On 2013 Jun 13, Robert Tibshirani commented:

This paper came about by happenstance. Prof Gil Chu and his bright young grad student Virginia Goss contacted me, and asked my advice on how to analyse their data measured on this new technology called "microarrays". I had never heard of microarrays, and together we formulated a simple approach based in t-tests and FDR, estimated by permutations. My colleague Narasimhan Balasubramanian and I built some software--- an Excel-addin called SAM (Significance Analysis of Microarrays). [Trevor Hastie suggested the convenient Excel interface.) SAM became popular at Stanford and around the world. This paper, although simple in its ideas, has become one of my most cited papers.

On 2013 Jun 18, Jill Barnholz-Sloan commented:

This paper proposes a computationally simple approach for adjustment for potential population stratification bias in case control studies. Genomic control and structured association methods, such as STRUCTURE, are widely used to test for and adjust for potential population stratification bias. Genomic control has been compared and contrasted with STRUCTURE (http://www.ncbi.nlm.nih.gov/pubmed/18852890)

On 2013 Jul 10, Matthew Stephens commented:

I'm interested in whether anyone has explored connections between the ideas here, and the "empirical null" ideas of Efron (eg Large-scale simultaneous hypothesis testing: the choice of a null hypothesis, JASA 2004) http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.179.2729

It seems the two have a similar goal - here one of the ideas (and probably the one that has most influence in practice, since it is now widely used) is to use the median of the test statistics to estimate an inflation factor (lambda). Efron also uses the test statistics near the center of the empirical distribution to do a similar thing, but in a different way. It might be interesting to compare the two approaches.

On 2017 Oct 24, Tamás Ferenci commented:

Weisser K, 2017 provides a reimplementation of the model presented in this paper using more standard notation.

On 2017 May 23, Morten Oksvold commented:

This article was retracted April 27 2017 together with eight other articles from the same group due to data manipulations.

Please note that the retraction notice is visible in the PDF document only

http://www.jbc.org/content/276/27/24490.full.pdf?sid=192794b9-fa3c-402f-b9d0-e2643b9c92ae

"This article has been withdrawn by the authors. One cell from the 12-h, -TPA panel was duplicated in the 6-h, +TPA panel in Fig. 1A. The 12-h, -TPA panel from Fig. 1A was duplicated in the ERK2, +TPA panel from Fig. 5. Also in Fig. 5, the cells shown in the ALC, -TPA panel were duplicated. The phosphorylated MBP panel from Fig. 4 was inappropriately manipulated. In Fig. 9, the ALC, -TPA and the 183A, +TPA panels were inappropriately manipulated. Because the original data are no longer available, in the interest of maintaining accuracy in the published scientific literature, the authors wish to withdraw this article. However, the authors have full confidence in the findings and conclusions of this paper."

On 2016 May 18, Lydia Maniatis commented:

This highly-cited article is celebrated as seminal, pioneering, influential. (See for example Bauer, 2015). In contrast, I find the arguments facile, incomplete, and inadequate to support a bold but very vague and seemingly implausible proposal. I'll deal with separate issues in separate comments here, beginning with the one that is easiest for me to make. It deals with the second to last section of the paper, titled "Visual Contrast Illusions and Set Representations." The style of argument of this section is a good illustration of the casualness of the authors arguments in general.

Here's my comment:

Ariely argues that the Ebbinghaus illusion is amenable to explanation in terms of “set representation.” Specifically, he says that the circle surrounded by large circles appears smaller than the one surrounded by small circles because each is “judged relative to the set properties of the circles surrounding it. If the basic representation of a set contains the relationship of an object to the mean of its set, it follows that the [former] will be judged smaller than the [latter].”

Assuming that what applies to the central circle applies to every circle, Ariely is saying that the “basic representation of a set” includes, in its composition, the relationship of each object to the mean of the set. That means five sub-representations in addition to the representation of the mean size of the set and of each individual member (adjusted for set mean). And since he also suggests that mean representations are created for other features as well, e.g. color, shape, we would have to add these to the hypothetical representations. (If efficiency of representation is the goal, this does not seem to fit the bill.)

Ariely even presents a kind of test of his claim by citing a study that showed that when the central circles are surrounded by triangles, the effect is attenuated. This is no where near good enough. Many logical and empirical falsifications of his thesis are close to hand.

Ariely overlooks the fundamental fact that the Ebbinghaus illusion is contingent on configuration. It should be pretty clear that it would be a trivial project create sets of circles (putting them in a row, for example, and adjusting which is adjacent to which) for which his prediction would fail.

In addition, while he only focusses on size, Ariely does not limit his claims to size. But it is also trivial to show that it doesn't work for, e.g. lightness, color, or shape even to the extent that it might be can be made to appear to work for size. There are countless demonstrations, involving sets of discrete figures, of so-called assimilation effects in which this explanation, involving a “contrast” effect, would fail. And it obviously fails for shape.

So we are dealing with a facile, ad hoc explanation that should at least have been challenged during review, and certainly not have been admitted as a serious argument after the fact.

Finally, it's worth pointing out that the Ebbinghaus effect is evident and robust under leisurely inspection. If the effects Ariely is proposing are this salient, why does he choose to present his multi-item stimuli using only brief presentation times (thus allowing time for only a couple of saccades) and without a blank period before (briefly) presenting the comparison figures (thus incurring possible masking effects)? Why use sub-optimal conditions rather than make his case using longer presentation times and clear and robust perceptual effects such as the Ebbinghaus? Nowhere does he explain his methodological choices.

But the priority is to explain the easy falsifications, otherwise the there is no viable hypothesis.

p.s. More conceptual inconsistencies: In his account of the Ebbinghaus, Ariely is saying that the triangles are not perceived as part of a set including the central circle. Yet a. they do group with it visually, and b. earlier in the article he says that "orientation, aspect ration, mean hue, and shape (however represented" may all be set properties." So why don't we see the circle changing shape, and why does shape difference preclude set affiliation?

On 2016 May 22, Lydia Maniatis commented:

(Second comment) Comment on section titled “The Economy of Set Representations"

Ariely begins this section by saying that: “Although the exquisite sensitivity of the human visual system ...is a source of wonder and delight, a computer can be equally sensitive. Much harder to solve, and currently far beyond the abilities of computer vision systems, is the problem of knowing what information to throw away.” He considers it problematic, therefore, that “in research in spatial vision, the focus has been more on reproducing the image exactly, on compressing the representation without losing information (e.g. Watson, 1987)” and suggests that “”If our models do not lose any of the original data, then no decisions have been made, no information has been extracted.”

These statements are strikingly naive with respect to basic theoretical and empirical facts of perception.

By “the original data” Ariely can only be referring to the photons hitting the retina. If the visual system accurately encoded the intensity of each and every one of these, then the only information it would possess would be the intensity of each and every one of these. If it recorded the relative intensities of each and every one of these, then that would the only information it would possess. Something is missing, and that is the understanding that to be informative, the “original data” must be massively leveraged, organised via complex principles which group, inflate, complete, emphasize or de-emphasize - in general interpret these points to create 3D impressions of shape, light, movement, space. The fundamental problem is not compression but “going beyond the information given.” This is a very old misunderstanding for which there's no longer any excuse, and which should not be recycled, decade after decade. To correct Ariely's statement above, “If our models do not interpret the original data, no information has been created.” The processes Ariely is positing are actually post-organisation, his "original data" are the visual system's perceptual constructs, that are then to be averaged, or whatever. This is not less work, it is more.

Finally, “The reduction of a set of similar items to a mean (or prototypical value), a range, and a few other important statistical properties may preserve just the information needed to navigate in the real world, to form a global percept, and to identify candidate locations of interest.”

Leaving aside the vagueness of the term “set,” the idea that sets of “similar” (how similar?) objects – a set of chairs, a group of kids – is reduced to a group mean and a range defies both experience and logic. The most important units in our environment are objects, not loose collections thereof. We see items, groups of items, but I have never seen a mean of a group of items. The idea that our perception of such groups turns into a random hall of mirrors of sizes, colors, shapes when they are simply near each other...where does that come from?

On 2016 May 22, Lydia Maniatis commented:

(Third comment) Arbitrary methodological choices, data presentation

The title of the paper is “Seeing sets,” and question of interest is said to be “to determine what observers know about the members of a set and what they know about the statistical properties of the set (mean and distribution)” and that “sets of objects could be represented in a qualitatively different way than single items.”

These are quite broad objectives, and don't imply any particular methodology.

The author uses a very specific methodology that places demands on subjects that go beyond straightforward perception, and imposes conditions that compromise straightforward perception.

He uses brief presentation times, 500ms for the first figure and 500s for the comparison figure, with no blank space in between.

This means that there is time for about two saccades and fixations (barely), and involves potential masking effects. How did he choose these parameters? Do they matter? Would we expect the same results with longer presentation times? With a blank interval? Also, the circles increase in size geometrically, not linearly and the mean that we are talking about is the geometric, not the arithmetic mean. Why not a linear progression and an arithmetic mean?

It's been understood for a long time that by adjusting experimental conditions we can get pretty much any result we want, which is why such conditions should come with a theoretical rationale attached. Because the author's choices here seemingly make the task much more difficult than it should be given the goal, they need to be explained, not just flatly asserted.

Another blank check is to be found in a footnote referring to a “small study” which was the basis for selecting/describing one of the parameters in the reported study (“members differed in size from non-members by at least 18%, about three times the size-discrimination threshold for sets of same-size spots [as determined in the “small study”].” In a personal communication, Ariely told me that this study used about ten subjects, and was mostly about studying “within-subject variation.” Such a study could also have given an indication of between-subject variation. Given the link between the two studies, and the oddity of using only two observers (why only two?), some more specific info on results/methods of this "small study" would seems called for.

The presentation of the data is also rather weird. For the mean-discrimination experiment, we aren't given information on the proportions of correct answers the two observers achieved. Maybe this information is hidden in the opaque measure that is provided (and which assumes normality in the data without any justification - isn't that a problem?). This measure is the "mean-discrimination threshold" derived using "a standard profit analysis (Finney, 1971) ...to determine the mean-discrimination threshold (the standard deviation of the best-fitting cumulative normal distribution." Is best-fitting the same thing as "well-fitting"?

Given the method, and assuming that it really is the case that subjects were better at guessing the mean rather than the size of individual members, I could speculate on why that might be. First of all, observers never had to play the "yes-no" game with means (why not?). All they had to do was say "larger-smaller." This seems like an inherently easier task. Further, given the time constraint, there wasn't enough time to inspect each of the four different circle sizes individually. Observers only had time for one or two. So for half of each set, at least, they were out of luck on each trial in the individual member task. For the mean estimation, if they could learn to target the middle two on each trial - not the largest, not the smallest - then they could ballpark the mean. Who knows? The situation is as Runeson (1995) has described for a different type of vision study:

"For perception and cognition research in general, it is noteworthy that the cue-based style of theorising exhibits a certain lack of inherent correctives for ineffectual experiments because of its emphasis on weak and irregular performance. Thus, an experiment that is unsuitable in design or procedure could easily provide supportive-looking data at least as long as cues, salience limits, and trade-off functions are not specified in detail....data that represent suboptimal observer performance seem to have provided spurious support for untenable theoretical commitments,... "

On 2016 May 22, Lydia Maniatis commented:

(Fourth comment) Ariely's claims that his size results (such as they are) can be extended to shape, color, aspect ratio, orientation, are falsifiable. In the simplest case, a set of rectangles that includes one item (not corresponding to the mean) that has an aspect ratio of one will be registered and remembered with precision, biasing the results in favour of the individual items. The mean of the set, on the other hand, would most likely be less precisely registered. Familiar faces in a group will be remembered precisely, their mean, huh? A set of red, white and green objects would be registered, at least categorically with precision, their "mean" probably at all. The shapes in a set of triangles, squares, circles would be remembered precisely; their "mean," not so much.

These may seem like trivial examples, but there is nothing to exclude them from Ariely's broad and vague claims. That this vagueness is used as license to perform an odd and arbitrary experiment whose hugely variable and limited datasets may be favourably (if obscurely) interpreted doesn't let him off the hook.

On 2016 May 22, Lydia Maniatis commented:

(Fifth comment). Some more thoughts: Ariely's main concepts - sets, similarity - are vague. He could have explained what, for the purpose of his claims, he intends them to mean. But he doesn't - they're just placeholders.

What, for Ariely, is a set? He refers to "a collection of items." He challenges the idea that "representations of complex scenes still consist of many individual representations" suggesting instead that in many cases where "proximal items are somewhat similar the representation of a set may contain information about...the average size, color, orientation, aspect ratio, and shape of the items in the set and essentially no information about individual items."

So it would seem that Ariely's working definition of a "set" is a collection of proximal, somewhat similar items (which may differ in pretty much any respect, including shape). So vague - the description "somewhat similar" is absolutely without content - as to be practically useless, and as noted earlier, many or most of the implications are falsifiable. As noted above, even the author's own attempt to explain the alternative Ebbinghaus groups involves a contradiction of that definition.

In my discussion of the arbitrary methodological choices, I didn't mention the main one, which is the decision to use black circles and to focus on size. The reason he gives is that "such sets have the advantage that the members do not fall into distinct categories, as they could if they varied in color, shape, or orientation." So they would be "sets," but variations other than strictly size would be "disadvantageous." In what sense would they be disadvantageous? There's no discussion about this; it seems like an evasion.

Even limiting our discussion to size, we could introduce intractable complications that even Ariely's "novel paradigms" couldn't make fit. What if each circle consisted of a set of concentric circles, variously spaced? Would we construct an average of the envelope, an average of each subset of circles? What if the large group of circles, due to a configurational accident, visually grouped into two or three subsets (as may indeed have happened)? Would we have three different averages, and would these be averaged in turn? Etc.

On 2015 Jun 16, thomas samaras commented:

There's lots of evidence indicating that shorter, lighter people live longer. Throughout most of the world,shorter women live longer than taller men. In animals where the female is larger than the male, the female has a mortality rate. When I compared American males and females, I found that males were 9% taller and had a 9% shorter life expectancy.

Chan, Suzuki and Yamamoto studied Okinawan centenarians and found they were short and lean. Other centenarians studies have found similar results, including those adjusted for shrinkage with age.

In addition, US government mortality data over the entire adult age range found that that Asians had the lowest mortality. Latinos and Native Americans had a higher mortality and Whites and Blacks had the highest mortality. Asians are the shortest ethnic group, followed by Latinos and Native Americans. Blacks and Whites are the tallest.

Recent studies have found shorter people live longer. One was based on 8000 elderly Japanese-Hawaiian males tracked for over 40 years. Another involved men in a small village in Sardinia. The third one was a review of evidence from eight different types of studies. Many more papers are listed in www.humanbodysize.com

The Director of the Aging and Longevity Research Laboratory at the University of Southern Illinois also published a review paper in Gerontology and concluded that smaller body size appears to be best for good health and longevity.

These papers are listed below.

He Q, Morris BJ, Grove JS, Petrovitch H, Ross W, Masaki KH, et al. Shorter men live longer: Association of height with longevity and FOXO3 genotype in American men of Japanese ancestry. Plos ONE 9(5): e94385. doi:10.1371/journal.pone.0094385.

Salaris L, Poulain M, Samaras TT. Height and survival at older ages among men born in an inland village in Sardinia (Italy), 1866-2006. Biodemography and Social Biology, 58:1, 1-13.

Samaras TT. Evidence from eight different types of studies showing that smaller body size is related to greater longevity. Journal of Scientific Research & Reports. 2014: 3 (16): 2150-2160, 2014; article no. JSRR.2014.16.003.

Bartke A. Healthy Aging: Is Smaller better? A mini-review. Gerontology 2012; 58:337-43.

On 2014 Jul 03, Arnaud Chiolero MD PhD commented:

One of the very rare paper of major importance for clinicians, as well as for public health specialists and epidemiologists

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2016 Feb 01, Morten Oksvold commented:

Please note that this article is 1 out of 15 publications for which an independent investigation initiated by the University of Copenhagen has found suspicion of scientific dishonesty. The conclusion from the report was published July 23, 2012:

http://news.ku.dk/all_news/2012/2012.8/indications_of_fraud_in_penkowas_early_research/

This articles should therefore not be cited.

On 2013 Oct 30, Jamie Horder commented:

This 2001 paper was discussed in a 2010 feature in the British Medical Journal Newman M, 2010

"Study 329, a study of 275 adolescents, was one of three clinical trials conducted by SmithKline Beecham (as GSK was then known) in the mid 1990s.

Study 329’s results showed that paroxetine was no more effective than the placebo according to measurements of eight outcomes specified by Martin Keller, professor of psychiatry at Brown University, when he first drew up the trial.

Two of these were primary outcomes: the change in total Hamilton Rating Scale (HAM-D) score, and the proportion of “responders” at the end of the eight week acute treatment phase (those with a ≥50% reduction in HAM-D, or a HAM-D score ≤8). The drug also showed no significant effect for the initial six secondary outcome measures.

The drug only produced a positive result when four new secondary outcome measures, which were introduced following the initial data analysis, were used instead. Fifteen other new secondary outcome measures failed to throw up positive results.

An internal SmithKline Beecham document discussing these results and those of another trial that had failed to show paroxetine’s effectiveness noted that it would be “commercially unacceptable to include a statement that efficacy had not been demonstrated.”

SmithKline Beecham commissioned medical communications company Scientific Therapeutics Information to produce a manuscript. An employee of Scientific Therapeutics Information, Sally Laden, drew up a first draft.

The manuscript was then sent to JAMA, which rejected it after peer reviewers highlighted methodological and other problems... The paper was rewritten and sent on to JAACAP. The journal’s peer reviewers noted that the results did not “clearly demonstrate efficacy for paroxetine” and asked whether, given that 50% of placebo treated teenagers improved, selective serotonin reuptake inhibitors were “an acceptable first-line treatment.”

JAACAP nevertheless accepted the paper."

On 2015 May 25, Raphael Stricker commented:

Single-Dose Antibiotic Prophylaxis of Lyme Disease: Too Little Too Late?

Over the years since the article by Nadelman et al. was published in 2001 (1), doctors have been using single-dose doxycycline prophylaxis to treat patients following a tickbite. Newer research in animals and humans suggests that this prophylaxis may be ineffective.

The study by Nadelman et al. forms the basis for the Lyme prophylactic treatment guidelines of the Infectious Diseases Society of America (IDSA), and the IDSA guidelines recommend starting prophylaxis “within 72 hours of the time that the tick was removed.” However in 2004 Zeidner et al. noted that a single dose of doxycycline prevented infection in only 43% of mice exposed to Borrelia burgdorferi, the agent of Lyme disease, and a follow-up study in 2008 showed that only 20-30% of mice were protected from combined infection with B. burgdorferi and Anaplasma phagocytophilum following single-dose doxycycline prophylaxis (2). To explain prophylactic treatment failure, Piesman and Hojgaard recently published a mouse study showing the importance of the time interval between tick removal and prophylactic treatment (3).

In commenting on the study by Nadelman et al., Piesman and Hojgaard state: “The authors enrolled subjects if the tickbite occurred within 3 days of their clinical visit, but did not analyze the data based on the exact time between tick removal and delivery of prophylaxis….We found that two treatments of doxycycline delivered by oral gavage to mice on the day of removal of a single potentially infectious nymphal I. scapularis tick protected 74% of test mice compared to controls. When treatment was delayed until 24h after tick removal, only 47% of mice were protected; prophylactic treatment was totally ineffective when delivered ≥2 days after tick removal.” The loss of prophylactic efficacy over this time interval is supported by well-documented observations of rapid transmission of Lyme disease within 24 hours of a tickbite in humans (4). A review of the pertinent literature revealed that the risk of B. burgdorferi transmission within 24 hours of a tickbite was 7% under experimental conditions in mice and up to 25% in clinical studies involving humans (5).

In summary, animal and human studies of exposure to B. burgdorferi suggest that there may be a very narrow window for prophylactic treatment following tick removal. In failing to take this narrow prophylactic window into account, the study by Nadelman et al. appears to put patients at risk of developing Lyme disease following antibiotic prophylaxis that may be too little too late.

References

1. Nadelman RB, Nowakowski J, Fish D, Falco RC, Freeman K, McKenna D, Welch P, Marcus R, Aguero-Rosenfeld ME, Dennis DT, Wormser GP. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tickbite. N Engl J Med. 2001;345: 79-84.
2. Zeidner NS, Massung RF, Dolan MC, Dadey E, Gabitzsch E, Dietrich G, Levin ML. A sustained-release formulation of doxycycline hyclate (Atridox) prevents simultaneous infection of Anaplasma phagocytophilum and Borrelia burgdorferi transmitted by tick bite. J Med Microbiol. 2008;57(Pt 4):463-8.
3. Piesman J, Hojgaard A. Protective value of prophylactic antibiotic treatment of tickbite for Lyme disease prevention: An animal model. Ticks Tick Borne Dis. 2012;3:193-6.
4. 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.
5. Cook MJ. Lyme borreliosis: a review of data on transmission time after tick attachment. Int J Gen Med. 2014;8:1-8.

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 2017 May 24, Morten Oksvold commented:

This article was retracted April 27 2017 together with eight other articles from the same group due to data manipulations.

Please note that the retraction notice is visible in the PDF document only.

http://www.jbc.org/content/276/38/35280.full.pdf?sid=f3f9c372-75a2-438d-8ee9-4c20dff5c06e

"This article has been withdrawn by the authors. In Fig. 3, the CT, EGF panel contained duplicated features. Several panels shown in Fig. 3 were assembled as a composite. The Elk1 and pERK immunoblots in Fig. 4B were inappropriately manipulated. Because the original data are no longer available, in the interest of maintaining accuracy in the published scientific literature, the authors wish to withdraw this article. However, the authors have full confidence in the findings and conclusions of this paper."

On 2014 Apr 29, John Wallace commented:

With more structural data now available, revisiting this topic may prove interesting.

On 2014 Apr 29, G L Francis commented:

Yes a good comment, with much better structural data for the IGF-I receptor available since this study was undertaken. The responsiveness of muscle satellite cells cultured from turkeys at various ages of maturity would also be interesting in light of recent knowledge about the role of tissue specific stem cells during development, tissue repair,and role in aging.

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2014 Nov 24, Ivan Oransky commented:

The second author of this paper has agreed to retract it and five others following a finding of misconduct by the Office of Research Integrity: http://retractionwatch.com/2014/11/20/former-vanderbilt-scientist-faked-nearly-70-images-will-retract-6-papers-ori/

On 2014 Jan 11, Brett Snodgrass commented:

Dear Reader,

Please provide your kind consideration to the distinction between the Thebesian veins and the vessels of Wearn.

It is possible in this report, that both connections permit drainage into the left ventricle.

The article states "Egress of blood from this vessel was observed to take place by way of the Thebesian system, through the ventricular septum and thence into the left ventricle."

The authors presume that it was taking place through the Thebesian veins and not the vessels of Wearn. Since the vessels of Wearn previously had no name, they may have been referred to as Thebesian vessels. This is problematic because if someone reads prior reports about what Thebesius studied, they will likely identify the terms "Thebesian veins" and note that Thebesius reported venular-cameral connections.

In this particular case, the venular hypoplasia probably resulted in increased backpressure and egress of blood from both the Thebesian veins and vessels of Wearn into the left ventricle.

Please see

1. http://bit.ly/JTWearn

2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1933738/

3. http://bit.ly/vasaThebesii

4. http://bit.ly/ThebesianByPratt

My opinion is that accurate anatomic terminology is a basic principle underlying good medical science, and I ask others to consider whether the aforementioned definitions are appropriate. If this comment is not helpful, please let me know how it might be improved.

Comments and suggestions are welcome.

Thank you very much.

On 2016 Feb 01, Morten Oksvold commented:

Please note that this article is 1 out of 15 publications for which an independent investigation initiated by the University of Copenhagen has found suspicion of scientific dishonesty. The conclusion from the report was published July 23, 2012:

http://news.ku.dk/all_news/2012/2012.8/indications_of_fraud_in_penkowas_early_research/

This articles should therefore not be cited.

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2017 Jan 18, Romain Brette commented:

This is a seminal paper on the energetics of the brain, where the authors derive estimates of the energy (ATP) consumption of various components of the nervous system, and in particular that due to excitatory neural activity, not including myelinated axons. The methods contain theoretical reasoning to calculate the energy cost of an action potential and of maintaining the resting potential, in particular. Thus I would highly recommend anyone interested in the theory of neural energetics to read this paper. It is also a good source of relevant empirical data.

There are two theoretical approaches to derive energetic estimates. One is to estimate ATP consumption for various intracellular processes, for example using the stoechiometry of the Na/K pump (3 Na+ out, 2 K+ in, 1 ATP consumed). The problem with this approach is metabolic processes are very complex and only partially known, so any theoretical approach is bound to make more or less drastic approximations. The other is rather based on thermodynamic theory, where one calculates the change in free energy due to transmembrane ion movements. From this, one can then derive the minimal rate of ATP consumption. The disavantage of this approach is it only gives a lower bound on ATP consumption. However, if we assume that metabolic processes are quite efficient, then it should still give a correct order of magnitude. This paper chooses the first approach.

I have a few criticisms however about the calculation of the energy consumption of the resting potential (first part of the methods).

1) The calculation is based on a model with two linear currents (Na+ and K+), following the Hodgkin-Huxley formalism. However, even in the HH model, the leak current (represented here by the K+ current) is carried by several ions. It is a mixture of currents (Na+, K+, Cl-). Implicitly, the approach of the authors assumes that the neuron’s resting potential is above the reversal potential of K+ because there is a Na+ flux at rest. But according to H&H, the leak current (at least in the squid axon) is mostly carried by chloride, which has a higher reversal potential than potassium. Therefore, the fact that the resting potential is above EK tells us little about the flux of Na+ at rest. In fact, the resting potential is more accurately predicted by the GHK voltage equation, as a function of the permeabilities to Na+, K+ and Cl-. Unfortunately, the sole knowledge of resting potential and input resistance (2 observations) does not allow us to deduce the fluxes of 3 different ions.

2) The model considers only the Na/K pump. However, such a system cannot be stable; there has to be at least another pump (or three pumps if we include Cl-). Presumably, this simplification was made because the Na/K pump is the major source of energy, and because other relevant pumps are not electrogenic. Indeed there are co-transporters such as NKCC1 (moves Na+, K+, Cl- into the cell, with 1:1:2 stoechiometry) but these do not consume energy. However, including these in the model (which as mentioned is necessary for stability of ionic concentrations) changes the balance of fluxes and therefore the activity of the Na/K pump. This relates to the comment above on the approach based on the stoechiometry of a few selected processes.

3) The authors estimate the cost of Na+ extrusion at the resting potential. However, it would be more relevant to apply the calculation to the mean potential, not the resting potential. This is typically quite a bit higher.

4) This final point is in my view more problematic. The theory relates ATP consumption rate to the input resistance; that is, it is inversely proportional to Rin. This is indeed logical since the ionic fluxes are proportional to the total membrane conductance. However, the relevant quantity here is total conductance summed over the entire membrane area of the neuron (everywhere where there are ionic fluxes), but the quantity that is used in the paper is the input resistance measured at the soma, which corresponds essentially to the soma and proximal dendrites. It does not, for example, include the area of the axonal membrane, which is a least an order of magnitude larger than the soma. So the result will be incorrect by at least an order of magnitude.

Point (1) leads to substantial overestimation of ATP consumption rate; points (3) and especially (4) lead to substantial underestimation of ATP consumption rate. Together, this makes the energy consumption due to resting potentials very uncertain.

Regarding the calculation of the cost of propagated action potentials, I believe the approach is correct, except the 1/4 efficiency factor (Na+ flux is 4 times larger than necessary to charge the membrane capacitance) comes from the Hodgkin-Huxley model of the squid axon, while vertebrate axons are more efficient. But this has been corrected in subsequent studies.

On 2017 Jan 31, David Attwell commented:

Our answers to Dr Brette’s comments are as follows.

(1a) Ohmic vs Goldman-Hodgkin-Katz dependence of current on voltage

We assumed an ohmic dependence on voltage of the ‘leak’ currents for Na⁺ and K⁺ for simplicity. The maths can also be done for a GHK dependence of Na⁺ and K⁺ current on voltage (e.g. see Johnston & Wu (1995), Foundations of Cellular Neurophysiology, Chapter 2, Example 2.3), but it is more convenient to assume an ohmic dependence because that then allows easier conversion of input resistances (1/(GNa+GK)) reported in the literature into ATP consumption (without the need to assume a value for [Na⁺ ]i). In any case, the GHK equation makes assumptions (https://en.wikipedia.org/wiki/GHK_flux_equation) that are unlikely to all be correct.

(1b) Cl^- permeability

Our paper was for the grey matter of the mammalian neocortex. The permeability of the membrane to chloride is reported to be very low in mammalian cortical neurons (see Fig 5c and p121 of the Discussion of Thompson, Deisz & Prince, 1988, J Neurophysiol 60, 105, available at http://jn.physiology.org/content/jn/60/1/105.full.pdf). Similarly, for rat parasympathetic neurons, Xu & Adams (1992, J Physiol 456, 405, https://www.ncbi.nlm.nih.gov/pubmed/1284080) found that for the resting membrane PCl/PK<0.001.

Nevertheless, we extended our analysis slightly, to include the Cl^- component of the membrane permeability, here: Howarth, Peppiatt-Wildman & Attwell (2010) JCBFM 30, 403 http://journals.sagepub.com/doi/pdf/10.1038/jcbfm.2009.231

(2) Pumps

Dr Brette states “The model considers only the Na/K pump. However, such a system cannot be stable; there has to be at least another pump”.

This is simply incorrect, and the system is stable. The pump exports 3 Na⁺ and imports 2 K⁺ for each ATP consumed. The equations in our paper are set up so that there is no net current across the membrane (the sum of the Na⁺ , K⁺ and pump currents are zero), and so that the magnitude of the pump current is 1/3 of the Na⁺ charge entry (so d[Na⁺ ]i/dt=0) and 1/2 of the K⁺ charge exit through the resting conductance (so d[K⁺ ]i/dt=0). This can be seen by evaluating the resting potential for zero net current (following equations 1-3 of Attwell & Laughlin, 2001), and then calculating the ion fluxes.

(3) Cost of Na⁺ extrusion at the mean potential

We assume this point is based on the notion that the energy needed to extrude Na⁺ should be voltage-dependent, so that the ATP needed would be smaller at a more depolarised potential. In fact the stoichiometry of the Na/K pump is apparently not significantly voltage-dependent (between 0 and -60mV), so that the ATP used is always 1/3 of the Na⁺ pumped (see Rakowski, Gadsby & de Weer, 1989, J Gen Physiol 93, 903, https://www.ncbi.nlm.nih.gov/pubmed/2544655), as we assumed.

(4) What input resistance tells us

The Attwell & Laughlin (2001) paper attempted to provide order of magnitude estimates for the ATP used on different subcellular processes in neurons, and this involved assuming that input resistance measured at the soma can give us a rough estimate of ATP use on the resting potential. The analysis addressed energy use only in the grey matter, excluding the majority of the cortical neuron axon in the white matter (which we dealt with here: https://www.ncbi.nlm.nih.gov/pubmed/22219296). Nevertheless, of course voltage is non-uniform in spatially distributed neurons, and input resistance measured at the soma will then not precisely define the resting influx of Na⁺ measured all over the cell. In later work (Howarth, Peppiatt-Wildman & Attwell (2010) JCBFM 30, 403 http://journals.sagepub.com/doi/pdf/10.1038/jcbfm.2009.231; Howarth, Gleeson & Attwell (2012) JCBFM 32, 1222, http://journals.sagepub.com/doi/pdf/10.1038/jcbfm.2012.35) we estimated resting Na⁺ influx in different cellular locations. Thus, there is plenty of scope for improving estimates of the energy consumed on resting potentials, as more data become available.

Summary

Broadly, most of these points reflect the fact that theoretical work often requires simplifying assumptions. Clearly the assumptions that we made have been useful, because (according to Web of Science or Google Scholar respectively) the paper has been cited 1067 or 1752 times. However, there is always room for improvement and we look forward to seeing Dr Brette’s own detailed analysis.

David Attwell & Simon Laughlin, 31-1-17

On 2017 Feb 10, David Attwell commented:

The answers to Dr Brette’s new points are as follows.

(1a) Ohmic vs Goldman dependence of current on voltage

For a cell as assumed in Attwell & Laughlin (2001) (i.e. 200 Megohm membrane measured with a 10mV hyperpolarizing step, VNa=+50mV, VK=-100mV, Vrp=-70mV, [Na]o=[K]i=140mM, T=37C), assuming a Goldman voltage dependence for the Na⁺ and K⁺ fluxes through ion channels leads to PNa/PK=0.0746 and a Na⁺ influx at the resting potential of 130pA, corresponding to an ATP consumption of 2.7x10⁸ molecules/sec. This is 21% less than the 3.42x10⁸ molecules/sec we calculated using an ohmic dependence of the currents on voltage. This difference is negligible given the variation of measured input resistances and the range of other assumptions that we needed to make. Furthermore, there are no data establishing whether the voltage-dependence of Na+ influx is better described by an ohmic or a Goldman equation.

(In a later post Dr Brette claims that the error arising is 40%. We suspect that his value arises from forgetting the contribution of the Na/K pump current to setting the resting potential, which leads erroneously to PNa/PK=0.05, and a 41.3% lower value than the ohmic dependence predicts.)

(1b) Cl^- permeability

Our point was that the Cl^- permeability was negligible. Which equation was used to derive that fact is therefore irrelevant.

(2) Pumps

We still disagree with the notion that, for a membrane with just Na⁺ and K⁺ fluxes, the system is unstable if it only has a Na/K pump. The Na pump rate is adjusted to match activity via its dependence on [Na⁺ ]i and by the insertion of more pumps when needed.

(3) Cost of Na⁺ extrusion at the mean potential

Tonic synaptic activity may depolarize cells by a mean value of ~4-8mV (Paré et al., 1998, J Neurophysiol 79, 1450). This will affect the calculation of “resting” Na+ influx negligibly (e.g. by ~6mV/120mV = 5% for a 6mV depolarization with Vrp=-70mV and VNa=+50mV). As stated in our earlier comment, this depolarization does not affect the ATP used per Na⁺ pumped by the Na/K pump. Finally the ATP used on extruding synaptic ion entry is considered separately in the calculations.

(4) What input resistance tells us

For cortical L2/3 pyramidal cells the majority of the membrane area is in the basal dendrites, which have an electrotonic length of ~0.24 space constants, while the apical dendrites have an electrotonic length of ~0.69 space constants (mean data at body temperature from Trevelyan & Jack, 2002, J Physiol 539, 623). Larkman et al. (1992, J Comp Neurol 323, 137) similarly concluded that most of the dendrites of L2/3 and L5 pyramidal cells were within 0.5 space constants of the soma.

Elementary cable theory shows that, for a cable (dendrite or local axon) with a sealed end, with current injection at one end, the ratio of the apparent conductance to the real conductance, and thus the ratio of our calculated ATP usage (on Na⁺ pumping to maintain the cable’s resting potential) to the real ATP usage, is given by (1/L).(exp(2L) - 1)/(exp(2L) + 1) where L is the electrotonic length (cable length/space constant). For L=0.24, 0.5 and 0.69, respectively, this predicts errors in the calculated ATP use of 1.9%, 7.6% and 13.3%, which are all completely negligible in the context of the other assumptions that we had to make.

For the axon collaterals near the soma, there is less information on electrotonic length, but the few measurements of axon space constant that exist (Alle & Geiger, 2006, Science 311, 1290; Shu et al., 2006, Nature 441, 761) suggest that the axon collaterals near the soma will similarly be electrically compact and thus that their conductance will be largely reflected in measurements of input resistance at the soma. We excluded the part of the axon in the white matter from our analysis, but did include the terminal axon segments in the grey matter (where the white matter axon rises back into a different cortical area. Re-reading after 16 years the source (Braitenberg & Schüz, 1991, Anatomy of the Cortex, Chapter 17) of the dimensions of these axons, it is clear that those authors were uncertain about the contribution of the terminal axon segments to the total axon length, but assumed that they contributed a similar length to that found near the soma in order to account for the total axon length they observed in cortex. It is unlikely that these distant axon segments will contribute much to the conductance of the cell measured at the soma but, partly compensating for this, part of the axon in the white matter will. This, along with the electrical compactness of the dendrites and proximal axons discussed above, implies that our calculated ATP use on the resting potential is likely to be correct to within a factor of 1/f = 1.57 (where f=0.64 is the fraction of the cell area that is electrically compact [ignoring the minor voltage non-uniformity quantified above], i.e. the soma, dendrites and proximal axons, calculated from the capacitances in Attwell & Laughlin and assuming that the proximal axons provide half of the total axon capacitance in the grey matter).

In fact the situation is likely to be better than this, because this estimate is based on membrane area, but ATP use is proportional to membrane conductance. Estimated values of the conductance of axons (Alle & Geiger, 2006, Science 311, 1290) suggest that the specific membrane conductance per unit area in axons is significantly lower than that in the soma and dendrites (see the Supplementary Information section on Granule Cells in Howarth et al. (2010) JCBFM 30, 403), which reduces the ATP used on maintaining the resting potential of axons.

General reflections on what people expect from the Attwell & Laughlin paper

Our paper tried to introduce a new way of thinking about the brain, based on energetics. Given the large number of assumptions involved it would be a mistake to expect individual values of ATP consumption to be highly accurate. Remarkably, the total energy use that we predicted for the grey matter turned out to be pretty well exactly what is measured experimentally. Nevertheless, constant updating of the assumptions and values is, of course, essential. It is interesting that the value we derived for the ATP used per cell on the action potential (3.84x10⁸ ATP) was initially revised downwards nearly 4-fold in the light of papers showing less temporal overlap of the voltage-gated Na⁺ and K⁺ currents than occurs in squid axon (Alle et al., 2009, Science 325, 1405), but has increased with more recent estimates back to be close to our original estimate (3.77-8.00x10⁸ ATP, Hallermann et al., 2012, Nature Neuroscience 15, 1007).

The most important assumption that we made was that all cells were identical, which immediately implies that this can only be an approximate analysis. We were very happy that the total energy use that we predicted from measured ionic currents, cell anatomy and cell densities was so close to the correct value.

General reflections on post-publication peer comments

We believe that if someone has questions about a paper then the most productive way to get them answered is: (i) to think about the issues; if that fails (ii) to write to the authors and ask them about the questions, rather than posting some vague and erroneous comments that will forever be linked to the paper, regardless of their validity; and if that fails (iii) to write a paper or review which goes through peer review, pointing out the problems. Peer review is crucial for determining whether the points are valid or not - it potentially saves many readers the time needed to read possibly erroneous comments.

It takes a long time to reply to such comments, and we feel that Dr Brette could have done the calculations that we have provided in our two sets of responses. We will not be posting further responses therefore.

David Attwell & Simon Laughlin, 09-02-17

On 2017 Jun 08, Monica Green commented:

There is a typographical error in this entry (PMID: 11624264). The title of the study should correctly read: In search of an "Authentic" women's medicine: the strange fates of Trota of Salerno and Hildegard of Bingen.

On 2014 Nov 19, Wei Liu commented:

After a long 20 years, the results are confirmed by another scientist Michael Bailey.

On 2015 Jan 08, David Mage commented:

Jack Finklea, first Director of the EPA Health Effects Research Laboratory, RTP/NC, wrote here as follows: "We should use what we know in preventive programs and in directing future research. We will make some mistakes when we apply incomplete knowledge, but I think that our need for an excellent scientific information base should not mask the need for society to act on what we do know to clean-up the workplace, and environmental pollution."

The five major mistakes EPA made in setting the first Particulate Matter (PM) National Ambient Air Quality Standard were as follows:

1) The PM standard was for Total Suspended Particulate (TSP) as measured by a highvol sampler that collected all PM with aerodynamic diameters (AD) ranging up to 40 microns. This included PM too large to be inhaled. It was later revised to reflect only respirable PM that were < 10 um and < 2.5 um AD.

2) The first PM NAAQS was 75 ug/m3 TSP as a 1-year geometric mean (GM) based on PMID 6017082. This was a major mistake because two values 5 and 5 have an arithmatic mean (AM) of 5 and a GM of 5 but 0 and 10 have an AM of 5 and a GM of 0! But note, the health effect of {0,10} is greater than the health effect of {5,5}. In addition the GM is not relatable to the dose of inhaled PM even if the total volume of air inhaled during the year were known.

3) The PM NAAQS were, and still are now, based upon the collected mass of the PM, not its molecular composition. From first principles, the cardio-pulmonary toxicity of any PM molecule depends upon its molecular structure and not its molecular weight. Thus if two PM samplers collect the identical number of molecules of the same AD in the same amount of time, EPA would consider the PM collection with the higher average molecular weight to produce more of a health effect (e.g., it is more toxic) than the other collection. This mistake has not been corrected and still underlies virtually all PM studies.

4) All PM NAAQS are based upon the PM concentration measured at an ambient PM monitoring station location meeting various siting and location criteria. Given that no subject spends 24-hours continuously breathing only the ambient air at the station location, the personal PM exposure of all people living in the area will not be numerically equal to the official ambient PM concentration that EPA compares to the NAAQS.

5) The PM NAAQS and all PM epidemiology studies upon which it is based assume the PM health effects follow an ambient PM concentration response relation or a personal PM exposure response relation. They follow neither! They must follow a dose response relation with dose given a value with units specific to the health effect under consideration. For instance: i) if the health effect is systemic, then the dose should be reported as mg/kg-day; ii) if the health effect is related to pulmonary airway surface irritation, then the dose should be reported as mg/m2-day where the mg might, for example, refer to the mass of PM deposited on the non-ciliated sensitive area of alveoli of the pulmonary tract, and m2 refers to that area (not the entire area of the pulmonary tract).

On 2015 Apr 02, Harri Hemila commented:

Cochrane review (2001) on vitamin C and asthma by Kaur B, 2001 misled readers for a decade due to the errors in the extraction and analysis of data.

The Cochrane review (2001) on vitamin C and asthma by Kaur B, 2001 has substantial errors. I found errors in the 2009 update of that review by Kaur B, 2009. My comments of the 2009 update are available as a separate document. Then I found that the errors originated in the first version by Kaur B, 2001, and they were repeated in the updates by Ram FS, 2004 and by Kaur B, 2009, until the review was withdrawn by Kaur B, 2013. Thus the Cochrane review (2001) on vitamin C and asthma misled readers for over a decade due to the errors in the extraction and analysis of data. Here I briefly describe the errors in the first version of the Cochrane review (2001) on vitamin C and asthma by Kaur B, 2001.

As relevant background knowledge, it was known long before Kaur B, 2001 that exercise can cause exercise-induced bronchoconstriction (EIB or EIA, exercise-induced asthma), eg Mahler DA, 1993, and that respiratory virus infections can cause exacerbations of asthma, eg Nicholson KG, 1993. Thus, if vitamin C influences bronchoconstriction, the effects might be most pronounced during exercise and/or viral infections.

Errors in the extraction of data

Kaur B, 2001 wrote in the Results section (p.4): “there were two studies where the protective effects of vitamin C were investigated using exercise challenge. Both these studies reported pulmonary function outcomes, but one (Cohen 1997) reported absolute mean value post-exercise, while the other (Schachter 1982) reported absolute change post-exercise .”

In Comparison 01: Outcomes 01 and 02 (p. 10), Kaur B, 2001 presented the results of those two studies. However, Cohen HA, 1997 had 20 participants, yet Kaur B, 2001 showed data for only 11 participants, without revealing to the reader that data for 9 of Cohen's participants are missing from their review. Cohen showed the data of 11 participants on the basis that vitamin C was beneficial for them. However, it is inappropriate and violates the ITT principle to show such a biased subgroup in the Cochrane review by Kaur B, 2001, without explaining that another 9 participants were excluded. Cohen HA, 1997 also reported that on the placebo day, 20/20 of the participants had EIB, whereas on the vitamin C day, 10/20 had EIB. This comparison does not need any imputations, but these data were not extracted for the Cochrane review by Kaur B, 2001.

A decade before the Kaur B, 2001 review, papers reported that “EIA symptoms start after exercise, peak 8 to 15 minutes after exercise” so that there is a delay between the end of exercise and the peak of FEV1 decline, and “a fall of 10% or more in the FEV1 after exercise is diagnostic” so that the relative change in FEV1 (in %) is the most reasonable outcome when assessing EIB, eg Mahler DA, 1993. Such facts are relevant when analyzing EIB trials.

Kaur B, 2001 considered that “exercise challenge” was a particular issue in the Cohen HA, 1997 and Schachter EN, 1982 studies, see the above extract. However, in Outcome 01 (p.10) the Cochrane review showed data on the pre-exercise FEV1 levels, which is not an outcome influenced by exercise. In Outcome 02 (p.10) the Cochrane review extracted data on the absolute post-exercise FEV1 level for Cohen HA, 1997 and absolute FEV1 change for Schachter EN, 1982. These outcomes are not relevant, since the standard outcome for EIB is the relative change in FEV1 (in %), see above.

Furthermore, the greatest decline in FEV1 occurs about 8 to 15 min after the end of exercise, above. However, in Outcome 02 (p.10), Kaur B, 2001 shows Schachter's FEV1 changes immediately after exercise in Schachter's Table II, instead of FEV1 changes 5 min after exercise which Schachter reported in Table III. The latter is much more relevant in a study on EIB, since “EIA symptoms ... peak 8 to 15 minutes after exercise”, Mahler DA, 1993.

Kaur B, 2001 (p.4) write that “Anah did not report data in a manner that permitted further analysis”. However, in the following paragraph, Kaur B, 2001 wrote that, in the Anah study, “there were 9 exacerbations in the intervention group which had 22 patients and 35 exacerbations in the placebo group which had 19 patients ”. Thus, Anah CO, 1980 did report data that can be statistically analyzed, see below.

Errors in the analysis of data

Schachter EN, 1982 and Cohen HA, 1997 were cross-over studies so that the same participants were randomly administered vitamin C or the placebo. Such data should be analyzed by the paired t-test.

In Outcomes 01 and 02 (p.10), Kaur B, 2001 analyzed Schachter and Cohen data by the unpaired t-test, which is unsound for paired data. Kaur B, 2001 reported no difference between the vitamin C and placebo days for 11 of Cohen's participants with P=0.4 (unpaired t-test), whereas the correct paired t-test yields P=0.003.

Furthermore, given that the goal was to examine the effect of vitamin C on EIB, Kaur B, 2001 should have calculated the relative changes in FEV1 (in %), see above.

Schachter EN, 1982 published the data for all their 12 participants, and Kaur B, 2001 could have used the paired t-test to analyze the relative changes.

Similarly, Kaur B, 2001 could have calculated the relative changes for the 11 participants published by Cohen HA, 1997, and could have imputed eg “no effect” for the 9 participants who had missing data.

Nevertheless, using the paired t-test is a simplistic analysis of FEV1 changes, since it is possible that the effect of vitamin C depends on the severity of EIB. Hemilä H, 2013 analyzed the two studies using linear regression. Schachter EN, 1982 showed a 55% reduction in the postexercise FEV1 decline (95%CI 32% to 78%) with vitamin C. Imputation of “no effect” to the 9 participants with missing data of Cohen HA, 1997 yielded an estimated 42% reduction in the postexercise FEV1 decline (19% to 64%) with vitamin C. Finally, Cohen HA, 1997 also published the EIB status, which has no missing data. On the placebo day, 100% (20/20) of participants suffered from EIB, whereas on the vitamin C day, only 50% (10/20) suffered from EIB. Thus vitamin C caused a 50 percentage point decrease (23 to 68) in the occurrence of EIB, see Hemilä H, 2013.

Kaur B, 2001 (p. 4) claimed that “Anah did not report data in a manner that permitted further analysis,” which is incorrect. Anah CO, 1980 reported that in the placebo group (n=19), there were 35 asthma attacks, but in the vitamin C group (n=22), only 9 attacks. By using the standard Poisson approach, these data give RR=0.22 (0.09 to 0.47). Anah did not publish the individual level data and it might be over-dispersed, see Glynn RJ, 1996. Nevertheless, Anah published partial descriptions of the asthma attack distributions which can be used to impute more realistic distributions for the treatment groups, yielding a 95%CI of 0.06 to 0.81, which is still far from the null effect, see Hemilä H, 2013. Furthermore, the exact distribution of severe and moderate asthma attacks in the vitamin C group can be inferred from Anah CO, 1980 and this outcome needs few imputations. Vitamin C reduced the incidence of severe and moderate asthma attacks by RR=0.11 (0.02 to 0.48).

In conclusion, had Kaur B, 2001 extracted data correctly, and had they properly carried out the statistical analysis, they could have concluded in 2001 that there was strong evidence that vitamin C was beneficial against EIB in Cohen HA, 1997 and in Schachter EN, 1982, and against common cold-induced asthma exacerbations in Anah CO, 1980.

Secondary analysis of the Cohen HA, 1997, Schachter EN, 1982 and Anah CO, 1980 studies has been carried out by Hemilä H, 2013, Hemilä H, 2013, and Hemilä H, 2014.

On 2014 Jan 08, Brett Snodgrass commented:

Dear Authors,

Thank you for the excellent report.

Is it possible that the fistula might alternatively be described as an unusually prominent vessel of Wearn? These vessels are unusually prominent in PAIVS, probably due to the hypertensive right ventricle.

http://www.ncbi.nlm.nih.gov/pubmed/23332812

For additional commentary, please see

https://twitter.com/BrettSnodgrass1/status/412868120508788736/

Comments and suggestions are welcome.

Thank you kindly.

On 2016 Jan 23, Daniel Schwartz commented:

This paper addresses a practical consideration when providing dialysis to a patient with a toxic alcohol ingestion - the need to plan the nursing hours likely needed to run dialysis, which is often in the on-call/overnight period.

The model has been converted to a web and mobile app based tool to support easier usage: http://qxmd.com/calculate/dialysis-duration-needed-for-methanol-ingestion

Conflict of interest: Medical Director, QxMD

On 2016 Feb 01, Morten Oksvold commented:

Please note that this article is 1 out of 15 publications for which an independent investigation initiated by the University of Copenhagen has found suspicion of scientific dishonesty. The conclusion from the report was published July 23, 2012:

http://news.ku.dk/all_news/2012/2012.8/indications_of_fraud_in_penkowas_early_research/

This articles should therefore not be cited.

On 2016 Feb 19, E M Martínez-Cáceres commented:

In the light of the recent PubMed comment by Morten Oksvold, the referenced research study was performed entirely in our research centre by the research team led by Dr. Martínez-Cáceres at the time with Dr. Espejo as predoctoral researcher. Hence, the EAE in vivo experiments were performed in Barcelona with no involvement from Dr. Penkowa, who was engaged as an expert histopathologist. Dr. Penkowa received processed and encoded samples with which she performed some of the histopathological studies. The results were returned to us for overall analysis and submission for publication. It was agreed that Dr. Penkowa would be co-author of the published work.

On 2013 Oct 24, Tom Kindlon commented:

Test of "physical fitness" used seems far from ideal for this cohort

The authors state in the abstract that "an empirically defined fatigue syndrome 6 months after onset" was associated with "lower physical fitness". "Lower physical fitness" is a term that is regularly used throughout this paper. However, has it been properly defined especially for this post-viral group? And what can be inferred from the correlation?

Firstly it should be remembered that the study used two measures of physical fitness from the exercise test: What they called "exercise power" was calculated as "the number of stairs climbed, multiplied by the height of each stair, and the participant's weight." A measure of "physical fitness" was calculated by "dividing the number of stairs climbed by the exercise pulse-rate difference". It seems rather arbitrary to ignore the first when mentioning "physical fitness" in the study and abstract.

It also needs to be pointed out that this is an unusual way to define fitness and may not be suitable for people with CFS and related post-viral syndromes. For example, Postural Orthostatic Tachycardia Syndrome (POTS) has found to be more common in this sort of population than in other populations. A recent study¹ using a standing test of 2 minutes duration found a prevalence rate of POTS of 27% compared to 9% in a control group (p=0.006). A previous case control study of orthostatic intolerance in children/adolescents with chronic fatigue syndrome had found a significant higher rate (p=0.01) POTS without hypotension in the patients with CFS compared to the controls (but no difference of the rate of POTS with hypotension).² Other researchers in the field feel POTS is an important issue in the area of CFS, ME and related syndromes.³ So in the light of these findings it seems questionable that this is a suitable test to test for "physical fitness".

It should also be remembered that it is not easy to test somebody's fitness when they have an infection - a "fit" person such as (say) a sportsperson can seem unfit if one tests them when they are ill but within a short period of time could be playing sport competitively and generally showing better physical fitness than could be explained by any physical training in the interim.

References:

[1] Hoad A, Spickett G, Elliott J, Newton J. Postural orthostatic tachycardia syndrome is an under-recognized condition in chronic fatigue syndrome. QJM. 2008 Sep 19.

[2] Galland BC, Jackson PM, Sayers RM, Taylor BJ. A matched case control study of orthostatic intolerance in children/adolescents with chronic fatigue syndrome. Pediatr Res. 2008 Feb;63(2):196-202.

[3] Spence V & Stewart J (2004) Standing up for ME, Biologist 51(2): 65-70.

On 2013 Oct 24, Tom Kindlon commented:

This study did not have information on the physical fitness of the patients before becoming ill. The authors suggest that the patients may have been more inactive before becoming ill. However the evidence is stacking up that this is not generally the case and indeed that patients who develop CFS may, on average, be a little more active or fitter than the general population.

A recent prospective population study¹ on the illness 4779 people from birth for the first 53 years of their lives. At age 53, 34 reported a diagnosis of CFS. Amongst other things, it found that "increased levels of exercise throughout childhood and early adult life and a lower body mass index were associated with an increased risk of later CFS." As it was a prospective study, there was no issue of recall bias. It also wasn't simply self-rated, as it also involved reporting by a teacher at age 13. Also they used the subject's BMI index - patients who went on to have CFS at age 53 had a (statistically significant) lower BMI than those who did not go on to develop CFS at ages 36 and 43 (before they had CFS). The authors say this "this may provide some indirect but objective evidence of increased levels of activity at these ages, especially as this difference had resolved by the age of 53 years" (when the people with CFS were no longer more active).

A study involving the corresponding author² found that, compared to healthy controls, patients with chronic, unexplained fatigue rated themselves as more active before their illness. In this study, they also reported that "the high levels of physical activity reported by patients have been corroborated by their spouses, partners, or parents" (in another study³ ). At least three other retrospective studies reporting that CFS patients perceived themselves as more active before their illness began than healthy controls.^4-6

In 2006, a CDC-funded prospective cohort study following patients from the time of acute infection with Epstein-Barr virus (glandular fever), Coxiella burnetii (Q fever), or Ross River virus (epidemic polyarthritis) was published.⁷ 253 patients were enrolled and followed at regular intervals over 12 months by self report, structured interview, and clinical assessment. It found that prolonged illness was "characterised by disabling fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disturbance was evident in 29 (12%) of 253 participants at six months, of whom 28 (11%) met the diagnostic criteria for chronic fatigue syndrome. This post-infective fatigue syndrome phenotype was stereotyped and occurred at a similar incidence after each infection. The syndrome was predicted largely by the severity of the acute illness".

Given only a correlation was found and that no intervention was tested in the current study, along with the preceeding information, I believe the authors' suggestion that "prevention of postinfectious fatigue by an early return to physical activity may be possible" is highly speculative (this claim was recently re-iterated by the corresponding author at a conference on CFS when presenting data from this study⁸ ).

1 Harvey SB, Wadsworth M, Wessely S, Hotopf M: Etiology of Chronic Fatigue Syndrome: Testing Popular Hypotheses Using a National Birth Cohort Study. Psychosom Med. 2008 Mar 31

2 Smith WR, White PD, Buchwald D. A case control study of premorbid and currently reported physical activity levels in chronic fatigue syndrome. BMC Psychiatry. 2006 Nov 13;6:53.

3 Van Houdenhove B, Neerinckx E, Onghena P, Lysens R, Vertommnen H: Premorbid "overactive" lifestyle in chronic fatigue syndrome and fibromyalgia: an etiological relationship or proof of good citizenship? J Psychosom Res 2001, 51:571-6.

4 Riley MS, O'Brien CJ, McCluskey DR, Bell NP, Nicholls DP: Aerobic work capacity in patients with chronic fatigue syndrome. BMJ 1990, 301:953-6.

(contd.)

On 2016 Mar 29, Jonathan Wren commented:

Relocated to: http://dbtss.hgc.jp/

On 2014 Nov 23, Harri Hemila commented:

A manuscript version is available at handle

On 2015 Jun 02, thomas samaras commented:

Additional information on height, CHD, longevity the environment is available from these recent publications.

Samaras TT. Shorter height is related to lower cardiovascular disease risk—A narrative review. Indian Heart Journal 2013; 65: 66-71.

Samaras, TT. Is short height really a risk factor for coronary heart disease and stroke mortality? A review. Med Sci Monit 2004; 10(4): RA63-76.

Samaras TT. Evidence from eight different types of studies showing that smaller body size is related to greater longevity. Journal of Scientific Research & Reports. 2014: 3 (16): 2150-2160, 2014; article no. JSRR.2014.16.003.

Samaras TT. Human Scaling and Body Mass Index. In: Samaras TT (ed): Human Body Size and the Laws of Scaling: Physiological Performance, Growth, Longevity and Ecological Ramifications. New York: Nova Science Pub; 2007: pp 17-32.

He Q, Morris BJ, Grove JS, Petrovitch H, Ross W, Masaki KH, et al. Shorter men live longer: Association of height with longevity and FOXO3 genotype in American men of Japanese ancestry. Plos ONE 9(5): e94385. doi:10.1371/journal.pone.0094385.

Salaris L, Poulain M, Samaras TT. Height and survival at older ages among men born in an inland village in Sardinia (Italy), 1866-2006. Biodemography and Social Biology, 58:1, 1-13.

Bartke A. Healthy Aging: Is Smaller better? A mini-review. Gerontology 2012; 58:337-43.

On 2016 Feb 03, Daniel Schwartz commented:

The SLEDAI-2K can easily be calculated using an online tool or mobile app: http://qxmd.com/calculate/sledai-2k

Conflict of interest: Medical Director, QxMD

On 2015 Jun 02, thomas samaras commented:

Additional information on height, CHD, and longevity is available from these recent publications.

Samaras TT. Shorter height is related to lower cardiovascular disease risk—A narrative review. Indian Heart Journal 2013; 65: 66-71.

Samaras, TT. Is short height really a risk factor for coronary heart disease and stroke mortality? A review. Med Sci Monit 2004; 10(4): RA63-76.

Samaras TT. Evidence from eight different types of studies showing that smaller body size is related to greater longevity. Journal of Scientific Research & Reports. 2014: 3 (16): 2150-2160, 2014; article no. JSRR.2014.16.003.

Samaras TT. Human Scaling and Body Mass Index. In: Samaras TT (ed): Human Body Size and the Laws of Scaling: Physiological Performance, Growth, Longevity and Ecological Ramifications. New York: Nova Science Pub; 2007: pp 17-32.

He Q, Morris BJ, Grove JS, Petrovitch H, Ross W, Masaki KH, et al. Shorter men live longer: Association of height with longevity and FOXO3 genotype in American men of Japanese ancestry. Plos ONE 9(5): e94385. doi:10.1371/journal.pone.0094385.

Salaris L, Poulain M, Samaras TT. Height and survival at older ages among men born in an inland village in Sardinia (Italy), 1866-2006. Biodemography and Social Biology, 58:1, 1-13.

Bartke A. Healthy Aging: Is Smaller better? A mini-review. Gerontology 2012; 58:337-43.

On 2016 Sep 13, Gerhard Nebe-von-Caron commented:

the paper states I claimed problems with the sorting of gram positive bacteria which is factually incorrect as I never made such statement, and definitively not in the cited paper.

On 2013 Dec 11, Gary Ward commented:

This paper is a classic in the field of parasite cell biology. The stunning electron micrographs provide the first high-resolution look at the substructure of the conoid, a unique cytoskeletal structure found in a variety of apicomplexan parasites. The paper shows that the fibers of the conoid are composed of tubulin, but the protofilament arrangement within the individual fibers is unlike that of any other known tubulin-based structure: rather than a closed tube, the 9 protofilaments are arranged into a “comma” shape. This unique structure may enable the high degree of curvature required of these filaments within the thimble-shaped conoid (diameter 380 nm). FRAP experiments revealed the tubulin subunits are incorporated into the conoid during the early stages of daughter formation, but not in mature parasites. Remarkably, the authors also show that the pitch of the filaments changes as the conoid extends and retracts during parasite motility and host cell invasion.

In the years since this paper was published, additional isoforms of α- and β-tubulin have been discovered for a total of three each (Hu et al. PLOS Pathog [2006] 2(2): e13). It would be interesting to see whether any of these isoforms localize specifically to the conoid or to the other tubulin-based structures within the parasite.

Posted by Gary Ward on behalf of the University of Vermont Toxoplasma Journal Club (UVM ToxoJC); members include Jenna Foderaro, Anne Kelsen, Shruthi Krishnamurthy, Jacqueline Leung, Pramod Rompikuntal, Luke Tilley & Gary Ward

On 2013 Oct 23, ANDREW SU commented:

!MOVED http://biogps.org

The URL in the original abstract has now been retired. This data set (together with other gene expression data sets) are now hosted at http://biogps.org.

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2013 Nov 25, Colleen Doherty commented:

One interesting thing I discovered after this publication. To achieve the observed difference in CBF2 induction levels between wild type and camta3 mutant plants, these experiments had to be performed at the same time of day relative to imbibition, even in constant light. This time seems to correspond with dawn as it is the highest point of CBF2 induction in wild type plants.

Some critical citations were missing from this article:

The following papers were critical in our focus on this family of transcription factors. They were essential for our investigation into the CAMTA family. I believe the citations were omitted when we were rewriting the intro and the sentences referencing these early works were cut or reworded.

YANG, T. and POOVAIAH, B.W. 2002. A Calmodulin-binding CGCG box DNA-binding protein family involved in multiple signaling pathways in plants. J. Biol. Chem. 277: 45049-45058.

YANG, T. and POOVAIAH, B.W. 2000. An early ethylene up-regulated gene encoding a calmodulin-binding protein involved in plant senescence and death. J. Biol. Chem. 275: 38467-38473

The position of the T-DNA insertions were overlaid on a figure taken from this paper. Although we do cite this paper elsewhere in the article, this is not properly cited as the source in the supplemental figure.

Bouché, N., Scharlat, A., Snedden, W., Bouchez, D., and Fromm, H. (2002). A novel family of calmodulin-binding transcription activators in multicellular organisms. J. Biol. Chem. 277 21851–21861.

On 2015 Oct 15, Lydia Maniatis commented:

There was absolutely no reason for this study, which tests two highly-flammable straw men. That it was deemed worth doing indicates either ignorance of fundamental principles of perception or an inexplicable failure to take them into account.

What is supposedly being tested is the impossible notion that we are able to estimate the physical illumination of a scene directly. Nobody believes this, because a. it is logically impossible and b. there are mountains of evidence against it. The authors don't suggest that any believes it, saying only that a “natural expression of the illumination-estimation hypothesis is that perceived illumination is determined by [actual illumination].” But there is nothing natural about such a claim, logically or empirically. First, there is no conceivable mechanism by which direction and intensity of (often partially-obstructed and/or multiple) light sources (which, furthermore, we never look at directly) falling on each local surface could be estimated. (This applies to the conditions of this experiment as well). Second, if illumination could be directly evaluated, then interpretation of the lightness of surfaces would not require a global, ratio-based approach, but could be estimated based on local luminance info only, by factoring out the independently-estimated illumination. If illumination could be directly evaluated, then a photograph of sunlight and shadow would completely lack this character if placed under a visible light-bulb evenly-illuminating the entire surface. In general, graphic representations of shadows, transparencies, etc. would be impossible. It is a fundamental fact of visual perception that the visual system uses the light reflected from a scene, not the light impinging on it, to estimate reflectance, illumination and everything else. The authors are, naturally aware of this, as reflected in their casual acknowledgment that “good constancy” under changing illumination “depends critically on the scene manipulations (Kraft and Brainard, 1999)” and when they say that the “poor constancy” they found in this experiment might be to the lack of a “number of [stimulus] cues often taken to support constancy.” Direct estimation of the illuminant would not need the support of such “cues” coming from the stimulus itself. No surprise, then, that the proposed “hypothesis” is falsified. Furthermore, the authors are unable to suggest any plausible interpretation of their results.

A second pseudo-hypothesis tested is that simultaneous contrast is a consequence of perceived illumination differences, even though we know that it arises when illumination appears homogeneous. This was also falsified.

A strange suggestion made (and rejected) in the conclusion of the paper is that “one could attempt to understand our results while preserving the elegance of the [our version of the] illumination estimation hypothesis by replacing the physical luminance ...with a perceived quantity.” I'm not sure what this means, but luminance is not perceived. If it is, then what does it look like? On what info would this evaluation be based?

On 2016 Feb 01, Morten Oksvold commented:

Please note that this article is 1 out of 15 publications for which an independent investigation initiated by the University of Copenhagen has found suspicion of scientific dishonesty. The conclusion from the report was published July 23, 2012:

http://news.ku.dk/all_news/2012/2012.8/indications_of_fraud_in_penkowas_early_research/

This articles should therefore not be cited.

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2016 Mar 12, Mark Milton commented:

This article contains the following statement "Recombinant proteins with a molecular weight of greater than 60 kd may be taken up by the reticuloendothelial system and catabolized by the liver." No reference was provided to substantiate this statement and is in conflict with "conventional wisdom" regarding the clearance of proteins, including therapeutic IgG antibodies. I would encourage readers not to cite this article when describing how therapeutic proteins and antibodies are cleared from the body.

On 2016 Jan 09, Chao Liu commented:

There are also a good body of evidence, both from animal and human, shows that glucocorticoids could promote renal water and sodium excretion. Thus, patients with decompensated heart failure may benefit from glucocorticoids.

1. Hunter RW, Ivy JR, Bailey MA. Glucocorticoids and renal Na+ transport: implications for hypertension and salt sensitivity. J Physiol. 2014 Apr 15;592(Pt8):1731-44.

2. Landínez RAS, Romero MFL, Maurice EH (2014). Efectos de la prednisona sobre la función renal a corto plazo en pacientes con Insuficiencia Cardíaca Descompensada. Venezolana de Medicina Interna 30(3): 176-192.

3. Liu C, Chen Y, Kang Y, Ni Z, Xiu H, Guan J, et al. (2011). Glucocorticoids Improve Renal Responsiveness to Atrial Natriuretic Peptide by Up-Regulating Natriuretic Peptide Receptor-A Expression in the Renal Inner Medullary Collecting Duct in Decompensated Heart Failure. J Pharmacol Exp Ther 339(1): 203-209.

4. Liu C, Liu G, Zhou C, Ji Z, Zhen Y, Liu K (2007). Potent diuretic effects of prednisone in heart failure patients with refractory diuretic resistance. Can J Cardiol 23(11): 865-868.

5. Liu C, Liu K (2014a). Effects of glucocorticoids in potentiating diuresis in heart failure patients with diuretic resistance. Journal of cardiac failure 20(9): 625-629.

6. Liu C, Liu K (2014b). Reply to Day et al.--hypouricemic effect of prednisone in heart failure: possible mechanisms. Can J Cardiol 30(3): 376 e373.

7. Liu C, Zhao Q, Zhen Y, Gao Y, Tian L, Wang L, et al. (2013). Prednisone in Uric Acid lowering in Symptomatic Heart Failure Patients With Hyperuricemia (PUSH-PATH) study. Can J Cardiol 29(9): 1048-1054.

8. Liu C, Zhao Q, Zhen Y, Zhai J, Liu G, Zheng M, et al. (2015). Effect of Corticosteroid on Renal Water and Sodium Excretion in Symptomatic Heart Failure: Prednisone for Renal Function Improvement Evaluation Study. J Cardiovasc Pharmacol 66(3): 316-322.

9. Meng H, Liu G, Zhai J, Zhen Y, Zhao Q, Zheng M, et al. (2015). Prednisone in Uric Acid Lowering in Symptomatic Heart Failure Patients with Hyperuricemia - The PUSH-PATH3 Study. The Journal of rheumatology 42(5): 866-869.

On 2017 Jan 20, Eric Yarnell commented:

The authors family and given names have been thoroughly mixed up. The author citation should be (from the original article directly): Ho YK, Kim SH, Lee WJ, Byrne HK

On 2015 Dec 03, S A Ostroumov commented:

ABSTRACT: The article presents a new fundamental concept of how biodiversity helps towards a better environmental stability and water quality. The author made an innovative analysis of his experimental data and formulated the following fundamental principle: to maintain water quality, it is vital to protect the functionally active biodiversity of water ecosystems. In other words, according to the author’s new concept, the protection of functionally active biodiversity, including filter-feeders, is a key to maintenance of water quality. This concept was supported by many facts obtained in experiments of the author and reported in his previous publications. This article presents new facts in support of his concepts. Among new facts obtained and reported in the paper: a chemical pollutant (exemplified by the laundry detergent IXI, at a sublethal concentration 20 mg/L) inhibited water filtration by the aquatic bivalve mollusks, marine mussels Mytilus galloprovincialis (3-25 min, 18 pro mille, 22.8ºC). Another synthetic detergent (exemplified by the laundry detergent Deni-Automat), at a sublethal concentration 30 mg/L, also inhibited the water filtration by the marine bivalves oysters Crassostrea gigas (2-40 min, 25.2ºC).]. These new data as well as the other related data obtained by the same author and reported in his other publications, supported the author’s fundamental concept.

On 2015 Dec 03, S A Ostroumov commented:

Full text, free, is available online, of this article: Biodiversity protection and water quality: the role of feedbacks in ecosystems. https://www.researchgate.net/publication/259497389;

On 2016 Jan 06, S A Ostroumov commented:

In the top 25% of all research outputs scored by Altmetric. https://www.researchgate.net/publication/11371556; DOI 10.1023/A:1014465220673.

http://www.altmetric.com/details/3041761;

On 2015 Jun 02, thomas samaras commented:

Additional information on height, CHD, and longevity is available from these recent publications.

Samaras TT. Shorter height is related to lower cardiovascular disease risk—A narrative review. Indian Heart Journal 2013; 65: 66-71.

Samaras, TT. Is short height really a risk factor for coronary heart disease and stroke mortality? A review. Med Sci Monit 2004; 10(4): RA63-76.

Samaras TT. Evidence from eight different types of studies showing that smaller body size is related to greater longevity. Journal of Scientific Research & Reports. 2014: 3 (16): 2150-2160, 2014; article no. JSRR.2014.16.003.

Samaras TT. Human Scaling and Body Mass Index. In: Samaras TT (ed): Human Body Size and the Laws of Scaling: Physiological Performance, Growth, Longevity and Ecological Ramifications. New York: Nova Science Pub; 2007: pp 17-32.

He Q, Morris BJ, Grove JS, Petrovitch H, Ross W, Masaki KH, et al. Shorter men live longer: Association of height with longevity and FOXO3 genotype in American men of Japanese ancestry. Plos ONE 9(5): e94385. doi:10.1371/journal.pone.0094385.

Salaris L, Poulain M, Samaras TT. Height and survival at older ages among men born in an inland village in Sardinia (Italy), 1866-2006. Biodemography and Social Biology, 58:1, 1-13.

Bartke A. Healthy Aging: Is Smaller better? A mini-review. Gerontology 2012; 58:337-43.

On 2017 Sep 10, Erik Gotfredsen commented:

The name "Turpinia ternata" is misspelled in the abstract

On 2017 Jul 07, Morten Oksvold commented:

This article should have been retracted after an investigation by The University of Maryland found this article to contain "compromised" data (a total of 26 articles in 11 journals were affected). The journal Cancer Research was informed in August 2016, according to Retraction Watch.

http://retractionwatch.com/2017/04/26/university-asked-numerous-retractions-eight-months-later-three-journals-done-nothing/

On 2015 Sep 04, Lydia Maniatis commented:

Lower region was not a new cue in 2002. Rubin discussed it in his article "Visual wahrgenommene Figuren" (1921). I haven't read it, but Kohler mentions it in a book called "Dynamics in Psychology" ((1940): "Rubin found that in such cases certain rules decide which part will preferably acquire the figure-character. One of these rules says that, if two adjacent areas appear one above the other, and if no other principle interferes, the lower part rather than the upper will be seen as shaped and as substantial" (p. 23).

It might be worth translating Rubin's original work into English.

On 2015 Dec 03, S A Ostroumov commented:

Full text of this paper is available online free: A new type of effect of potentially hazardous substances: uncouplers of pelagial–benthal coupling. https://www.researchgate.net/publication/200576296

On 2015 Dec 03, S A Ostroumov commented:

ABSTRACT of this article: A new type of effect of potentially hazardous substances: uncouplers of pelagial–benthal coupling. - Doklady Biological Sciences. 2002. Vol. 383 (1-6): 127-130. Bibliogr.15. ISSN 0012-4966. Discovery of a new type of negative impact of pollutants on the biosphere, as a result of inhibition of water filtration by filter-feeders / suspension feeders. The water filtration and associated removal of suspended matter from water is part of migration of matter. As V.I. Vernadsky stressed, organisms are mediators or driving force of “biogenic migration of atoms in the biosphere”. This migration is partly implemented in the framework of pelagial–benthal coupling via the activity of filter-feeders, which remove the organic suspended matter from water and excrete pellets. The tables contains the following data: the average percentage of assimilated (16-90%) and non-assimilated (10-84%) food matter for 15 large taxa of invertebrates (Table 1); potassium bichromate inhibited water filtration by mussels Mytilus galloprovincialis (Table 2); surfactants, detergents, pesticides inhibited filtration by filter-feeders, marine and freshwater bivalves and rotifers (Table 3). A prediction is made: "Further research and experimental studies are expected to provide new evidence that sublethal concentrations of chemical pollutants induce a significant decrease in the filtration capacity of freshwater and marine filter feeders" (p.129). "The uncoupling process considered above is an anthropogenic violation of two basic laws (empirical rules or biogeochemical principles) of the biosphere functioning: (1) biogenic migration of atoms of chemical elements in the biosphere always tends toward its maximum expression; (2) on the geological time scale, the evolution of species gives rise to the forms of life that are stable in the biosphere, and is so directed that the biogenic migration of atoms in the biosphere increases" (p.129).]; DOI 10.1023/A:1015385723150;

On 2015 Dec 03, S A Ostroumov commented:

ABSTRACT: Ostroumov S.A. New definitions of the concepts and terms ecosystem and biogeocenosis. - Doklady Biological Sciences, 2002, Volume 383, p. 141-143. [MAIK Nauka/Interperiodica distributed by Springer Science+Business Media LLC. ISSN 0012-4966 (Print) 1608-3105 (Online)]. In 1935, the term 'ecosystem' was coined by Prof.A. Tansley. In the 1940s, another important term 'biogeocoenosis' was introduced by Prof. V. N. Sukachev. Since that time, a significant amount of new facts was accumulated in ecology. It is necessary to revisit the formulation of the basic concepts and terms in ecology, including the two terms mentioned above. The author proposed some new variants of the definition of the two terms that (1) reflect the modern understanding of the basics of ecology; and (2) avoid the vicious circle of using other terms that in turn request their definitions. The author realizes that the new variants of the terms cannot be ideal and some other variants of the definitions are also possible. 5 specific features of the proposed definition of ecosystem (Table 1). 8 specific features of the proposed definition of biogeocenosis, and 8 distinctions between the proposed definition and the classical definition by V.N.Sukachev (Table 2)].

On 2015 Dec 03, S A Ostroumov commented:

Full text of this article, free, is available online: https://www.researchgate.net/publication/200577836

On 2015 Dec 12, S A Ostroumov commented:

Review (favorable) of this article was published. See: https://www.researchgate.net/publication/286625953

On 2015 Dec 14, S A Ostroumov commented:

Full text of a review (with favorable evaluation) of this paper: https://www.researchgate.net/publication/286865472

On 2016 Jan 12, S A Ostroumov commented:

At World Catalog, the paper was reviewed and rated as excellent.

On 2016 Jan 12, S A Ostroumov commented:

Citation of this article, in Chile: https://www.researchgate.net/publication/277720835_La_transformacion_del_paisaje_rural-urbano_y_su_efecto_sobre_los_servicios_ecosistemicos_en_una_microcuenca_de_Santiago_Chile

On 2016 Jan 12, S A Ostroumov commented:

In the top 25% of all research outputs scored by Altmetric

On 2016 Jan 12, S A Ostroumov commented:

DOI: 10.1023/a:1015393924967

On 2016 Jan 12, S A Ostroumov commented:

This article has also its Russian version, published in the journal of Russian Academy of Sciences. The Russian version of this article is cited here: Rozenberg G.S. Idealizing object and fundamental notions of the modern ecology (with examples from vegetation ecology). ПОВОЛЖСКИЙ ЭКОЛОГИЧЕСКИЙ ЖУРНАЛ. 2002. № 3. С. 246 – 256.

On 2015 Dec 03, S A Ostroumov commented:

Full text, free, available online: https://www.researchgate.net/publication/259579921

On 2015 Dec 03, S A Ostroumov commented:

ABSTRACT: System of principles for conservation of the biogeocenotic function and the biodiversity of filter-feeders.- Doklady Biological Sciences. 2002. Vol. 383: 147-150. Bibliogr. 15 refs. ISSN 0012-4966 (Print) 1608-3105 (Online). Distributed by Springer, orderdept@springer-sbm.com. ** Text of the ABSTRACT: As a result of the author’s studies of filter-feeders (previous publications in Russian: Doklady akademii nauk [DAN], 1998, Vol. 362, P. 574-576; Doklady akademii nauk [DAN], 2001, Vol. 378, P. 283-285), it is clear that the filtering activity of populations of filter-feeders in natural habitats might be significantly reduced if the concentrations of some pollutants reach certain levels. The role of filter-feeders as factors of water purification in ecosystems is so important that their inhibition is a danger for the entire ecosystem. The author emphasizes that not only the biodiversity of filter-feeders but also their level of functional (filtration) activity is to be protected. In order to do so, the author suggested establishing a new type of protected areas whose main purpose is to protect functionally active populations of filter-feeders, including bivalves and other organisms. Those protected areas could be named hydrobiological (some variants: biofiltering, or malacological) reserves (some variants: refuges, sanctuaries, etc.). The author formulated 5 principles of nature conservation requirements in malacological and hydrobiological reserves (Tabl. 3). Among them is principle 2, "conservation of filtration activity of organisms and populations". The paper contains data on how 5 detergents (1-50 mg/L) inhibited the filtration activity of Unio tumidus, Mytilus galloprovincialis, Crassostrea gigas (Tabl. 2); on effects on the efficiency of elimination (EEE) of suspended matter from water were measured (Tabl. 2); on the number of days (0.3 – 10) needed to filter the volume of aquatic (freshwater and marine) ecosystem by the local bivalves (a review of data from literature) (Tabl. 1). "I suggest that the existing system of protected terrestrial and water areas should be supplemented with special sites intended to conserve populations of filter-feeders. In addition to biodiversity conservation, these populations should be conserved because they fulfill a very important biogeocenotic function of water filtration and purification" (p.149). "The system of five principles…is proposed to provide an ecological basis of the environment conservation conditions at these sites (malacological and hydrobiological reserves)" (p.149).]. DOI 10.1023/A:1015398125876; www.springerlink.com/index/1MNVLNAYW36TC92R.pdf

On 2016 Jan 06, S A Ostroumov commented:

In the top 25% of all research outputs scored by Altmetric. https://www.researchgate.net/publication/259579921 DOI: 10.1023/A:1015398125876; PMID: 12053567 [PubMed - indexed for MEDLINE]; www.ncbi.nlm.nih.gov/pubmed/12053567;

http://www.altmetric.com/details/3046537

On 2015 Aug 31, Steve Alexander commented:

This article was retracted in 2005 http://www.sciencedirect.com/science/article/pii/S0006291X05011563

On 2013 Oct 21, Hilda Bastian commented:

The predominant weight for safety concerns about single-session debriefing in this systematic review are carried by a single trial, at high risk of bias. See discussion in my comment here: Bisson JI, 1997. The method of imputation of adverse events in this trial does not appear to be described in this review.

A critical quality assessment of that trial was in part made by a systematic review author who was also an author of the trial. A more recent systematic review conducted by others (Gartlehner G, 2013), found the evidence on this intervention to be generally weak. There is further discussion in this blog post.

On 2013 Oct 21, Hilda Bastian commented:

The two ongoing studies discussed in this review have since been published. They are Ishikawa H, 2005 and Burn J, 2011, as discussed in this blog post.

On 2014 Apr 02, Vinay Gopalani commented:

this is not a free article

On 2015 Mar 29, Harri Hemila commented:

English translation is available at: http://www.mv.helsinki.fi/home/hemila/T10.pdf

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2017 Sep 09, Michael Allen commented:

The equations for disease impact number (DIN) and population impact number (PIN) are confusing according to the following examples in which the proportion with the diseased exposed to the treatment and the proportion of the population with the disease are both 0.1

In example 1 NNT=100; DIN=1000; PIN=10000 In example 2 NNT=10; DIN=100; PIN=1000

In these examples the only difference is the NNT (100 in example 1; 10 in example 2). A smaller NNT indicates a larger effect.

However changing the NNT from 100 to 10 leads to a smaller DIN and PIN indicating a smaller effect.

I have checked the way I calculated DIN and PIN against the authors' examples and they are correct.

It seems the authors' equations for the DIN and PIN may be incorrect. Or am I missing something?

On 2015 May 15, Christopher Southan commented:

Full text http://figshare.com/articles/Proteomic_approaches_to_central_nervous_system_disorders/1415926

On 2015 Oct 12, James Tsung commented:

Link to video: https://youtu.be/qocmUqu8Rqs

On 2015 Jul 07, Bill Cayley commented:

A good example of when "less" is "more" - https://lessismoreebm.wordpress.com/2015/05/11/suturing-versus-conservative-management-of-lacerations-of-the-hand-randomised-controlled-trial/

On 2014 Jun 02, Pedro Reche commented:

RANKPEP is now available at: http://imed.med.ucm.es/Tools/rankpep.html

On 2014 Feb 12, Diana Frame commented:

A note for researchers, MESH indexing terms on this article erroneously tag it as non-small cell lung cancer (NSCLC). It should be under Small Cell Lung Carcinoma[MeSH].

On 2015 Jun 02, thomas samaras commented:

None

On 2015 Jun 02, thomas samaras commented:

Additional information on height, CHD, and longevity is available from these recent publications.

Samaras TT. Shorter height is related to lower cardiovascular disease risk—A narrative review. Indian Heart Journal 2013; 65: 66-71.

Samaras, TT. Is short height really a risk factor for coronary heart disease and stroke mortality? A review. Med Sci Monit 2004; 10(4): RA63-76.

Samaras TT. Evidence from eight different types of studies showing that smaller body size is related to greater longevity. Journal of Scientific Research & Reports. 2014: 3 (16): 2150-2160, 2014; article no. JSRR.2014.16.003.

Samaras TT. Human Scaling and Body Mass Index. In: Samaras TT (ed): Human Body Size and the Laws of Scaling: Physiological Performance, Growth, Longevity and Ecological Ramifications. New York: Nova Science Pub; 2007: pp 17-32.

He Q, Morris BJ, Grove JS, Petrovitch H, Ross W, Masaki KH, et al. Shorter men live longer: Association of height with longevity and FOXO3 genotype in American men of Japanese ancestry. Plos ONE 9(5): e94385. doi:10.1371/journal.pone.0094385.

Salaris L, Poulain M, Samaras TT. Height and survival at older ages among men born in an inland village in Sardinia (Italy), 1866-2006. Biodemography and Social Biology, 58:1, 1-13.

Bartke A. Healthy Aging: Is Smaller better? A mini-review. Gerontology 2012; 58:337-43.

On 2014 Nov 24, Ivan Oransky commented:

The fourth author of this paper has agreed to retract it and five others following a finding of misconduct by the Office of Research Integrity: http://retractionwatch.com/2014/11/20/former-vanderbilt-scientist-faked-nearly-70-images-will-retract-6-papers-ori/

On 2017 May 09, Sophien Kamoun commented:

Can a biologist fix a smartphone? https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-017-0378-2

On 2013 Dec 28, Måns Magnusson commented:

Probably similar to post saccadic oscillations

On 2016 Nov 07, David Juurlink commented:

The primary outcome reported in this study differs considerably from the originally intended outcome. Readers are directed to our Cochrane Review Buckley NA, 2011 and an earlier related review Buckley NA, 2005 for details.

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2014 Aug 01, Amanda Capes-Davis commented:

Please be aware that this article has been retracted. Cell line TEC61 is not a thyroid cell line; it is actually JEG3, which is a choriocarcinoma cell line. Many thanks to the authors for providing this information.

On 2013 Oct 21, Gary Ward commented:

This is a seminal paper in the field, for two reasons:

1) It reported the development of a new, Tet-transactivator-based system for controlling gene expression in T. gondii. This system has since been widely adopted as a way to make conditional knockout parasites and is particularly useful for studying the function of essential genes in this haploid organism. For a powerful extension of this system based on promoter replacement, see Sheiner et al PLOS Pathogens 7 (2011) e1002392.

2) In the first application of the new system, the authors demonstrated directly the importance of the parasite’s Class XIV myosin, TgMyoA, for gliding motility, host cell invasion and host cell egress. This observation led to a great deal of subsequent work on the myosin motor complex and its role in the biology of T. gondii and other apicomplexan parasites.

Posted by Gary Ward on behalf of the University of Vermont Toxoplasma Journal Club (UVM ToxoJC); members include Jenna Foderaro, Anne Kelson, Shruthi Krishnamurthy, Jacqueline Leung, Pramod Rompikuntal, Luke Tilley & Gary Ward

On 2014 Oct 30, induprabha yadev commented:

the only one prospective study included in the recent systematic review by Goh et all

On 2016 Feb 01, Morten Oksvold commented:

Please note that this article is 1 out of 15 publications for which an independent investigation initiated by the University of Copenhagen has found suspicion of scientific dishonesty. The conclusion from the report was published July 23, 2012:

http://news.ku.dk/all_news/2012/2012.8/indications_of_fraud_in_penkowas_early_research/

This articles should therefore not be cited.

On 2016 Feb 19, E M Martínez-Cáceres commented:

In the light of the recent PubMed comment by Morten Oksvold, the referenced research study was performed entirely in our research centre by the research team led by Dr. Martínez-Cáceres at the time with Dr. Espejo as predoctoral researcher. Hence, the EAE in vivo experiments were performed in Barcelona with no involvement from Dr. Penkowa, who was engaged as an expert histopathologist. Dr. Penkowa received processed and encoded samples with which she performed some of the histopathological studies. The results were returned to us for overall analysis and submission for publication. It was agreed that Dr. Penkowa would be co-author of the published work.

On 2014 Nov 24, Ivan Oransky commented:

The first author of this paper has agreed to retract it and five others following a finding of misconduct by the Office of Research Integrity: http://retractionwatch.com/2014/11/20/former-vanderbilt-scientist-faked-nearly-70-images-will-retract-6-papers-ori/

On 2015 Dec 03, S A Ostroumov commented:

ABSTRACT: Identification of a New Type of Ecological Hazard of Chemicals: Inhibition of Processes of Ecological Remediation. - Doklady Biological Sciences, Vol. 385, 2002, pp. 377–379. Translated from Doklady Akademii Nauk, Vol. 385, No. 4, 2002, pp. 571–573. The author (Moscow University) discovered and quantitatively characterized a new type of ecological hazard of chemical pollution of water, which involves inhibition of important processes of ecological remediation of ecosystems (water filtration by aquatic bivalves). Experiments were performed using mollusks (oysters), Crassostrea gigas Thunberg, and a cell suspension in the seawater. The cell suspension was a model of suspended matter in aquatic ecosystem; this species of one-cell organisms was taken just for convenience, as a model of suspended particles. The laundry detergent Lanza-Automat inhibited water filtration by oysters (Crassostrea gigas). As a result, the removal of the suspended particles from water was inhibited. This demonstrated a new type of ecological hazard caused by water pollution with chemical pollutants at sublethal concentrations. This hazard is associated with the fact that chemical pollution of water causes inhibition of the physiological activity of filter-feeders, thereby inhibiting the important ecological processes of water filtration. These ecological processes contribute significantly to improving water quality, water purification and the related remediation of aquatic ecosystems (their ecological repair).

On 2015 Dec 03, S A Ostroumov commented:

Full text of this article is available, online free: https://www.researchgate.net/publication/259402820

On 2016 Jan 06, S A Ostroumov commented:

In the top 25% of all research outputs scored by Altmetric. https://www.researchgate.net/publication/259402820; Article titled: Identification of a New Type of Ecological Hazard of Chemicals: Inhibition of Processes of Ecological Remediation. DOI 10.1023/A:1019929305267; www.ncbi.nlm.nih.gov/pubmed/12469618; http://www.altmetric.com/details/3052799

On 2013 Nov 10, GianCarlo Panzica commented:

The conclusions of this study have been partially corrected by the results of a following study (Pierman S, 2008), where we demonstrated that the administration of estradiol and dihydrotestosterone to adult ArKO males restored AVP-immunoreactivity in the lateral septum of ArKO males to levels observed in intact wild type males. Therefore the decrease of AVP immunoreactivity described in the present study is due to a lack of activational effects of estradiol, rather than to an organizational effect.

On 2013 Dec 30, Tom Kindlon commented:

My response, published in BMJ USA, "The need for history (and epistemology) lessons"

My response, "The need for history (and epistemology) lessons", can be read at: http://www.bmj.com/rapid-response/2011/10/29/need-history-and-epistemology-lessons

A version of this was published in BMJ USA(1)

References:

[1]. Kindlon TP. The need for history (and epistemology) lessons. BMJ USA 01/2003; BMJ:E190-191. doi:10.1136/bmjusa.03020004

On 2014 Jul 24, DATTATRAY PAWAR commented:

An incorrect link has been provided for the full text. Kindly correct it. Regards.

On 2013 Nov 24, John Sotos commented:

Using a mortality-only model of smallpox vaccination policies, Bozzette et al (1) calculate that pre-emptively vaccinating the general population saves lives if the probability of a high-impact airport attack is greater than 0.01.

However, vaccine-related mortality generally occurs almost immediately, while vaccine-related protection fully lasts, it is thought, 3 to 5 years (2)(3). Thus, pre-emptive vaccination saves lives if the probability of attack is greater than 0.01 over 3 to 5 years, i.e. if the annual probability is 0.002 to 0.003 or higher. The 482 deaths predicted to result from a policy of pre-emptively vaccinating the population approximately equal the deaths from lightning strikes in the United States during a 5-year period (4).

Furthermore, although the attack scenarios used in the model were developed in consultation with experts, the evil ingenuity of some humans should not be underestimated. Attack plans targeting entire cities certainly exist (5). Prudent policy-making would, therefore, model an “Attack Scenario X” which is more lethal than the worst attack experts can publicly discuss.

These considerations make a policy of pre-attack population vaccination more attractive.

1. Bozzette SA, Boer R, Bhatnagar V, et al. A model for a smallpox-vaccination policy. New Engl J Med 2003;348:416-25.

2. http://www.bt.cdc.gov/agent/smallpox/overview/faq.asp, viewed on 9 Feb 2003.

3. Arita I. Duration of immunity after smallpox vaccination: a study on vaccination policy against smallpox bioterrorism in Japan. Jpn J Infect Dis 2002;55:112-6.

4. Lightning-Associated Injuries and Deaths Among Military Personnel — United States, 1998-2001. MMWR 2002;51:859-862.

5. Alibek K. Biohazard: The Chilling True Story of the Largest Covert Weapons Program in the World — Told from the Inside by the Man Who Ran It. New York: Delta, 2000; 21.

On 2013 Nov 24, John Sotos commented:

The Journal‘s editorial oversight of Mack’s analysis of smallpox (1) was so flawed that the article should have been presented as medical history, not as a contribution to biodefense policy.

Mack describes “average” smallpox characteristics in naturally occurring outbreaks. This represents a best-case scenario. The next outbreak will not be natural, and it may not be average.

The Soviets, for example, weaponized a highly virulent variola strain (2) and treated their variola “with plastics and resins to increase its potency and longevity in the air” (3). Responsible policy cannot, therefore, assume that attacks will use an average strain and natural delivery of variola.

Mack’s suggestion that “the media should provide more information about the dangers of vaccination” is exactly opposite the true need. In the same issue, Blendon et al (4) report that 25% of Americans believe death is a “likely” outcome of smallpox vaccination. The Journal should have caught the contradiction, and should have used its bully pulpit with lay readers and journalists to provide reminders of the safety of vaccination in appropriate populations.

(1) Mack T. A different view of smallpox and vaccination. N Engl J Med 2003;348:460-3.

(2) Alibek K. Biohazard. New York: Dell Publishing, 1999. Page 112

(3) Statement for the Record by Richard Preston Before The Senate Judiciary Subcommittee on Technology, Terrorism & Government Information and the Senate Select Committee on Intelligence. Chemical and Biological Weapons Threats to America: Are We Prepared? April 22, 1998. Available at: http://judiciary.senate.gov/oldsite/preston.htm

(4) Blendon RJ, DesRoches CM, Benson JM, Herrmann MJ, Taylor-Clark K, Weldon KJ. The public and the smallpox threat. N Engl J Med 2003;348:426-32.

On 2016 Feb 01, Morten Oksvold commented:

Please note that this article is based on earlier research data by J. Sudbø, which again originate from data which has been shown to be manipulated and partly fabricated. An independent investigation at Oslo University Hospital concluded that this article should be retracted:

http://www.ous-research.no/general/?k=general%2Fnews_articles&aid=5473

(in Norwegian, please use link at the end of the article to get the full report)

This article should therefore not be cited.

On 2015 Jun 02, thomas samaras commented:

Additional information on height and longevity is available from these publications.

Samaras TT. Evidence from eight different types of studies showing that smaller body size is related to greater longevity. Journal of Scientific Research & Reports. 2014: 3 (16): 2150-2160, 2014; article no. JSRR.2014.16.003.

Samaras TT. Human Scaling and Body Mass Index. In: Samaras TT (ed): Human Body Size and the Laws of Scaling: Physiological Performance, Growth, Longevity and Ecological Ramifications. New York: Nova Science Pub; 2007: pp 17-32.

He Q, Morris BJ, Grove JS, Petrovitch H, Ross W, Masaki KH, et al. Shorter men live longer: Association of height with longevity and FOXO3 genotype in American men of Japanese ancestry. Plos ONE 9(5): e94385. doi:10.1371/journal.pone.0094385.

Salaris L, Poulain M, Samaras TT. Height and survival at older ages among men born in an inland village in Sardinia (Italy), 1866-2006. Biodemography and Social Biology, 58:1, 1-13.

Bartke A. Healthy Aging: Is Smaller better? A mini-review. Gerontology 2012; 58:337-43.

On 2014 Jan 14, Alex Lancaster commented:

The link in the PubMed Central article is outdated, the current URL of the project is: http://www.pypop.org/

On 2016 Sep 23, Alexander Kraev commented:

http://dx.doi.org/10.1101/075671

On 2017 Aug 19, thomas samaras commented:

Forsen studied 165,000 military recruits and found that blood pressure increased with height. In addition, he found that birth weight correlated with height and weight at 18 years of age.

On 2016 Mar 29, Jonathan Wren commented:

Relocated to: https://loinc.org/

On 2015 May 20, Egon Willighagen commented:

This paper was recently made gold Open Access (CC-BY): http://chem-bla-ics.blogspot.nl/2015/04/cc-by-with-acs-author-choice-cdk-and.html

On 2017 Jun 06, Egon Willighagen commented:

A third paper about the CDK was published today in the J. Cheminform.: https://doi.org/10.1186/s13321-017-0220-4