

1 Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic fatigue syndrome – a clinically empirical approach to its definition and study. BMC Med. 2005;3:19.

2 Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome; a comprehensive approach to its definition and study. Ann Int Med 1994, 121:953-959.

3 Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, Morrissey M, Devlin R. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr. 2007 Jun 8;5:5.

4 Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC: Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Int Med 2003, 163:1530-1536.

5 Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang CF, Plioplys S. A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999 Oct 11;159(18):2129-37.

6 Jason, LA, Najar N, Porter N, Reh C. Evaluating the Centers for Disease Control's empirical chronic fatigue syndrome case definition. Journal of Disability Policy Studies 2008, doi:10.1177/1044207308325995.

7 Kindlon T. Criteria used to define chronic fatigue syndrome questioned. Psychosom Med. 2010 Jun;72(5):506-7

On 2015 Aug 12, Tom Kindlon commented:

This study uses the (so-called) empiric CFS criteria (Reeves et al., 2005)

This study used the Reeves et al. (2005) criteria(1) for defining Chronic Fatigue Syndrome (CFS) (sometimes described by the CDC as an operationalization of the Fukuda et al. (1994) criteria (2)).

These (Reeves) criteria greatly increased the prevalence of CFS. The "empirical" definition gives a prevalence rate of 2.54% of the adult population(3) compared to 0.235% (95% confidence interval, 0.142%-0.327%) and 0.422% (95% confidence interval, 0.29%-0.56%) when the Fukuda definition was used in previous population studies in the US(4,5).

The definition lacks specificity. For example, one research study(6) found that 38% of those with a diagnosis of a Major Depressive Disorder were misclassified as having CFS using the empirical/Reeves definition. A letter of mine discussed my concerns in more detail(7).

Due to the problems with the criteria, these criteria have not been used by researchers outside those contracted to analyse CDC data (apart from Leonard Jason's research team who studied it and showed problems with it (6)).

References:

1 Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic fatigue syndrome – a clinically empirical approach to its definition and study. BMC Med. 2005;3:19.

2 Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome; a comprehensive approach to its definition and study. Ann Int Med 1994, 121:953-959.

3 Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, Morrissey M, Devlin R. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr. 2007 Jun 8;5:5.

4 Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC: Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Int Med 2003, 163:1530-1536.

5 Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang CF, Plioplys S. A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999 Oct 11;159(18):2129-37.

6 Jason, LA, Najar N, Porter N, Reh C. Evaluating the Centers for Disease Control's empirical chronic fatigue syndrome case definition. Journal of Disability Policy Studies 2008, doi:10.1177/1044207308325995.

7 Kindlon T. Criteria used to define chronic fatigue syndrome questioned. Psychosom Med. 2010 Jun;72(5):506-7

On 2013 Oct 31, John Cannell commented:

The authors stated that markers of oxidative stress are present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take

On 2013 Oct 31, John Cannell commented:

The authors found markers oxidative stress is present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take the Ameri

On 2013 Oct 31, John Cannell commented:

The authors found markers oxidative stress is present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take the Ameri

On 2017 Aug 15, Andrea Messori commented:

Pearl-I trial: incremental benefit between patients treated with ulipristal 5 mg/day and those receiving placebo

Andrea Messori, HTA Unit, Regional Health Service, 50100 Firenze, Italy

In the Pearl-I trial [1], women with symptomatic fibroids, excessive uterine bleeding (PBAC score>100) and anemia were randomized to receive oral ulipristal (dose: 5 mg/day for 13 weeks) or placebo (48 women). A third arm received 10 mg/day of ulipristal. In the comparison between ulipristal 5 mg/day and placebo, the end point of controlled uterine bleeding (PBAC score<75) was achieved by 91% of the patients in the treatment group vs 19% in the controls receiving placebo. Figure 2 (Panel A) of the article by Donnez et al.[1] shows the time-to-event curve for treated patients and controls. Nagy et al.[2] have estimated that the value of utility is around 0.83 for patients with mild-to-moderate bleeding vs 0.72 for patients with severe bleeding (see Table 3 of Nagy’s article). We have carried out an analysis of the results of the Pearl-I trial in order to estimate the magnitude of the incremental benefit between patients treated with ulipristal 5 mg/day and those receiving placebo by expressing this benefit in quality-adjusted life years (QALYs). For this purpose, we employed a statistical tool (WebPlotDigitizer program) with which we analyzed the time-to-event curves reported in Figure 2 Panel A of the Pearl-I trial (time interval: from 0 to 100 days). As regards the ulipristal group, this statistical program estimated an average of 77.38 days per patient after achievement of the end-point vs 22.62 days per patient without achievement of the end-point. Likewise, in the control group there were on average 13.30 days per patient after achievement of the end-point vs 86.70 days per patient without achievement of the end-point. Using the two values of utility previously mentioned, these figures generated the following estimates of quality-adjusted survival: 80.51 quality adjusted days per patient in the treatment group (i.e. 0.22058 QALYs) and 73.46 quality adjusted days per patient in the control group (i.e. 0.20127 QALYs). The difference between these two QALY values yields 0.01931 QALYs per patient (around 7 quality-adjusted days per patient), which represents the incremental benefit between patients treated with ulipristal 5 mg/day and those receiving placebo.

References

[1] Donnez J, Tatarchuk TF, Bouchard P, Puscasiu L, Zakharenko NF, Ivanova T, Ugocsai G, Mara M, Jilla MP, Bestel E, Terrill P, Osterloh I, Loumaye E; PEARL I Study Group. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med. 2012 Feb 2;366(5):409-20.

[2] Nagy B, Timár G, Józwiak-Hagymásy J, Kovács G, Merész G, Vámossy I, Ágh T, László Á, Vokó Z, Kaló Z. The cost-effectiveness of ulipristal acetate tablets in treating patients with moderate to severe symptoms of uterine fibroids. Eur J Obstet Gynecol Reprod Biol. 2014 Apr;175:75-81.

[3] Rohatgi A. WebPlotDigitizer, Version: 3.12, Austin, Texas, available at http://arohatgi.info/WebPlotDigitizer, last accessed 15 August 2017

On 2015 Sep 17, Tom Kindlon commented:

This study uses the (so-called) empiric CFS criteria (Reeves et al., 2005)

This study used the Reeves et al. (2005) criteria(1) for defining Chronic Fatigue Syndrome (CFS) (sometimes described by the CDC as an operationalization of the Fukuda et al. (1994) criteria (2)).

These (Reeves) criteria greatly increased the prevalence of CFS. The "empirical" definition gives a prevalence rate of 2.54% of the adult population(3) compared to 0.235% (95% confidence interval, 0.142%-0.327%) and 0.422% (95% confidence interval, 0.29%-0.56%) when the Fukuda definition was used in previous population studies in the US(4,5).

The definition lacks specificity. For example, one research study(6) found that 38% of those with a diagnosis of a Major Depressive Disorder were misclassified as having CFS using the empirical/Reeves definition. A letter of mine discussed my concerns in more detail(7).

Due to the problems with the criteria, these criteria have not been used by researchers outside those contracted to analyse CDC data (apart from Leonard Jason's research team who studied it and showed problems with it (6)).

References:

1 Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic fatigue syndrome – a clinically empirical approach to its definition and study. BMC Med. 2005;3:19.

2 Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome; a comprehensive approach to its definition and study. Ann Int Med 1994, 121:953-959.

3 Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, Morrissey M, Devlin R. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr. 2007 Jun 8;5:5.

4 Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC: Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Int Med 2003, 163:1530-1536.

5 Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang CF, Plioplys S. A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999 Oct 11;159(18):2129-37.

6 Jason, LA, Najar N, Porter N, Reh C. Evaluating the Centers for Disease Control's empirical chronic fatigue syndrome case definition. Journal of Disability Policy Studies 2008, doi:10.1177/1044207308325995.

7 Kindlon T. Criteria used to define chronic fatigue syndrome questioned. Psychosom Med. 2010 Jun;72(5):506-7

On 2013 Oct 29, Tom Kindlon commented:

Findings may be relevant for some patients diagnosed with myalgic encephalomyelitis or chronic fatigue syndrome

I would like to thank the authors for taking the time to write up this case report, as well as thanking the patient for giving permission for the use of her story.

I thought it was worth pointing out that the symptoms described by the authors and the patient would be quite similar to the symptoms patients with myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) would report.^1-7 I don't believe patients with an ME or CFS diagnosis are often assessed for a mitochondrial myopathy using the tests mentioned although a novel test did find evidence for mitochondrial dysfunction.⁸ At least two studies have found carnitine supplementation to be of benefit in patients diagnosed with CFS.^9,10

Excessive acidosis on exercise has been found in patients.^11,12 One study, looking for an association with enterovirus infection, found that 58% of CFS patients had an abnormal lactate response to subanaerobic threshold exercise test.¹³

CFS is increasingly recoognized as being heterogeneous.¹⁴ Despite its name, more symptoms than fatigue are generally associated with it.¹⁵ Mitochondrial problems could relevant for some patients even if they may not be relevant for all patients.

References:

(1) Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: A comprehensive approach to its definition and study. Annals of Internal Medicine. 1994;121:953-959.

(2) Sharpe MC, Archard LC, Banatvala JE, et al. A report--chronic fatigue syndrome: guidelines for research. J R Soc Med. 1991 Feb;84(2):118-21.

(3) Carruthers B, Jain A, de Meirleir K, Peterson D, Klimas N, Lemer A, et al.: Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. J Chronic Fatigue Syndrome 2003;11(1):7-33

(4) Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med. 1988 Mar;108(3):387-9.

(5) Jason LA, Evans M, Porter N, et al. The development of a revised Canadian Myalgic Encephalomyelitis-Chronic Fatigue Syndrome case definition. American Journal of Biochemistry and Biotechnology. 2010:6;120–135. Retrieved from http://www.scipub.org/fulltext/ajbb/ajbb62120-135.pdf

(6) Carruthers BM, van de Sande MI, De Meirleir KL, et al. Myalgic Encephalomyelitis: International Consensus Criteria. J Intern Med. 2011 Jul 20. doi: 10.1111/j.1365- 2796.2011.02428.x. [Epub ahead of print]

(7) Goudsmit EM, Shepherd C, Dancey CP, Howes S. ME: Chronic fatigue syndrome or a distinct clinical entity? Health Psychology Update, 2009, 18, 1, 26-33.

(8) Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med. 2009;2(1):1-16. Epub 2009 Jan 15.

(9) Vermeulen RC, Scholte HR. Exploratory open label, randomized study of acetyl- and propionylcarnitine in chronic fatigue syndrome. Psychosom Med. 2004 Mar-Apr;66(2):276-82.

(10) Plioplys AV, Plioplys S. Amantadine and L-carnitine treatment of Chronic Fatigue Syndrome. Neuropsychobiology. 1997;35(1):16-23.

(11) Arnold DL, Bore PJ, Radda GK, Styles P, Taylor DJ. Excessive intracellular acidosis of skeletal muscle on exercise in a patient with a post-viral exhaustion/fatigue syndrome. A 31P nuclear magnetic resonance study. Lancet. 1984 Jun 23;1(8391):1367-9.

(12) Jones DE, Hollingsworth KG, Jakovljevic DG, Fattakhova G, Pairman J, Blamire AM, Trenell MI, Newton JL. Loss of capacity to recover from acidosis on repeat exercise in chronic fatigue syndrome: a case-control study. Eur J Clin Invest. 2012 Feb;42(2):186-94.

(13) Lane RJ, Soteriou BA, Zhang H, Archard LC. Enterovirus related metabolic myopathy: a postviral fatigue syndrome. J Neurol Neurosurg Psychiatry. 2003 Oct;74(10):1382-6.

(14) Jason, L.A., Corradi, K., Torres-Harding, S., Tay

On 2013 Oct 31, John Cannell commented:

The authors stated that markers of oxidative stress are present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take

On 2013 Oct 31, John Cannell commented:

The authors stated that markers of oxidative stress are present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take

On 2013 Oct 31, John Cannell commented:

The authors found markers oxidative stress is present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take the Ameri

On 2013 Dec 19, Raphael Stricker commented:

Clinical Evidence for Rapid Transmission of Lyme Disease Following a Tickbite: Response to Binnicker et al.

Raphael B. Stricker, MD,* Eleanor D. Hynote, MD,* and Phyllis C. Mervine, EdM.*

*International Lyme and Associated Diseases Society, P.O. Box 341461, Bethesda, MD 20827-1461. www.ILADS.org

Binnicker et al. dispute the clinical diagnosis of Lyme disease in our patients based on three factors: (1) a “physician-diagnosed target lesion” was not present at the site of the tickbite; (2) although an IgM antibody response was present, conversion to an IgG response was not documented; and (3) recovery of Borrelia burgdorferi, the spirochetal agent of Lyme disease, was not demonstrated by culture or molecular techniques.

First, it is important to recall that Lyme disease is a clinical diagnosis according to the Centers for Disease Control and Prevention (CDC), which states that “general symptoms” such as fatigue, chills, fever, headache, muscle and joint aches, and swollen lymph nodes “may be the only evidence of infection” in early Lyme disease (CDC, 2012). In addition, the erythema migrans (EM) rash manifests as a “target lesion” in only 9% of cases (Stonehouse et al, 2010), may take up to 30 days to develop (CDC, 2012) and may be completely absent in up to 50% of patients with Lyme disease, as it was in our three patients (Steinberg et al, 1996; Stricker et al, 2006; Kudish et al, 2007). Second, in the setting of a tickbite and clinical symptoms of acute Lyme disease, the prompt administration of antibiotics may abort the typical serological response, as acknowledged by Binnicker et al. and others (Dattwyler et al. 1988; Aguero-Rosenfeld et al, 1996). Few studies have evaluated the serological evolution in Lyme disease patients treated as promptly as ours were (see below). Third, culture and molecular testing is highly insensitive in blood samples and even in tissue or synovial fluid from Lyme disease patients (Coulter et al, 2005; Stricker, 2007; Babady et al, 2008). Thus from a symptom-based and serological perspective, our patients met the CDC case definition of acute Lyme disease even in the absence of a target-shaped EM rash and insensitive laboratory procedures.

Binnicker et al. also mention the CDC “recommendation” that Lyme serology should be performed using a two-tier algorithm. This serological analysis involves a screening enzyme immunoassay or immunofluorescence assay and confirmatory Western blot performed with kits approved by the Food and Drug Administration (FDA) for commercial sale. However the CDC states that this algorithm was developed “for the purposes of surveillance” and was not intended for diagnosis of Lyme disease (CDC, 2011). Furthermore, the FDA-approved commercial two-tier test system has a sensitivity of only 46% and yields results that appear to be biased against women (Binnicker et al, 2008; Stricker and Johnson, 2011). Our patients were tested using a “gender neutral” system that has a sensitivity and specificity of >90% (Shah et al, 2010). Thus our patients had laboratory evaluation that was appropriate for the diagnosis of Lyme disease.

Our report confirms studies in both animals and humans that document transmission of Lyme disease within 24 hours of a tickbite (Piesman et al, 1987; Patmas and Remorca, 1994; Strle et al, 1996a, 1996b; Angelov, 1996; Sood et al, 1997). When animal and human studies produce apparently conflicting results, the contradictory findings should be given serious consideration, even if they contravene existing clinical dogma.

References

1. Aguero-Rosenfeld ME, Nowakowski J, Bittker S, Cooper D, Nadelman RB, Wormser GP. Evolution of the serologic response to Borrelia burgdorferi in treated patients with culture-confirmed erythema migrans. J Clin Microbiol. 1996;34:1-9.
2. Angelov L. Unusual features in the epidemiology of Lyme borreliosis. Eur J Epidemiol. 1996;12:9-11.
3. Babady NE, Sloan LM, Vetter EA, Patel R, Binnicker MJ. Percent positive rate of Lyme real-time polymerase chain reaction in blood, cerebrospinal fluid, synovial fluid, and tissue. Diagn Microbiol Infect Dis. 2008 ;62:464-6.
4. Binnicker MJ, Jespersen DJ, Harring JA, Rollins LO, Bryant SC, Beito EM. Evaluation of two commercial systems for automated processing, reading, and interpretation of Lyme borreliosis Western blots. J Clin Microbiol. 2008;46:2216-21.
5. Binnicker MJ, Theel ES, Pritt BS. Lack of evidence for rapid transmission of Lyme disease following a tick bite. Diagn Microbiol Infect Dis. 2012;73:102-3.
6. Centers for Disease Control and Prevention (CDC, 2011). Lyme disease (Borrelia burgdorferi) 2011 case definition. Available at http://wwwn.cdc.gov/NNDSS/script/casedef.aspx?CondYrID=752&DatePub=1/1/2011 12:00:00 AM. Accessed December 4, 2013.
7. Centers for Disease Control and Prevention (CDC, 2012). Signs and symptoms of Lyme disease. Available at http://www.cdc.gov/lyme/signs_symptoms/index.html. Accessed December 4, 2013.
8. Coulter P, Lema C, Flayhart D, Linhardt AS, Aucott JN, Auwaerter PG, Dumler JS. Two-year evaluation of Borrelia burgdorferi culture and supplemental tests for definitive diagnosis of Lyme disease. J Clin Microbiol. 2005;43:5080-4.
9. Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG. Seronegative Lyme disease. Dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi. N Engl J Med. 1988;319:1441-6.
10. Hynote ED, Mervine PC, Stricker RB. Clinical evidence for rapid transmission of Lyme disease following a tickbite. Diagn Microbiol Infect Dis. 2012;72:188-92.
11. Kudish K, Sleavin W, Hathcock L. Lyme disease trends: Delaware, 2000 - 2004. Del Med J. 2007;79:51-8.
12. Patmas MA, Remorca C. Disseminated Lyme disease after short-duration tick bite. J Spiro Tick Dis. 1994;1:77-78.
13. Piesman J, Mather TN, Sinsky RJ, Spielman A. Duration of tick attachment and Borrelia burgdorferi transmission. J Clin Microbiol. 1987;25:557-8.
14. Shah JS, Du Cruz I., Narciso W, Lo W, Harris NS. Improved clinical sensitivity for detection of antibodies to Borrelia burgdorferi by Western blots prepared from a mixture of two strains of B. burgdorferi, 297 and B31, and interpreted by in-house criteria. European Infect Dis. 2010;4:56–60.
15. Sood SK, Salzman MB, Johnson BJ, Happ CM, Feig K, Carmody L, Rubin LG, Hilton E, Piesman J. Duration of tick attachment as a predictor of the risk of Lyme disease in an area in which Lyme disease is endemic. J Infect Dis. 1997;175:996-9.
16. Steinberg SH, Strickland GT, Pena C, Israel E. Lyme disease surveillance in Maryland, 1992. Ann Epidemiol. 1996;6:24-9.
17. Stonehouse A, Studdiford JS, Henry CA. An update on the diagnosis and treatment of early Lyme disease: "focusing on the bull's eye, you may miss the mark". J Emerg Med. 2010;39:e147-51.
18. Stricker RB, Lautin A, Burrascano JJ. Lyme disease: the quest for magic bullets. Chemotherapy. 2006;52:53-9.
19. Stricker RB. Counterpoint: long-term antibiotic therapy improves persistent symptoms associated with lyme disease. Clin Infect Dis. 2007;45:149-57.
20. Stricker RB, Johnson L. The pain of chronic Lyme disease: moving the discourse backward? FASEB J. 2011;25:4085-7.
21. Stricker RB, Hynote ED, Mervine PC. Clinical evidence for rapid transmission of Lyme disease following a tickbite: response to Piesman and Gray. Diagn Microbiol Infect Dis. 2012;73:104-5.
22. Strle F, Nelson JA, Ruzic-Sabljic E, Cimperman J, Maraspin V, Lotric-Furlan S, Cheng Y, Picken MM, Trenholme GM, Picken RN. European Lyme borreliosis: 231 culture-confirmed cases involving patients with erythema migrans. Clin Infect Dis. 1996a;23:61-5.
23. Strle F, Maraspin V, Furlan-Lotric S, Cimperman J. Epidemiological study of a cohort of adult patients with Erythema migrans registered in Slovenia in 1993. Eur J Epidemiol. 1996b ;12:503-7.

On 2013 Oct 31, John Cannell commented:

The authors stated that markers of oxidative stress are present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take

On 2017 Aug 22, Raphael Stricker commented:

Another LYMErix Whitewash.

Raphael B. Stricker, MD

Union Square Medical Associates, San Francisco, CA, USA. rstricker@usmamed.com

The Aronowitz article presents an unsatisfactory analysis of the LYMErix vaccine debacle. The spin in the article is a classic example of blaming the victims for their misfortune while ignoring the problems leading to that misfortune.

The spin in the article is that the science underlying the LYMErix vaccine was sound and beyond question, that the vaccine was proven to be safe beyond a shadow of a doubt, and that the antiscience lobbying of misguided Lyme activists brought down the vaccine. Considering that the LYMErix vaccine was the object of a class-action lawsuit brought by patients who claimed to have been harmed by the vaccine (1), and in view of the safety concerns described below, the article spin is impossible to defend.

The premise of the article is that the LYMErix vaccine was proven to be safe. This ignores substantial reports of LYMErix-induced patient harm in the peer-reviewed medical literature (2-6), and studies using animal models and in vitro systems support these safety concerns (7,8). The vaccine-induced rheumatological and neurological complications are what alarmed the Lyme community and ultimately led to rejection of the vaccine as unsafe. An intriguing and disturbing scientific aspect of the LYMErix vaccine is that, although it was made from a subunit protein, the vaccine elicited all manner of immune responses in vaccinees, and these remain unexplained (9,10). Thus there was significant clinical and laboratory evidence underlying doubts about the safety of this ill-fated vaccine.

Another curious spin is that the author blames Lyme activists for spreading fear about the vaccine that ultimately diminished its use and prevented an adequate assessment of its clinical value. In reality, the vaccine was pulled off the market to avoid disclosure of Phase IV data that would have shown limited efficacy and significant safety concerns related to LYMErix (11-13).

Aronowitz divides the Lyme universe into "orthodox" and "heterodox" camps. The "orthodox" camp defines Lyme disease in a narrow fashion that excludes various clinical manifestations and chronic forms of the disease despite growing evidence to the contrary (14). Thus a patient who develops fibromyalgia or fatigue symptoms after receiving the Lyme vaccine would not have complications related to the vaccine because fibromyalgia and fatigue are separate entities unrelated to Lyme disease. This narrow definition serves to enhance the benefit of the vaccine (ie, no Lyme symptoms) while dismissing potential complications of the vaccine (ie, fibromyalgia and fatigue are separate and unrelated problems). It is easy to see why the Lyme community would be reluctant to go along with this selective view of the vaccine.

In contrast, Aronowitz defines the "heterodox" camp as having a broad view of Lyme disease that requires prolonged treatment with antibiotics rather than any attempt to prevent the disease. The implication that this patient group is opposed to a Lyme vaccine because its members are invested in being chronically ill and taking prolonged courses of antibiotics strains credibility. The recognition that numerous patients fail the "orthodox" approach to Lyme disease and remain chronically ill is what drives these patients to seek better treatment, and certainly a vaccine that is safe and effective would be welcome (15). Unfortunately as outlined above, LYMErix was not it.

References 1. LDA website: Vaccine lawsuit. Available at: https://www.lymediseaseassociation.org/about-lyme/controversy/vaccine/1157-vaccine-suit-lda-ltr-a-judgement. Accessed July 22, 2017. 2. Rose et al, J Rheumatol. 2001;28:2555-7. 3. Latov et al, Periph Nerv Syst. 2004;9:165-7. 4. Souayah et al, Vaccine 2009;27:7322-5. 5. Nardelli et al, Future Microbiol. 2009;4:457-69. 6. Marks DH, Int J Risk Saf Med. 2011;23:89-96. 7. Croke et al, Infect Immun. 2000;68:658-63. 8. Alaedini & Latov, J Neuroimmunol. 2005;159:192-5. 9. Molloy et al, Clin Infect Dis. 2000;31:42-7. 10. Fawcett et al, Clin Diagn Lab Immunol. 2001;8:79-84. 11. Hanson & Edelman, Expert Rev Vaccines 2003;2:683-703. 11. Nigrovic & Thompson, Epidemiol Infect. 2007;135:1-8. 13. LDA website: LYMERIX Meeting; LDA Meets with FDA. Available at https://www.lymediseaseassociation.org/about-lyme/controversy/vaccine/261-lymerix-meeting. Accessed July 22, 2017. 14. Stricker RB, Fesler MC. Chronic Dis Int 2017;4:1025. 15. Stricker RB, Johnson L. Lancet Infect Dis 2014;14:12.

Disclosure: RBS is a member of the International Lyme and Associated Diseases Society (ILADS) and a director of LymeDisease.org. He has no financial or other conflicts to declare.

On 2013 Dec 20, Raphael Stricker commented:

Clinical Evidence for Rapid Transmission of Lyme Disease Following a Tickbite: Response to Sugar.

Raphael B. Stricker, MD,* Eleanor D. Hynote, MD,* and Phyllis C. Mervine, EdM.*

*International Lyme and Associated Diseases Society, P.O. Box 341461, Bethesda, MD 20827-1461. www.ILADS.org

Sugar complains about the lack of seroconvesion from IgM to IgG in our promptly treated patients, but then acknowledges that the IgM response may be persistent, as seen in our patient with acute Lyme disease and Babesia duncani coinfection. Although the IgM response may persist for long periods in some patients with Lyme disease (Craft et al, 1986; Aguero-Rosenfeld et al, 1996; Kalish et al, 2001; Porwancher et al, 2011), reversion to seronegative status has been associated with response to treatment in other patients with acute infection (Engstrom et al, 1995; Trevejo et al, 1999). Contrary to the statement by Sugar, serological testing appears to have adequate sensitivity and specificity to establish a diagnosis of Babesia infection (Abrams, 2008; Prince et al, 2010). Thus the clinical and laboratory features of our cases comply with standards for the diagnosis of tickborne diseases.

Our report confirms studies in both animals and humans that document transmission of Lyme disease within 24 hours of a tickbite (Piesman et al, 1987; Patmas and Remorca, 1994; Strle et al, 1996a, 1996b; Angelov, 1996; Sood et al, 1997). When animal and human studies produce apparently conflicting results, the contradictory findings should be given serious consideration, even if they contravene existing clinical dogma.

References

1. Abrams Y. Complications of coinfection with Babesia and Lyme disease after splenectomy. J Am Board Fam Med. 2008;21:75-7.
2. Aguero-Rosenfeld ME, Nowakowski J, Bittker S, Cooper D, Nadelman RB, Wormser GP. Evolution of the serologic response to Borrelia burgdorferi in treated patients with culture-confirmed erythema migrans. J Clin Microbiol. 1996;34:1-9.
3. Angelov L. Unusual features in the epidemiology of Lyme borreliosis. Eur J Epidemiol. 1996;12:9-11.
4. Craft JE, Fischer DK, Shimamoto GT, Steere AC. Antigens of Borrelia burgdorferi recognized during Lyme disease. Appearance of a new immunoglobulin M response and expansion of the immunoglobulin G response late in the illness. J Clin Invest. 1986;78:934-9.
5. Engstrom SM, Shoop E, Johnson RC. Immunoblot interpretation criteria for serodiagnosis of early Lyme disease. J Clin Microbiol. 1995;33:419-27.
6. Hynote ED, Mervine PC, Stricker RB. Clinical evidence for rapid transmission of Lyme disease following a tickbite. Diagn Microbiol Infect Dis. 2012;72:188-92.
7. Kalish RA, McHugh G, Granquist J, Shea B, Ruthazer R, Steere AC. Persistence of immunoglobulin M or immunoglobulin G antibody responses to Borrelia burgdorferi 10–20 years after active Lyme disease. Clin Infect Dis 2001;33:780–5.
8. Patmas MA, Remorca C. Disseminated Lyme disease after short-duration tick bite. J Spiro Tick Dis. 1994;1:77-78.
9. Piesman J, Mather TN, Sinsky RJ, Spielman A. Duration of tick attachment and Borrelia burgdorferi transmission. J Clin Microbiol. 1987;25:557-8.
10. Porwancher RB, Hagerty CG, Fan J, Landsberg L, Johnson BJ, Kopnitsky M, Steere AC, Kulas K, Wong SJ. Multiplex immunoassay for Lyme disease using VlsE1-IgG and pepC10-IgM antibodies: improving test performance through bioinformatics. Clin Vaccine Immunol. 2011;18:851-9.
11. Prince HE, Lapé-Nixon M, Patel H, Yeh C. Comparison of the Babesia duncani (WA1) IgG detection rates among clinical sera submitted to a reference laboratory for WA1 IgG testing and blood donor specimens from diverse geographic areas of the United States. Clin Vaccine Immunol. 2010;17:1729-33.
12. Sood SK, Salzman MB, Johnson BJ, Happ CM, Feig K, Carmody L, Rubin LG, Hilton E, Piesman J. Duration of tick attachment as a predictor of the risk of Lyme disease in an area in which Lyme disease is endemic. J Infect Dis. 1997;175:996-9.
13. Stricker RB, Hynote ED, Mervine PC. Clinical evidence for rapid transmission of Lyme disease following a tickbite: response to Piesman and Gray. Diagn Microbiol Infect Dis. 2012;73:104-5.
14. Strle F, Nelson JA, Ruzic-Sabljic E, Cimperman J, Maraspin V, Lotric-Furlan S, Cheng Y, Picken MM, Trenholme GM, Picken RN. European Lyme borreliosis: 231 culture-confirmed cases involving patients with erythema migrans. Clin Infect Dis. 1996a;23:61-5.
15. Strle F, Maraspin V, Furlan-Lotric S, Cimperman J. Epidemiological study of a cohort of adult patients with Erythema migrans registered in Slovenia in 1993. Eur J Epidemiol. 1996b ;12:503-7.
16. Trevejo RT, Krause PJ, Sikand VK, Schriefer ME, Ryan R, Lepore T, Porter W, Dennis DT. Evaluation of two-test serodiagnostic method for early Lyme disease in clinical practice. J Infect Dis. 1999;179:931-8.

Disclosure: RBS is a member of the International Lyme and Associated Diseases Society (ILADS) and a director of LymeDisease.org. He has no financial or other conflicts to declare.

On 2016 Apr 18, PAMELA RONALD commented:

Following the publication of this Article, we discovered that Xanthomonas oryzae pv. oryzae (Xoo) lacking the peptide Ax21 is still able to trigger XA21-mediated immunity^1. Furthermore, we were unable to consistently reproduce experiments demonstrating that synthetic AxYS22 triggers XA21-mediated immunity^2,3,4.

In light of these results, we repeated the experiments reported in this Article. We found that neither AxYS22 nor Xoo enhance accumulation of the XA21-GFP protein beyond that observed following mock treatment. Shredding of leaf tissue (mock), with or without treatment, induces higher levels of XA21-GFP protein and correspondingly higher levels of the cleavage product as compared with the unshredded control. The presence of higher levels of cleavage product after wounding or Xoo treatment facilitates detection. Based on these results, we can no longer ascribe a role for Xoo or AxYs22 in XA21-GFP cleavage.

These findings do not alter the main conclusion of this Article that XA21-GFP is cleaved and translocates to the nucleus of protoplasts when transiently overexpressed and that the putative nuclear localization sequence (NLS) is required for localization. We are currently investigating the in vivo biological relevance of the putative NLS in the rice immune response. This notice of correction was first submitted to the editors April 7, 2014.

1. Bahar, O. P., Pruitt, R., Luu, D. D., Schwessinger, B., Daudi, A., Liu, F., Ruan, R., Fontaine-Bodin, L., Koebnik, R. & Ronald, P. C. The Xanthomonas Ax21 protein is processed by the general secretory system and is secreted in association with outer membrane vesicles. PeerJ 2, e242 (2014).
2. Lee, S. W., Han, S. W., Sririyanum, M., Park, C. J., Seo, Y. S. & Ronald, P. C. A type I-secreted, sulfated peptide triggers XA21-mediated innate immunity. Science 326, 850–853 (2009).
3. Lee S. W., Han S. W., Sririyanum M., Park C. J., Seo Y. S. & Ronald P. C. Retraction. Science 342, 191 (2013).
4. Ronald P. C. 2013. Lab Life: The Anatomy of a Retraction, Scientific American. October 10, 2013. http://blogs.scientificamerican.com/food-matters/2013/10/10/lab-life-the-anatomy-of-a-retraction/

On 2013 Oct 31, John Cannell commented:

The authors stated that markers of oxidative stress are present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take

On 2013 Oct 31, John Cannell commented:

The authors stated that markers of oxidative stress are present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014