Correction: Loss of the BMP Antagonist, SMOC-1, Causes Ophthalmo-Acromelic (Waardenburg Anophthalmia) Syndrome in Humans and Mice.

[This corrects the article DOI: 10.1371/journal.pgen.1002114.].

Polypharmacy, Infectious Diseases, Sexual Behavior, and Psychophysical Health Among Anabolic Steroid-Using Homosexual and Heterosexual Gym Patrons in San Francisco's Castro District.

BACKGROUND: Limited studies based in England and Australia reported misuse of anabolic-androgenic steroids (AAS) among homosexual men to enhance body image. Anecdotally, AAS are also being misused by homosexual men in the United States. Since many AAS and certain performance enhancing drugs (PEDs) are administered via injection, this poses a potential vector for the spread of infectious disease in an already at-risk population. OBJECTIVES: This study compared and contrasted homosexual and heterosexual male gym clients regarding use of AAS and PEDs, use of alcohol and illicit drugs, seroprevalence of infectious disease, engagement in risky injection practices and sexual behaviors, and presence of psychiatric conditions. METHODS: Recruitment and data collection occurred outside four exercise gyms in the San Francisco Castro District area between October 25, 2014 and March 10, 2015. Two hundred and twenty homosexual men and 73 heterosexual men completed the 114-item cross-sectional survey. RESULTS: Ten percent of homosexual men reported lifetime AAS use. Homosexual men had almost four times more sexual partners and were over 14 times more likely to knowingly have unprotected intercourse with a known HIV positive person than heterosexual men. In addition, a quarter of homosexual men who injected drugs admitted to sharing used syringes or needles with another person. Conclusions/Importance: The current study is the first to confirm AAS use among homosexual men in the United States. Homosexual men partook in high-risk sexual behaviors and injection practices which may place them at greater risks for contracting and spreading HIV and other infectious diseases.

Valproic acid-induced hyperammonemia and minimal hepatic encephalopathy prevalence among psychiatric inpatients.

BACKGROUND: Our purpose was to evaluate the relationship between valproic acid (VPA)-induced hyperammonemia (HA) and the prevalence of minimal hepatic encephalopathy (MHE) cognitive impairment among psychiatric inpatients. METHODS: Fifty-two psychiatric inpatients prescribed VPA were tested for MHE impairment after achieving steady-state VPA and ammonia concentrations during hospitalization between December 2013 and June 2014. The relationship between steady-state VPA and ammonia concentration was tested by correlation coefficient. Patients completed a battery of 5 psychometric tests that determined a Psychometric Hepatic Encephalopathy Score (PHES), which was used to test the association between a PHES <-4 cutoff for MHE impairment and HA exposure (ammonia >50 µmol/L) by chi-square testing. RESULTS: Steady-state VPA plasma concentration was not correlated significantly with ammonia concentration (r = 0.24, P = .093). The patients with HA did not have a higher proportion of MHE cognitive impairment than patients with normal ammonia exposure (43.8% vs 66.7% respectively, P = .806). CONCLUSIONS: Steady-state VPA concentration was not correlated with ammonia concentration and VPA-induced HA was not associated with a greater prevalence of MHE impairment. This suggests that the MHE impairment PHES cutoff might not detect VHE in psychiatric inpatients without cirrhosis, especially because inpatients could experience cognitive impairment related to acute mental illness.

Partial deletion of chromosome 8 ß-defensin cluster confers sperm dysfunction and infertility in male mice.

ß-defensin peptides are a family of antimicrobial peptides present at mucosal surfaces, with the main site of expression under normal conditions in the male reproductive tract. Although they kill microbes in vitro and interact with immune cells, the precise role of these genes in vivo remains uncertain. We show here that homozygous deletion of a cluster of nine ß-defensin genes (DefbΔ9) in the mouse results in male sterility. The sperm derived from the mutants have reduced motility and increased fragility. Epididymal sperm isolated from the cauda should require capacitation to induce the acrosome reaction but sperm from the mutants demonstrate precocious capacitation and increased spontaneous acrosome reaction compared to wild-types but have reduced ability to bind the zona pellucida of oocytes. Ultrastructural examination reveals a defect in microtubule structure of the axoneme with increased disintegration in mutant derived sperm present in the epididymis cauda region, but not in caput region or testes. Consistent with premature acrosome reaction, sperm from mutant animals have significantly increased intracellular calcium content. Thus we demonstrate in vivo that ß-defensins are essential for successful sperm maturation, and their disruption leads to alteration in intracellular calcium, inappropriate spontaneous acrosome reaction and profound male infertility.

Is lithium a neuroprotective agent?

BACKGROUND: Lithium was the first clinically effective mood stabilizer marketed worldwide. However, the medical literature suggests that lithium may have an indication as a neuroprotective agent. METHODS: This review discusses the pharmacologic activity and potential effectiveness of lithium in the context of Alzheimer disease (AD) and Parkinson's disease (PD), the 2 most prominent neurodegenerative disorders in the United States. The toxicities of lithium, including lithium-induced extrapyramidal symptoms (LI-EPS) and cognitive impairments at therapeutic blood levels, are discussed. Cases that are thought to illustrate LI-EPS and cognitive impairments are critiqued. RESULTS: Animal studies have shown positive results regarding the neuroprotective and antioxidant properties of lithium. Human studies indicate a potential benefit of lithium for improving cognition. Ongoing replicative studies are attempting to confirm the effectiveness and efficacy of lithium for treating patients diagnosed with AD or PD. CONCLUSIONS: The available medical literature supports the conclusion that lithium should be considered as a research candidate medication for the treatment of neurologic diseases of dementias and PD.

Aortic Root Enlargement with Ascending-to-Descending Aortic Bypass in Repair of Coarctation.

Ascending-to-descending aortic bypass is a valuable technique for addressing coarctation of the aorta when additional cardiac procedures are indicated in adults. Among these, aortic valve replacement is one of the most commonly performed concomitant procedures, and there are instances in which aortic root enlargement is required. Herein, a novel technique is described for performing simultaneous ascending-to-descending aortic bypass in conjunction with aortic root enlargement which incorporates the bypass graft as part of the aortic root enlargement.

Acute multiple organ failure in adult mice deleted for the developmental regulator Wt1.

There is much interest in the mechanisms that regulate adult tissue homeostasis and their relationship to processes governing foetal development. Mice deleted for the Wilms' tumour gene, Wt1, lack kidneys, gonads, and spleen and die at mid-gestation due to defective coronary vasculature. Wt1 is vital for maintaining the mesenchymal-epithelial balance in these tissues and is required for the epithelial-to-mesenchyme transition (EMT) that generates coronary vascular progenitors. Although Wt1 is only expressed in rare cell populations in adults including glomerular podocytes, 1% of bone marrow cells, and mesothelium, we hypothesised that this might be important for homeostasis of adult tissues; hence, we deleted the gene ubiquitously in young and adult mice. Within just a few days, the mice suffered glomerulosclerosis, atrophy of the exocrine pancreas and spleen, severe reduction in bone and fat, and failure of erythropoiesis. FACS and culture experiments showed that Wt1 has an intrinsic role in both haematopoietic and mesenchymal stem cell lineages and suggest that defects within these contribute to the phenotypes we observe. We propose that glomerulosclerosis arises in part through down regulation of nephrin, a known Wt1 target gene. Protein profiling in mutant serum showed that there was no systemic inflammatory or nutritional response in the mutant mice. However, there was a dramatic reduction in circulating IGF-1 levels, which is likely to contribute to the bone and fat phenotypes. The reduction of IGF-1 did not result from a decrease in circulating GH, and there is no apparent pathology of the pituitary and adrenal glands. These findings 1) suggest that Wt1 is a major regulator of the homeostasis of some adult tissues, through both local and systemic actions; 2) highlight the differences between foetal and adult tissue regulation; 3) point to the importance of adult mesenchyme in tissue turnover.

Loss of the BMP antagonist, SMOC-1, causes Ophthalmo-acromelic (Waardenburg Anophthalmia) syndrome in humans and mice.

Ophthalmo-acromelic syndrome (OAS), also known as Waardenburg Anophthalmia syndrome, is defined by the combination of eye malformations, most commonly bilateral anophthalmia, with post-axial oligosyndactyly. Homozygosity mapping and subsequent targeted mutation analysis of a locus on 14q24.2 identified homozygous mutations in SMOC1 (SPARC-related modular calcium binding 1) in eight unrelated families. Four of these mutations are nonsense, two frame-shift, and two missense. The missense mutations are both in the second Thyroglobulin Type-1 (Tg1) domain of the protein. The orthologous gene in the mouse, Smoc1, shows site- and stage-specific expression during eye, limb, craniofacial, and somite development. We also report a targeted pre-conditional gene-trap mutation of Smoc1 (Smoc1(tm1a)) that reduces mRNA to ∼10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc1(tm1a/tm1a)). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc1(tm1a/tm1a) embryos and pups. Thus partial loss of Smoc-1 results in a convincing phenocopy of the human disease. SMOC-1 is one of the two mammalian paralogs of Drosophila Pentagone, an inhibitor of decapentaplegic. The orthologous gene in Xenopus laevis, Smoc-1, also functions as a Bone Morphogenic Protein (BMP) antagonist in early embryogenesis. Loss of BMP antagonism during mammalian development provides a plausible explanation for both the limb and eye phenotype in humans and mice.

Final 1-Year Results of the TUTOR Randomized Trial Comparing Carpal Tunnel Release with Ultrasound Guidance to Mini-open Technique.

Background: Studies comparing carpal tunnel release with ultrasound guidance (CTR-US) to mini-open CTR (mOCTR) are limited. This randomized trial compared the efficacy and safety of these techniques. Methods: In this multicenter randomized trial, patients were randomized (2:1) to unilateral CTR-US or mOCTR. Outcomes included Boston Carpal Tunnel Questionnaire Symptom Severity Scale (BCTQ-SSS) and Functional Status Scale (BCTQ-FSS), numeric pain scale (0-10), EuroQoL-5 Dimension 5-Level (EQ-5D-5L), scar outcomes, and complications over 1 year. Results: Patients received CTR-US (n = 94) via wrist incision (mean 6 mm) or mOCTR (n = 28) via palmar incision (mean 22 mm). Comparing CTR-US with mOCTR, the mean changes in BCTQ-SSS (-1.8 versus -1.8; P = 0.96), BCTQ-FSS (-1.0 versus -1.0; P = 0.75), numeric pain scale (-3.9 versus -3.8; P = 0.74), and EQ-5D-5L (0.13 versus 0.12; P = 0.79) over 1 year were comparable between groups. Freedom from scar sensitivity or pain favored CTR-US (95% versus 74%; P = 0.005). Complications occurred in 2.1% versus 3.6% of patients (P = 0.55), all within 3 weeks postprocedure. There was one revision surgery in the CTR-US group, and no revisions for persistent or recurrent symptoms in either group. Conclusions: CTR-US and mOCTR demonstrated similar improvement in carpal tunnel syndrome symptoms and quality of life with comparable low complication rates over 1 year of follow-up. CTR-US was performed with a smaller incision and associated with less scar discomfort.

The effect of translocation-induced nuclear reorganization on gene expression.

Translocations are known to affect the expression of genes at the breakpoints and, in the case of unbalanced translocations, alter the gene copy number. However, a comprehensive understanding of the functional impact of this class of variation is lacking. Here, we have studied the effect of balanced chromosomal rearrangements on gene expression by comparing the transcriptomes of cell lines from controls and individuals with the t(11;22)(q23;q11) translocation. The number of differentially expressed transcripts between translocation-carrying and control cohorts is significantly higher than that observed between control samples alone, suggesting that balanced rearrangements have a greater effect on gene expression than normal variation. Many of the affected genes are located along the length of the derived chromosome 11. We show that this chromosome is concomitantly altered in its spatial organization, occupying a more central position in the nucleus than its nonrearranged counterpart. Derivative 22-mapping chromosome 22 genes, on the other hand, remain in their usual environment. Our results are consistent with recent studies that experimentally altered nuclear organization, and indicated that nuclear position plays a functional role in regulating the expression of some genes in mammalian cells. Our study suggests that chromosomal translocations can result in hitherto unforeseen, large-scale changes in gene expression that are the consequence of alterations in normal chromosome territory positioning. This has consequences for the patterns of gene expression change seen during tumorigenesis-associated genome instability and during the karyotype changes that lead to speciation.

Multicenter randomized trial of carpal tunnel release with ultrasound guidance versus mini-open technique.

BACKGROUND: Comparative studies of carpal tunnel release with ultrasound guidance (CTR-US) vs. mini-open CTR (mOCTR) are limited, prompting development of this randomized trial to compare efficacy and safety of these techniques. RESEARCH DESIGN AND METHODS: Patients were randomized (2:1) to CTR-US or mOCTR, treated by experienced hand surgeons (median previous cases: 12 CTR-US; 1000 mOCTR), and followed for 3 months. RESULTS: Among 149 randomized patients, 122 received CTR-US (n = 94) or mOCTR (n = 28). Mean incision length was 6 ± 2 mm in the wrist (CTR-US) vs. 22 ± 7 mm in the palm (mOCTR) (p < 0.001). Median time to return to daily activities (2 vs. 2 days; p = 0.81) and work (3 vs. 4 days; p = 0.61) were similar. Both groups reported statistically significant and clinically important improvements in Boston Carpal Tunnel Questionnaire Symptom Severity and Functional Status Scales, Numeric Pain Scale, and EuroQoL-5 Dimension 5-Level, with no statistical differences between groups. Freedom from wound sensitivity and pain favored CTR-US (61.1% vs. 17.9%; p < 0.001). Adverse event rates were low in each group (2.1% vs. 3.6%; p = 0.55). CONCLUSIONS: The efficacy and safety of CTR-US were comparable to mOCTR despite less previous surgical experience with CTR-US. The choice of CTR technique should be determined by shared decision-making between patient and physician. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT05405218.

Serotonin syndrome vs neuroleptic malignant syndrome: a contrast of causes, diagnoses, and management.

BACKGROUND: Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are uncommon but potentially life-threatening adverse reactions associated with psychotropic medications. Polypharmacy and the similar presentation of SS and NMS make diagnosis of the 2 syndromes problematic. METHODS: A MEDLINE search was performed for the period 1960 to 2011 for case reports, review articles, and studies pertaining to SS and NMS. RESULTS: The majority of available literature on SS and NMS consists of case reports, case-control studies, and retrospective reviews. In addition, diagnostic criteria have been developed to aid in the diagnosis and management of SS and NMS. CONCLUSIONS: SS presents as mental status changes, autonomic nervous system disturbances, neurologic manifestations, and hyperthermia. Similarly, NMS presents as muscle rigidity, hyperpyrexia, mental status changes, and autonomic instability. However, the clinical laboratory profile of elevations in creatine kinase, liver function tests (lactate dehydrogenase, aspartate transaminase), and white blood cell count, coupled with a low serum iron level, distinguishes NMS from SS among patients taking neuroleptic and serotonin agonist medications simultaneously. For both SS and NMS, immediate discontinuation of the causative agent is the primary treatment, along with supportive care. For NMS, dantrolene is the most effective evidence-based drug treatment whereas there are no evidence-based drug treatments for SS. A 2-week washout of neuroleptic medication minimizes the chance of recurrence.

Weightlifting's risky new trend: a case series of 41 insulin users.

Use of performance-enhancing drugs (PEDs) is common among strength-trained individuals, and a growing concern is the misuse of insulin. A 99-item Internet-based survey was posted on discussion boards of various fitness, bodybuilding, weightlifting, and anabolic steroid Web sites between February and June 2009. A case series of 41 nondiabetic insulin users is described. The typical insulin user was 30.7 ± 9.2 years old, male (97.6%), and Caucasian/white (86.8%) who classified himself as a "recreational exerciser" (47.5%). The average insulin user also used anabolic steroids (95.1%) and practiced polypharmacy by incorporating 16.2 ± 5.6 PEDs in his or her yearly routine. Hypoglycemia was reported by most of the subjects (56.8%), and one individual reported unconsciousness. Insulin was obtained most commonly from local sources (e.g., friends, training partners, gym member/dealer; 40.5%) and community pharmacies (37.8%), with most (80.6%) finding it "easy" to acquire their insulin. Strategies aimed to prevent insulin misuse are needed.

Diabetes prevalence estimates in schizophrenia and risk factor assessment.

BACKGROUND: Atypical antipsychotics have been indirectly associated with the diagnosis of type 2 diabetes mellitus (T2DM) in patients with schizophrenia. The purpose of this cross-sectional study was to determine the prevalence of T2DM and to examine the risk factors associated with T2DM among outpatients diagnosed with schizophrenia. The study also sought to determine which risk factors are of particular screening importance in monitoring the metabolic status of these patients. METHODS: This study included 202 patients diagnosed with schizophrenia. Data on a number of known and hypothesized risk factors for T2DM were collected. RESULTS: Risk factors for T2DM identified by bivariate analyses in this sample included older age, waist-to-hip ratio >1.0, sedentary lifestyle, number of hours worked per week, hyperlipidemia, previous screening for T2DM, higher random blood glucose, and number of years on atypical antipsychotics risperidone or olanzapine. However, further scrutiny using multiple logistic regression identified only sedentary lifestyle, waist-to-hip ratio ≥1.0, and a diagnosis of hyperlipidemia as significant risk factors in these patients. Similar to other studies, there was an 11.5% (22/192) lifetime prevalence rate of diabetes among this population. CONCLUSIONS: Risk factors traditionally associated with T2DM, as well as waist-to-hip ratio, are the factors most strongly associated with increased risk of diabetes in patients with schizophrenia.

An open-label trial of aripiprazole in the treatment of aggression in male adolescents diagnosed with conduct disorder.

BACKGROUND: The adverse effect profiles of typical and atypical antipsychotics are problematic because of their extrapyramidal and endocrine adverse effects, respectively. METHODS: Ten adolescent male patients diagnosed with conduct disorder received aripiprazole in doses of ≤20 mg/d in an open-label, intent-to-treat design to establish and characterize the efficacy of the drug in reducing aggressive behavior. RESULTS: Based on clinician and parent observations, aripiprazole was effective in reducing aggressive behavior in adolescent boys. The change in clinician-observed aggression ratings appears to have been driven by a decrease in physical aggression, whereas the change in parent-observed aggression ratings appears to have been driven by a decrease in verbal aggression and aggression against objects and animals. CONCLUSIONS: Aripiprazole was an effective and relatively well-tolerated treatment for overall aggression in adolescent males with conduct disorder, in the view of both clinicians and parents. Depending on the observer, aripiprazole improved aggression categorized as physical aggression, verbal aggression, and aggression against objects and animals.

Recruitment to the nuclear periphery can alter expression of genes in human cells.

The spatial organisation of the genome in the nucleus has a role in the regulation of gene expression. In vertebrates, chromosomal regions with low gene-density are located close to the nuclear periphery. Correlations have also been made between the transcriptional state of some genes and their location near the nuclear periphery. However, a crucial issue is whether this level of nuclear organisation directly affects gene function, rather than merely reflecting it. To directly investigate whether proximity to the nuclear periphery can influence gene expression in mammalian cells, here we relocate specific human chromosomes to the nuclear periphery by tethering them to a protein of the inner nuclear membrane. We show that this can reversibly suppress the expression of some endogenous human genes located near the tethering sites, and even genes further away. However, the expression of many other genes is not detectably reduced and we show that location at the nuclear periphery is not incompatible with active transcription. The dampening of gene expression around the nuclear periphery is dependent on the activity of histone deacetylases. Our data show that the radial position within the nucleus can influence the expression of some, but not all, genes. This is compatible with the suggestion that re-localisation of genes relative to the peripheral zone of the nucleus could be used by metazoans to modulate the expression of selected genes during development and differentiation.

Use of actigraphy and sleep diaries to assess sleep and academic performance in pharmacy students.

INTRODUCTION: Sleep parameters have been shown to correlate with academic performance. Current studies assessing sleep in doctor of pharmacy (PharmD) students rely on self-reported sleep parameters and academic performance. The objectives of this study were to describe and compare sleep parameters in pharmacy students using actigraphy and sleep diaries and to assess the correlation of sleep parameters with academic performance. METHODS: This prospective cohort study with convenience sampling assessed sleep parameters in pharmacy students. Thirty-five students completing the second year of a PharmD program participated in the study. Participants wore actigraph watches and maintained sleep diaries for seven consecutive days during the spring and fall semesters, while classes were in session, except for one week prior to exams and the week of exams. Academic performance was tracked during fall and spring semesters. RESULTS: Actigraphy and sleep diaries showed significant differences in sleep latency (SL), actual sleep time (AST), wake bouts, and sleep efficiency (SE). Actigraphy results indicated that the participants fell asleep faster (SL), slept a shorter duration (AST), had more wake bouts, and lower SE than results reported in the sleep diaries. SE and SL from the sleep diaries positively correlated with the fall semester pharmaceutical sciences course and overall spring semester academic performance. Actigraphy recorded AST correlated with performance in both semesters' clinical sciences courses. CONCLUSIONS: The results of actigraphy differed from the sleep diaries. More studies are needed to assess differences in detection of sleep parameters using sleep diaries and actigraphs.