Vitamin and mineral supplements are often given Rapid detoxifica

Vitamin and mineral supplements are often given. Rapid detoxification methods Clonidine-naltrexone detoxification This method29-31 combines a rapid, precipitated withdrawal by naltrexone producing severe withdrawal symptoms, with high doses of clonidine and benzodiazepines before and after the naltrexone to ameliorate the symptoms. While shortening withdrawal to 2 to 3 days, evidence is lacking of longer abstinence or naltrexone

retention.32 Rapid opioid withdrawal under general anesthesia To decrease further Inhibitors,research,lifescience,medical the time needed for withdrawal, a rapid detoxification procedure using general anesthesia was developed33 and gradually improved.34-37 A variety of medications have been used, including naltrexone or nalmefene, propofol anesthesia or heavy midazolam sedation, the antiemetic ondansetron, the antidiarrheal octreotide, and clonidine and benzodiazepines for other withdrawal symptoms, and has been carried Inhibitors,research,lifescience,medical out on either an inpatient or outpatient basis. Post-procedure

therapy varies widely. Claims of high rates of abstinence months after detoxification have been made, but no objective verification exists, and the samples are not representative.38 Significant withdrawal symptoms may persist for days or even weeks after the procedure in humans15,39, 40 or in rats,41 and there appears to be no longer-term improved outcome at 1 to 3 months Inhibitors,research,lifescience,medical later.15,42, 43 Internationally, over one dozen deaths have been reported, usually within 72 hours of the procedure, with pulmonary edema a common complication.44-47 Pregnancy Illicit opioid use during pregnancy can Inhibitors,research,lifescience,medical have numerous

harmful effects on the woman, fetus, and neonate. Residential abstinent treatment is usually not available. Methadone maintenance is thus the standard approach.48 While the infant will be physically dependent on methadone and about half need to be withdrawn, no birth defects are associated with such exposure, if prenatal care is adequate. Withdrawal from methadone maintenance is usually not preferable, Inhibitors,research,lifescience,medical but if carried out it should occur during the second trimester at no greater than 5 mg/week. Methadone metabolism is increased during pregnancy, and plasma half -life decreased. The clinician must balance the risk of illicit opioid use if the dose is too low, and the risks of the neonatal abstinence syndrome (NAS) mafosfamide if the dose is too high. This can be somewhat ameliorated by split dosing. Studies of pregnant methadone-maintained women found decreased narcotic use and improved health and prenatal care. Fetal growth and perinatal outcomes also improved. These benefits dimmish with continued use/abuse of licit (alcohol and tobacco) or illicit (cocaine and marijuana) substances.49 Maintenance on buprenorphine is a more recent development with published reports of over 300 pregnancies, with good fetal outcomes. Buprenorphine appears comparable to methadone on outcome GDC-0994 research buy measures as assessed by NAS and maternal and neonatal safety.

For such drugs, the prescribing information (known as the summary

For such drugs, the prescribing information (known as the summary of product characteristics “SPC” in Europe and “labeling” in the USA) would require careful crafting of the indication to reflect the population and the disease entity most, likely to benefit, as well as detailed information on the proarrhythmic risk with carefully selected dose regimen, appropriate contraindications, description of interactions, special precautions, and monitoring requirements during their clinical use.43 Reflecting the robust data on efficacy, restriction of an indication may be one way of minimizing the population

likely to be exposed Inhibitors,research,lifescience,medical to the NCE. Allied to the indication is the posology of the NCE. The posology section may be required to include information on starting dose, a shallow dose titration schedule depending on the half-life of the drug and the time required Inhibitors,research,lifescience,medical to reach steady state, maximum single dose, maximum daily dose, and the duration of therapy. The most recent example of restriction of indications is thioridazine. From

July 2000, the indication for Selleck Rapamycin Thioridazine in the US was amended by the FDA to state: “Thioridazine is now indicated only for schizophrenic Inhibitors,research,lifescience,medical patients who fail to show an acceptable response to adequate courses of treatment, with other antipsychotic drugs, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse Inhibitors,research,lifescience,medical effects. Thioridazine has not been systematically evaluated in controlled trials in treatment-refractory schizophrenic patients and its efficacy in such patients is unknown. ” In view of the long half-life of pimozide (55 h, but may be as high as 150 h in some), its dose schedule was

revised to recommended a starting Inhibitors,research,lifescience,medical dosage Ketanserin of 20 mg/day with a maximum dosage of 60 mg/day. Following reports of TdP and other ventricular arrhythmias, the dose schedule of pimozide for chronic schizophrenia was reamended to recommend an initial starting dosage of 2 mg/day (exceptionally 10 mg/day in acute schizophrenia, but even this recommendation too was subsequently removed). The dose was to be increased by a shallow dose titration (“dose increases should be made at weekly intervals or longer, and by increments of 2-4 mg in the daily dose”). The maximum dosage was reduced from 60 to 20 mg/day. The section of the SPC most likely to be effective in containing a clinical risk, if the prescribing physicians adhere to it, is that on contraindications.

An estimated 700 000 Vietnam veterans – almost a quarter of all s

An estimated 700 000 Vietnam veterans – almost a quarter of all soldiers sent to Vietnam from 1964 to 1973 – required some form of psychological help. The prevalence of delayed and chronic PTSD, in spite of the careful prevention of psychiatric casualties in Vietnam itself, was a rude awakening. Trying to explain this paradox called for new hypotheses,

for instance, that PTSD might be a common form of psychiatric casualty in “low-level“ warfare.28 Similar profiles had been observed in the French Inhibitors,research,lifescience,medical post-colonial wars in Indochina and Algeria.29 This post- Vietnam syndrome, increasingly diagnosed in veterans in the seventies, ultimately led to the adoption of PTSD as a diagnostic category in 1980 in DSM-III. It seems puzzling that no such category existed in DSM-II, which had even abandoned the former DSM-’I

category of so-called ”gross stress reaction,“ when it was published in 1968, the Inhibitors,research,lifescience,medical year of the Communist Jet Offensive in Vietnam. Retrospect There is currently a measure of consensus on the diagnosis and phenomenological description of PTSD, which is recognized as a specific syndrome in individuals who have experienced a major traumatic event. Most modem textbooks concur in describing this syndrome as comprising three groups of symptoms: (i) the recurrent and distressing reexperiencing Inhibitors,research,lifescience,medical of the event in dreams, thoughts, or flashbacks; (ii) emotional mTOR inhibitor numbing and avoidance of stimuli reminiscent of the trauma; (iii) and a permanent state of increased Inhibitors,research,lifescience,medical arousal. The first symptoms of PTSD are often delayed and they are separated from the trauma by a latency period;

however, once installed, the disorder tends to follow a chronic course and the symptoms do not abate with time. DSM-IV 30 has the merit of clearly distinguishing PTSD, a chronic syndrome, from acute stress disorder, which is short-lived and appears soon after the trauma. We tend to abusively interpret the literature of previous decades as if today’s diagnostic categories Inhibitors,research,lifescience,medical had always existed. However, a clear distinction between acute stress disorder and chronic PTSD is usually lacking in previous works. Also, there was little attempt to predict the enough risk of developing PTSD. Providing the trauma is severe enough, most individuals will go on to develop PTSD. However, one puzzling question is that many survivors seemingly do not develop symptoms even after a severe stressor.31 Likewise, the historical literature on PTSD offers few clues concerning effective treatment, once the symptoms have become chronic. Jhe practice of forward treatment aiming to prevent the development of chronic disorders may have inspired today’s psychological debriefing of disaster victims.
The human response to psychological trauma is one of the most important public health problems in the world.

8) 92 One of the most interesting candidate genes for schizophren

8).92 One of the most interesting candidate genes for schizophrenia and NVP-BGJ398 cell line psychosis came from the multistage GWAS analyzing over 20 000 cases and controls.93 In the initial GWAS (479 cases, 2937 controls), O’Donovan et al93 observed 12 loci to be moderately associated with schizophrenia (P<10-5). In the first replication sample (1664 cases, 3541 controls) association of 6 of the 12 SNPs was replicated. These six SNPs were genotyped in the second

replication sample (4143 cases, 6515 controls). In the complete replication sample set (stage one + two), three loci namely: Zinc finger protein 804A (ZNF804A, rs1344706, 2q32.1, P=9.25×10-5), intergenic regions on 11p14.1 (rs1602565, Inhibitors,research,lifescience,medical P=3. 22×10-4) and 16p13.12 (rs7192086, P=5.10×10-4) were modestly associated with schizophrenia.

In the combined sample from the initial stage plus the two replication sets, ZNF804A showed strong evidence of association (OR=1.12; P=1.6×10-7). Furthermore, when patients with bipolar disorder Inhibitors,research,lifescience,medical were included, the obser-vation became more significant, suggesting that ZNF804A might be a susceptibility gene for the broader psychosisphenotype. ZNF804A is a putative transcription factorand the risk allele of the rs1344706 polymorphism (intron2, C>A) has been recently shown to be associated withdisturbed connectivity between the dorsolateral Inhibitors,research,lifescience,medical pre-frontal cortex (DLPFC) and the hippocampus, as well asbetween left and right hemispheres. Also there wasaltered coupling of DLPFC with the amygdala.94 The former may lead to disturbed executive function and the latter can affect the interaction between prefrontal and limbic structures. The association of ZNF804A markerrs1344706 with schizophrenia was recently replicated inpatients Inhibitors,research,lifescience,medical from Ireland (n=1021 cases, 626 controls; P=0.01).95 Increased expression of the A allele comparedwith the C allele was observed in the dorsolateral pre-frontal

cortex of postmortem control brain samples. However, there was Inhibitors,research,lifescience,medical no difference between the two alleles in overall mRNA expression between postmortem schizophrenia cases and controls.94 The SNP rs1344706 was also significant in the GWAS conducted by theInternational Schizophrenia Consortium (P=0.029, OR (A-allele) =1.08).96 Additionally, Cediranib (AZD2171) in a large multicenterstudy, association of rs1344706 with schizophrenia (5164 cases and 20 709 controls; OR=1.08, P=0.0029) and psy-chosis (OR=1.09, P=0.00065) has been replicated.97 Based on this replication by three other independent groups, andthe demonstration of functional effect on brain connec-tivity, ZNF804A is a promising candidate gene for schiz-ophrenia and psychosis in general. The small effect sizes (OR 1.08-1.12) account for only 1% to 2% of the variancein risk for the disease. In general these replicating smalleffects are consistent with the common disease commonvariant hypothesis.

21 Evidence for the role of a frontostriatal system in cognition

21 Evidence for the role of a frontostriatal system in cognition and behavior was first suggested by a series of experimental observations.22 Specifically, lesions of electrical stimulation of the dorsolateral prefrontal cortex or of the anterodorsal head of the caudate nucleus, to

which this region projects, were found to produce deficits in the same behavioral domain- namely, delayed-response and delayed-alternation tasks.23 Similarly, lesions or electrical stimulation, either of the orbitofrontal cortex or of the Raf activity ventrolateral head of the caudate, resulted in comparable deficits in object alternation or response Inhibitors,research,lifescience,medical inhibition paradigms.14 Accordingly, disruption to cognitive processes following striatal injury was interpreted as the ”downstream“ interruption of anatomically Inhibitors,research,lifescience,medical congruent outflow from the frontal cortex.24,25 Basic circuit structure The five major frontal-subcortical circuits suggested by Alexander et al5,7-9 are now generally accepted. These include a motor circuit that originates in the supplementary motor area, and an oculomotor circuit originating in the frontal eye field. The motor circuit originates from neurons in the supplementary motor area, premotor Inhibitors,research,lifescience,medical cortex, motor

cortex, and somatosensory cortex, recently confirmed by fMRI findings.26 These areas project principally to the putamen in a somatotopic distribution. The putamen in turn projects to ventrolateral globus pallidus interna (GPi), globus Inhibitors,research,lifescience,medical pallidus externa (GPe), and caudolateral SN. The globus pallidus (GP) connects to the ventrolateral, ventral anterior, and centromedianum nuclei of the thalamus, whose major efferents Inhibitors,research,lifescience,medical are to the supplementary motor area, premotor cortex, and motor

cortex, completing the circuit. Thalamic nuclei have reciprocal connections with the putamen and cerebral cortex, in addition to the connections contained within the circuit. Throughout the circuit, all the discrete somatotopic organization of movement-related neurons is maintained. Information processing in the circuits is not strictly sequential; neurophysiological investigations of movement demonstrate preparatory premovement activity, serial processing of movements initiated in the cortex, and concurrent parallel processing in the structures of the circuit.8,27,28 The oculomotor circuit originates in the frontal eye field (Brodmann’s area 8) as well as prefrontal and posterior parietal cortex, and connects sequentially to the central body of the caudate nucleus, dorsomedial GP and ventrolateral SN, ventral anterior and mediodorsal thalamic nuclei, and frontal eye field.

Twenty-five percent of elders whose neuropsychological testing is

Twenty-five percent of elders whose neuropsychological testing is unimpaired prior to death meet full pathologic criteria for AD (Ince 2001), suggesting that this degree of pathology does not invariably result in clinical dementia. Educational and occupational exposure and leisure activities are considered Inhibitors,research,lifescience,medical that as related with a reduced risk of developing dementia (Stern 2009). Neuropathologic correlations support this theory showing that individuals with greater cognitive reserve, as reflected in years of education, are

better able to cope with AD brain pathology without observable cognitive deficits (Roe et al. 2007). However, results from studies examining the relation of the education level with other than the clinical onset aspects, such as the rate of cognitive Inhibitors,research,lifescience,medical decline, were not consistent. In a study of AD patients with mild or moderate stage, higher educational attainment was associated with a slower rate of cognitive decline on the Mini-Mental State Exam (MMSE) (Fritsch et al. 2001). Another study showed that higher educational attainment was associated with a slightly accelerated Inhibitors,research,lifescience,medical rate of cognitive deterioration (Wilson et al. 2009). Data analysis of a large cohort of participants in the Victoria Longitudinal Study

showed that years of education were strongly related to cognitive level in all domains, particularly verbal fluency, but education Inhibitors,research,lifescience,medical was not related to rates of change over time for any cognitive domain (Wilson et al. 2004). In a prospective community survey in

old subjects without an established clinical diagnosis of AD, education was robustly associated with level Inhibitors,research,lifescience,medical of cognitive function but not with the rate of cognitive decline (Zahodne et al. 2011). A meta-analysis of data of 34 previously published studies showed that education, hypertension, CXCR antagonist objective indices of health, cardiovascular disease, and apolipoprotein E (APOE) were associated with cognitive decline in old-age subjects (Anstey and Christensen 2000). As mild cognitive impairment (MCI) is a clinically and pathologically heterogeneous state, showing a conversion rate into dementia of 11-33% within 3-mercaptopyruvate sulfurtransferase 2 years (Gauthier et al. 2006) or approximately 12% per year (Petersen et al. 1999; Anchisi et al. 2005), the question about the appliance of the cognitive reserve theory in MCI has probable conflicting answers. Recent investigations based on neuroimaging measurements (Solé-Padullésa et al. 2009), biochemical methods (Rolstad et al. 2010), and epidemiological studies (Afgin et al. 2012) were indicative that the cognitive reserve hypothesis may be applied also in MCI subjects.

10,15,16 The spectrum of bacteria differs somewhat among pure met

10,15,16 The spectrum of bacteria differs somewhat among pure metabolic stones, pure infection stones, and mixed metabolic/infection stones (Table 3). Table 2 Upper Tract Surgical Stone Series and Stone Culture Results Since 1980 Table 3 Upper Tract Surgical Stone Series Reporting Results of Both Metabolic and Infection Stone Cultures Since 1980 Conclusions

Our case was certainly unique in that it represents the most bacterial species ever isolated Inhibitors,research,lifescience,medical from a surgically removed upper urinary tract stone. The role of stone culture is not clearly defined; however, it may be advisable during removal of large volume upper tract stones as it may permit more targeted antimicrobial therapy and perhaps avert some of the consequences of SIRS or sepsis. This will need to be verified with a randomized, controlled Inhibitors,research,lifescience,medical study, which to date has not been done. In addition, certain patients undergoing surgical removal of smaller upper tract stones may benefit from such testing, and the profiles of such patients will need to be determined. Main Points Despite the use of culture-specific or broad-spectrum antibiotic therapy prior to surgical removal of upper tract nephrolithiasis, certain patients still develop postoperative sepsis.

Some have reported that preoperative Inhibitors,research,lifescience,medical voided urine cultures from these patients may not be reflective of the bacterial environment within the stone that is to be treated. The development of a urinary tract infection is Inhibitors,research,lifescience,medical a common postoperative complication associated with removal of upper urinary tract stones; one-third of patients undergoing percutaneous nephrostolithotomy

experience this occurrence, which places patients at risk for developing sepsis and systemic inflammatory response syndrome, which can be fatal. Inhibitors,research,lifescience,medical Prescribing antimicrobial therapy that will eradicate the organism in the urine and provide broad-spectrum coverage for the potentially different bacteria harbored within the stone is desired. Levetiracetam In addition, performing a stone culture may help to identify organisms that are not covered by initial antibiotic therapy, providing an opportunity to institute earlier targeted therapy. Footnotes The authors report no real or apparent conflicts of interest.
Over 2300 posters, abstracts, and videos were presented at the annual meeting of the American Urological Association (AUA), held this year in Atlanta, Georgia, May 19–23, 2012. The editors of Reviews in Urology have culled an enormous volume of information from this premier source and present those findings that are the most relevant to the practicing urologist.

Another genetic factor which may contribute to high-altitude perf

Another genetic factor which may contribute to high-altitude performance is a polymorphism in the angiotensin-converting enzyme gene that appears to be more prevalent in elite mountaineers and in endurance athletes than in the general population.49 Individuals differ widely in their susceptibility to high-altitude disorders; some suffer the life-threatening complications of high-altitude cerebral or pulmonary edema at altitudes Inhibitors,research,lifescience,medical as low as 3,000 m, whereas others can climb to 8,000 m without supplemental oxygen. Genetic influences remain an active area of investigation.50

PRE-EXISTING DISEASES Recreational travelers, hikers, and skiers with Inhibitors,research,lifescience,medical underlying cardiac or pulmonary diseases often seek advice regarding high-altitude travel. AUY-922 Asymptomatic patients with coronary disease generally do well, although it is probably prudent to avoid highly strenuous exercise; patients with heart failure should avoid the hypoxia of high altitude.51 Severe anemia and sickle cell disease Inhibitors,research,lifescience,medical are also contra-indications to high-altitude travel.51 The advice for patients with lung disease depends on the underlying disease, its severity, and the anticipated altitude and activity

level; specific recommendations are contained in an extensive review of the subject.52 HIGH-ALTITUDE CEREBRAL Inhibitors,research,lifescience,medical EDEMA High-altitude cerebral edema (HACE) is likely a continuum of AMS. AMS is generally self-limiting, whereas HACE can be fatal. Individuals with high Lake Louise scores should be carefully

monitored for the signs of ataxia, confusion, and hallucinations which may mark the onset of HACE. HACE is a clinical diagnosis and consists of ataxia and altered consciousness in someone with AMS or high-altitude pulmonary edema. Individuals with AMS should not ascend until symptoms have resolved; if symptoms fail to resolve, they should descend. Individuals with HACE should descend immediately if at all Inhibitors,research,lifescience,medical possible and should never descend unaccompanied. The exact processes leading to high-altitude cerebral edema are ADP ribosylation factor unknown although the edema is probably extracellular, due to blood–brain barrier leakage (vasogenic edema), rather than intracellular, due to cellular swelling (cytotoxic edema).53 Vasogenic edema preferentially spreads along white matter tracts, whereas cytotoxic edema affects both gray and white matter. MRI studies of patients with HACE showed that the majority had intense T2 signal in white matter areas, particularly the splenium of the corpus callosum, but no gray matter abnormalities.53 The predilection for the splenium and corpus callosum is puzzling. Possibly the splenium has more easily perturbed cellular fluid mechanics than surrounding tissues.

They probed the interactions between cytokine systems and the hyp

They probed the interactions between cytokine systems and the hypothalamic-pituitary-adrenal axis (HPA), and suggested that increased cytokine activities may drive the

HPA axis and may underlie the hypercortisolemia found in subpopulations of patients with depression. Most basically, the central element of their 10058-F4 cost hypothesis is that the increased cytokine activity and the activation of acutephase or inflammatory processes in depression is a regulatory abnormality characteristic of depression, rather than a reflection of medical illness. An alternative hypothesis for a role of cytokines Inhibitors,research,lifescience,medical in the pathogenesis of depression is based upon concepts of “sickness behavior.”72-75 According to these models, infection, inflammation, or tissue injury can activate inflammatory processes and induce cytokines that can act locally or systemically to regulate Inhibitors,research,lifescience,medical homeostatic responses. Some of these responses, including those that involve acute-phase processes, occur in the periphery, while others involve (direct or indirect) actions of cytokines Inhibitors,research,lifescience,medical on the central nervous system. Some of these central nervous system-mediated effects, such as fever, are physiological, while others arc behavioral. The latter include a number of nonspecific behaviors associated with illness and

injury such as decreased exploratory activity, decreased sexual activity, anorexia, and changes in sleep structure. Studies of the behavioral pharmacology of the cytokines in experimental animals demonstrate that they can, in fact, cause these behaviors; however, questions

remain about the mechanisms through which the Inhibitors,research,lifescience,medical induction of cytokines in the periphery can cause centrally mediated effects. Nevertheless, this hypothesis proposes that depression can occur when cytokine-mediated processes are induced by illness or injury, and that the depressions that arise through these mechanisms are pathological variants of Inhibitors,research,lifescience,medical normal and adaptive sickness behaviors. As discussed above, it is possible to distinguish between two distinct cytokinc-rclatcd theories of depression, one in which the induction of cytokines occurs spontaneously as a result of regulatory deficits intrinsic to the depressive illness, and the other in which they arise in the context of medical illness. These models may, however, be Farnesyltransferase poles in a continuum. For example, cytokine-mediated processes initiated by illness could, in principle, remain activated after illness as a result of a failure in restorative mechanisms. Alternatively, regulatory abnormalities may allow for the extensive induction of cytokines by minor illness or injury. Thus, it is possible to propose a series of plausible cytokine theories of depression. The important question is, of course, whether there is empirical evidence to support any of them.

2009) Recent observations that galectins are increased after ac

2009). Recent observations that galectins are increased after acute CNS injuries and during chronic neurodegeneration (Byrnes et al. 2006; Zhou et al. 2010) may support a potential role for galectins in the adaptive immune response to the “threat” of cell stress, damage,

or death, and potentially, in the repair function(s) of innate immunity (Kono and Rock 2008). Galectins contain a conserved carbohydrate recognition domain (CRD) with affinity for β-galactosides. They are secreted via a nonclassical pathway, but also found in intracellular compartments (Gong et al. 1999; Hughes 1999). Extracellularly, galectins form cross-links with cell surface glycoconjugates or Inhibitors,research,lifescience,medical the extracellular matrix, where they preferentially bind N-acetyllactosamine (Galß13GlcNAc or Galß1-4GlcNAC) residues. Because many cell surface receptors, including those for cytokines, growth factors, and neurotransmitters, contain glycoconjugates, galectins Inhibitors,research,lifescience,medical may modulate transmembrane signaling events that affect a variety of cell functions (Boscher et al. 2011). Recently, expression profiling revealed increases in mRNA for several galectins within

the spinal cord during late-stage selleckchem disease in mouse models of ALS (Ferraiuolo et al. 2007; Gonzalez de Aguilar et al. 2008; Zhou et al. 2010). Expression of galectin-3, also known as Mac-2, Inhibitors,research,lifescience,medical correlates with microglial activation subsequent to neuronal degeneration in mouse models of ALS (Yamanaka et al. 2008; Saxena et al., Inhibitors,research,lifescience,medical 2009; Hossiani et al. 2011), but nevertheless, its role in the disease is unclear. In this study, we initially assessed expression of multiple galectins, during chronic motor neuron disease in the SOD1G93A mouse and in patients with sporadic ALS. As galectin-3 was the only galectin to progressively increase from early to late stage of disease in the mouse, and was also confirmed in patients with sporadic ALS, we then focused on the Inhibitors,research,lifescience,medical role of galectin-3 in disease progression. Currently, available galectin-3 antagonists are carbohydrate based and are neither particularly selective,

nor able to cross the blood–brain barrier significantly (Pieters 2006). see more Therefore, we generated C57BL6 SOD1G93A/Gal-3−/− knock-out transgenic mice for our studies. Materials and Methods Animals Animal procedures were performed following National Institutes of Health Guidelines for Animal Use and Welfare and supported by an approved institutional animal protocol. B6SJL (stock no. 002726) or C57BL6 (stock no. 004435) mice with the G93A human SOD1 mutation (SOD1G93A; Gurney et al. 1994) were obtained from Jackson Laboratories (Bar Harbor, ME). For all studies, data were collected only from male mice, to avoid confounding issues of disease progression due to sex. The B6SJL strain was used for the expression studies.