We collected demographic and clinical pretreatment information, onset and grade of CRS, clinical presentation, severity and pattern of neurotoxicity, serum levels of pretreatment lactate dehydrogenase (LDH) in lymphoma patients and acute-phase proteins in all patients, radiographic and EEG findings, treatment, use of steroids, and clinical outcome.

Gerät dieses normale Eiweiß PrPC in Kontakt mit einem PrPSc genannten Eiweiß (Prion Protein Scrapie; pathogene Form des Prion-Proteins, das in der Form zuerst bei an Scrapie erkrankten Tieren gefunden wurde), nimmt PrPC die Form von PrPSc an, „es klappt um“, es ändert seine Konformation. Es entwickelt sich eine Kettenreaktion, in der immer mehr PrPC in PrPSc umgewandelt werden. Große Mengen an PrPSc wirken zerstörerisch auf das Gehirn, da sie unlöslich sind und sich in den Zellen ablagern. Infolgedessen sterben diese Zellen ab; es entstehen Löcher im Gehirn, eine schwammartige Struktur entsteht. Daher auch der Name dieser Krankheit: spongiforme Enzephalopathie, schwammartige Gehirnerkrankung.

Die vereinfachte Prionhypothese und Besonderheiten der Prionkrankheiten[Bearbeiten | Quelltext bearbeiten] Eines der zahlreichen im tierischen Körper vorkommenden Eiweiße heißt PrPC (Prion Protein cellular = zelluläres Prion-Protein). Es findet sich vor allem im Nervensystem, speziell im Gehirn. Zwischen den verschiedenen Tierarten und gegebenenfalls auch innerhalb einer Tierart unterscheiden sich die Prionen mehr oder weniger geringfügig. PrPC kommt vor allem an der Zelloberfläche vor und schützt die Zellen vor zweiwertigen Kupfer-Ionen, H2O2 und freien Radikalen. Des Weiteren wird vermutet, dass es einer der ersten Sensoren in der zellulären Abwehr von reaktivem Sauerstoff und freien Radikalen ist und Auswirkungen auf den enzymatischen Abbau von freien Radikalen hat.[3]

A prion /ˈpriːɒn/ (listen) is a misfolded protein that can transmit its misfolded shape onto normal variants of the same protein and trigger cellular death.

Der Morbus Bechterew (Spondylitis ankylosans) ist eine unheilbare, chronisch-entzündliche Erkrankung, die zur völligen Versteifung der Wirbelsäule führen kann. Die Erkrankung hat eine erbliche Komponente (HLA-B27) und zeigt sehr variable Verläufe. Typisch ist ein Befall der Iliosakralgelenke sowie der Wirbelsäule mit schleichend einsetzenden, dumpfen Rückenschmerzen. Charakteristische klinische Zeichen in der Diagnostik sind ein Klopf- und Verschiebeschmerz der Iliosakralgelenke (Mennell-Zeichen) sowie ein pathologisches Ott- und Schober-Maß. Radiologisch wird neben dem konventionellen Röntgen auch die Magnetresonanztomografie (MRT) eingesetzt. Die MRT ist dabei insbesondere in der Frühdiagnostik zur Detektion einer Sakroiliitis dem konventionellen Röntgen deutlich überlegen. Wichtigstes Element der Therapie ist die Physiotherapie, welche bei konsequenter Anwendung zur Verlangsamung des Krankheitsprogresses beitragen kann.

What are the renin-angiotensin-aldosterone system (RAAS) steps? The renin-angiotensin-aldosterone system (RAAS) involves several steps, including: When your blood pressure falls, your kidneys release the enzyme renin into your bloodstream. Renin splits angiotensinogen, a protein your liver makes and releases, into pieces. One piece is the hormone angiotensin I. Angiotensin I, which is inactive (doesn’t cause any effects), flows through your bloodstream and is split into pieces by angiotensin-converting enzyme (ACE) in your lungs and kidneys. One of those pieces is angiotensin II, an active hormone. Angiotensin II causes the muscular walls of small arteries (arterioles) to constrict (narrow), which increases blood pressure. Angiotensin II also triggers your adrenal glands to release aldosterone and your pituitary gland to release antidiuretic hormone (ADH, or vasopressin). Together, aldosterone and ADH cause your kidneys to retain sodium. Aldosterone also causes your kidneys to release (excrete) potassium through your urine. The increase in sodium in your bloodstream causes water retention. This increases blood volume and blood pressure, thus completing the renin-angiotensin-aldosterone system.

Which hormones does the pituitary gland make? The anterior lobe of your pituitary gland makes and releases the following hormones: Adrenocorticotropic hormone (ACTH or corticotrophin): ACTH plays a role in how your body responds to stress. It stimulates your adrenal glands to produce cortisol (the “stress hormone”), which has many functions, including regulating metabolism, maintaining blood pressure, regulating blood glucose (blood sugar) levels and reducing inflammation, among others. Follicle-stimulating hormone (FSH): FSH stimulates sperm production in people assigned male at birth. FSH stimulates the ovaries to produce estrogen and plays a role in egg development in people assigned female at birth. This is known as a gonadotrophic hormone. Growth hormone (GH): In children, growth hormone stimulates growth. In other words, it helps children grow taller. In adults, growth hormone helps maintain healthy muscles and bones and impacts fat distribution. GH also impacts your metabolism (how your body turns the food you eat into energy). Luteinizing hormone (LH): LH stimulates ovulation in people assigned female at birth and testosterone production in people assigned male at birth. LH is also known as a gonadotrophic hormone because of the role it plays in controlling the function of the ovaries and testes, known as the gonads. Prolactin: Prolactin stimulates breast milk production (lactation) after giving birth. It can affect fertility and sexual functions in adults. Thyroid-stimulating hormone (TSH): TSH stimulates your thyroid to produce thyroid hormones that manage your metabolism, energy levels and your nervous system. The posterior lobe of your pituitary gland stores and releases the following hormones, but your hypothalamus makes them: Antidiuretic hormone (ADH, or vasopressin): This hormone regulates the water balance and sodium levels in your body. Oxytocin: Your hypothalamus makes oxytocin, and your pituitary gland stores and releases it. In people assigned female at birth, oxytocin helps labor to progress during childbirth by sending signals to their uterus to contract. It also causes breast milk to flow and influences the bonding between parent and baby. In people assigned male at birth, oxytocin plays a role in moving sperm.

Erste Wahl bei Depressionen im Alter sind selektive Serotonin-Wiederaufnahmehemmer (SSRI). Die konventionellen tri- und tetrazyklischen Antidepressiva (TZA) sind auch im Alter gut wirksam. Anticholinerge Nebenwirkungen beschränken aber ihre Anwendung. Deswegen spielen die neueren Antidepressiva bei der Behandlung alter Patienten eine dominierende Rolle. Mit Venlafaxin, Mirtazapin, Reboxetin und Moclobemid steht ein breite Palette nebenwirkungsarmer Substanzen zur Verfügung. Der Wirkmechanismus der Substanzen unterscheidet sich. Venlafaxin ist ein Noradrenalin- und Serotonin-Wiederaufnahmehemmer. Mirtazapin ist ein indirekter Serotonin- und Noradrenalinagonist, Reboxetin ein selektiver Noradrenalin-Rückaufnahmehemmer. Mit Moclobemid steht ein nebenwirkungsarmer reversibler MAO-Hemmer zur Verfügung. Bei leichten, mittelschweren, möglicherweise auch bei schweren Depressionen sind Johanneskrautextrakte vorteilhaft, weil viele ältere Patienten ein pflanzliches Mittel bevorzugen oder leichter von dieser Behandlung überzeugt werden können. Die Verträglichkeit ist im allgemeinen sehr gut. Der wirksame Bestandteil, Hyperforin, hemmt die Wiederaufnahme von Serotonin, Noradrenalin und Dopamin. Lithium ist im Alter weniger verträglich und weniger wirksam. Ein niedrigerer Spiegel ist zu empfehlen. Eine bestehende Prophylaxe oder Augmentation mit Lithium sollte im Alter weitergeführt werden, aber selten gibt es gute Gründe Lithium neu anzusetzen. In Zukunft werden wahrscheinlich Carbamazepin, Valproat oder Lamotrigin häufiger eine Alternative zu Lithium sein.

Verlauf [3] Symptomatik beginnt meist schubförmig (klinisch isoliertes Syndrom, schubförmig remittierende MS) und monosymptomatisch Häufige Erstsymptome Optikusneuritis Sensibilitätsstörungen Chronische Erschöpfbarkeit (Fatigue) Vollständige oder unvollständige Symptomrückbildung innerhalb von Tagen bis Wochen Auch langsame stetige Behinderungszunahme (mit oder ohne zusätzliche Schubereignisse) möglich Ab Krankheitsbeginn (primär progrediente MS) Nach schubförmigem Verlauf (sekundär progrediente MS) Häufige MS-Symptome [3] Optikusneuritis (Neuritis nervi optici, NNO): Entzündung des Sehnerven (i.d.R. dessen retrobulbärer Anteil: Retrobulbärneuritis) mit Demyelinisierung → Leitungsstörung I.d.R. einseitig, teilweise rezidivierend unter Einbeziehung der Gegenseite Afferente Pupillenstörung Schmerzen bei Augenbewegung Visusminderung bis zur passageren Erblindung Zentralskotom (fast immer) Farbsinnstörung Akutphase: Meist unauffällige Ophthalmoskopie (bei seltenerer Papillitis: Papillenschwellung)

Negative symptoms of schizophreniaThe negative symptoms of schizophrenia can often appear several years before somebody experiences their first acute schizophrenic episode.These initial negative symptoms are often referred to as the prodromal period of schizophrenia.Symptoms during the prodromal period usually appear gradually and slowly get worse.They include the person becoming more socially withdrawn and increasingly not caring about their appearance and personal hygiene.It can be difficult to tell whether the symptoms are part of the development of schizophrenia or caused by something else.Negative symptoms experienced by people living with schizophrenia include:losing interest and motivation in life and activities, including relationships and sexlack of concentration, not wanting to leave the house, and changes in sleeping patternsbeing less likely to initiate conversations and feeling uncomfortable with people, or feeling there's nothing to sayThe negative symptoms of schizophrenia can often lead to relationship problems with friends and family as they can sometimes be mistaken for deliberate laziness or rudeness.

The Dopamine HypothesisThe dopamine hypothesis of schizophrenia postulates that hyperactivity of dopamine D2 receptor neurotransmission in subcortical and limbic brain regions contributes to positive symptoms of schizophrenia, whereas negative and cognitive symptoms of the disorder can be attributed to hypofunctionality of dopamine D1 receptor neurotransmission in the prefrontal cortex (Toda & Abi-Dargham, 2007). In support of this, studies have shown an increased density of the dopamine D2 receptor in postmortem brain tissue of schizophrenia sufferers (Seeman et al., 2000). It is also reported that upregulation of D2 receptors in the caudate nucleus of patients with schizophrenia directly correlates with poorer performance in cognitive tasks involving corticostriatal pathways (Hirvonen et al., 2004). That dopamine-releasing drugs, such as amphetamine, possess psychotomimetic properties in addition to the D2-antagonist property common to many of the currently prescribed antipsychotic treatments, giving credence to the dopamine hypothesis of schizophrenia.

Opioid overdose[edit] Intravenous doses of nalmefene have been shown effective at counteracting the respiratory depression produced by opioid overdose.[

Nalmefene is an opioid antagonist medication used in the management of opioid overdose and alcohol dependence.[1][2] It is taken by mouth. Nalmefene is an opiate derivative similar in both structure and activity to the opioid antagonist naltrexone. Advantages of nalmefene relative to naltrexone include a longer elimination half-life, greater oral bioavailability, and no observed dose-dependent liver toxicity.[4] Nalmefene may precipitate acute withdrawal symptoms in people who are dependent on opioid drugs, or more rarely when used post-operatively, to counteract the effects of strong opioids used in surgery.[m

Aversive effects[edit] Whether naltrexone causes dysphoria, depression, anhedonia, or other aversive effects as side effects has been studied and reviewed.[39][40][41][42] In early studies of normal and opioid-abstinent individuals, acute and short-term administration of naltrexone was reported to produce a variety of aversive effects including fatigue, loss of energy, sleepiness, mild dysphoria, depression, lightheadedness, faintness, mental confusion, nausea, gastrointestinal disturbances, sweating, and occasional feelings of unreality.[41][43][44][45][46] However, these studies were small, often uncontrolled, and used subjective means of assessing side effects.[46][39] Most subsequent longer-term studies of naltrexone for indications like alcohol or opioid dependence have not reported dysphoria or depression with naltrexone in most individuals.[41][47][46] According to one source:[40]

Blockade of MORs is thought to be the mechanism of action of naltrexone in the management of opioid dependence—it reversibly blocks or attenuates the effects of opioids. It is also thought to be involved in the effectiveness of naltrexone in alcohol dependence by reducing the euphoric effects of alcohol.

Occupancy of the opioid receptors in the brain by naltrexone has been studied using positron emission tomography (PET).[58][75] Naltrexone at a dose of 50 mg/day has been found to occupy approximately 90 to 95% of brain MORs and 20 to 35% of brain DORs.[58] Naltrexone at a dose of 100 mg/day has been found to achieve 87% and 92% brain occupancy of the KOR in different studies.[76][75][77] Per simulation, a lower dose of naltrexone of 25 mg/day might be expected to achieve around 60% brain occupancy of the KOR but still close to 90% occupancy of the MOR.[75] In a study of the duration of MOR blockade with naltrexone, the drug with a single 50 mg dose showed 91% blockade of brain [11C]carfentanil (a selective MOR ligand) binding at 48 hours (2 days), 80% blockade at 72 hours (3 days), 46% blockade at 120 hours (5 days), and 30% blockade at 168 hours (7 days).[7][8] The half-time of brain MOR blockade by naltrexone in this study was 72 to 108 hours (3.0 to 4.5 days).[7][8] Based on these findings, doses of naltrexone of even less than 50 mg/day would be expected to achieve virtually complete brain MOR occupancy.[7][8] Blockade of brain MORs with naltrexone is much longer-lasting than with other opioid antagonists like naloxone (half-time of ~1.7 hours intranasally) or nalmefene (half-time of ~29 hours).[7][78][79] The half-life of occupancy of the brain MOR and duration of clinical effect of naltrexone are much longer than suggested by its plasma elimination half-life.[7][80][8][81] A single 50 mg oral dose of naltrexone has been found to block brain MORs and opioid effects for at least 48 to 72 hours.[80][8][82] The half-time of brain MOR blockade by naltrexone (72–108 hours) is much longer than the fast plasma clearance component of naltrexone and 6β-naltrexol (~4–12 hours) but was reported to correspond well to the longer terminal phase of plasma naltrexone clearance (96 hours).[7][8][39] As an alternative possibility, the prolonged brain MOR occupancy by opioid antagonists like naltrexone and nalmefene may be due to slow dissociation from MORs consequent to their very high MOR affinity (<1.0 nM).[79][83] Naltrexone blocks the effects of MOR agonists like morphine, heroin, and hydromorphone in humans via its MOR antagonism.[4][9] Following a single 100 mg dose of naltrexone, the subjective and objective effects of heroin were blocked by 90% at 24 hours, with blockade then decreasing up to 72 hours.[4] Similarly, 20 to 200 mg naltrexone dose-dependently antagonized the effects of heroin for up to 72 hours.[4] Naltrexone also blocks the effects of KOR agonists like salvinorin A, pentazocine, and butorphanol in humans via its KOR antagonism.[84][85][86][65] In addition to opioids, naltrexone has been found to block or reduce the rewarding and other effects of other euphoriant drugs including alcohol,[48] nicotine,[87] and amphetamines.[88

Major subtypes[edit] There are four major subtypes of opioid receptors.[12] OGFr was originally discovered and named as a new opioid receptor zeta (ζ). However it was subsequently found that it shares little sequence similarity with the other opioid receptors, and has quite different function. Receptor Subtypes Location[13][14] Function[13][14] G protein subunit delta (δ) DOR OP1 (I) δ1,[15] δ2 brain pontine nuclei amygdala olfactory bulbs deep cortex peripheral sensory neurons analgesia antidepressant effects convulsant effects physical dependence may modulate μ-opioid receptor-mediated respiratory depression Gi kappa (κ) KOR OP2 (I) κ1, κ2, κ3 brain hypothalamus periaqueductal gray claustrum spinal cord substantia gelatinosa peripheral sensory neurons analgesia anticonvulsant effects depression dissociative/hallucinogenic effects diuresis miosis dysphoria neuroprotection sedation stress Gi mu (μ) MOR OP3 (I) μ1, μ2, μ3 brain cortex (laminae III and IV) thalamus striosomes periaqueductal gray rostral ventromedial medulla spinal cord substantia gelatinosa peripheral sensory neurons intestinal tract μ1: analgesia physical dependence μ2: respiratory depression miosis euphoria reduced GI motility physical dependence μ3: possible vasodilation Gi Nociceptin receptor NOROP4 (I) ORL1 brain cortex amygdala hippocampus septal nuclei habenula hypothalamus spinal cord anxiety depression appetite development of tolerance to μ-opioid agonists zeta (ζ) ZOR heart liver skeletal muscle kidney brain pancreas fetal tissue liver kidney tissue growth embryonic development regulation of cancer cell proliferation

Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands.[1][2][3] The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors (SSTRs). Opioid receptors are distributed widely in the brain, in the spinal cord, on peripheral neurons, and digestive tract.

The N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons.

In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs.[1] The site that an allosteric modulator binds to (i.e., an allosteric site) is not the same one to which an endogenous agonist of the receptor would bind (i.e., an orthosteric site). Modulators and agonists can both be called receptor ligands.[2] Allosteric modulators can be 1 of 3 types either: positive, negative or neutral. Positive types increase the response of the receptor by increasing the probability that an agonist will bind to a receptor (i.e. affinity), increasing its ability to activate the receptor (i.e. efficacy), or both. Negative types decrease the agonist affinity and/or efficacy. Neutral types don't affect agonist activity but can stop other modulators from binding to an allosteric site. Some modulators also work as allosteric agonists.[2]

Ethanol and benzodiazepines act on the central nervous system by binding to the GABAA receptor, increasing the effects of the inhibitory neurotransmitter GABA (i.e., they act as positive allosteric modulators at these receptors).[15][4] In alcohol use disorder, one of the main mechanisms of tolerance is attributed to GABAA receptors becoming downregulated (i.e. these receptors become less sensitive to GABA).[4] When alcohol is no longer consumed, these down-regulated GABAA receptor complexes are so insensitive to GABA that the typical amount of GABA produced has little effect, leading to physical withdrawal symptoms;[4] since GABA normally inhibits neural firing, GABAA receptor desensitization results in unopposed excitatory neurotransmission (i.e., fewer inhibitory postsynaptic potentials occur through GABAA receptors), leading to neuronal over-excitation (i.e., more action potentials in the postsynaptic neuron). One of acamprosate's mechanisms of action is the enhancement of GABA signaling at GABAA receptors via positive allosteric receptor modulation.[15][16] It has been purported to open the chloride ion channel in a novel way as it does not require GABA as a cofactor, making it less liable for dependence than benzodiazepines. Acamprosate has been successfully used to control tinnitus, hyperacusis, ear pain, and inner ear pressure during alcohol use due to spasms of the tensor tympani muscle.[medical citation needed] In addition, alcohol also inhibits the activity of N-methyl-D-aspartate receptors (NMDARs).[19][20] Chronic alcohol consumption leads to the overproduction (upregulation) of these receptors. Thereafter, sudden alcohol abstinence causes the excessive numbers of NMDARs to be more active than normal and to contribute to the symptoms of delirium tremens and excitotoxic neuronal death.[21] Withdrawal from alcohol induces a surge in release of excitatory neurotransmitters like glutamate, which activates NMDARs.[22] Acamprosate reduces this glutamate surge.[23] The drug also protects cultured cells from excitotoxicity induced by ethanol withdrawal[24] and from glutamate exposure combined with ethanol withdrawal.[25] The substance also helps re-establish a standard sleep architecture by normalizing stage 3 and REM sleep phases, which is believed to be an important aspect of its pharmacological activity.[18]