Skeletal Muscle Differentiation Evokes Endogenous XIAP to Restrict the Apoptotic Pathway

Myotube apoptosis occurs normally during muscle development and aging but it can lead to destruction of skeletal muscle in neuromuscular diseases. Therefore, understanding how myotube apoptosis is regulated is important for developing novel strategies for treatment of muscle loss. We investigated the regulation of apoptosis in skeletal muscle and report a striking increase in resistance to apoptosis following differentiation. We find mitotic C2C12 cells (myoblast-like cells) are sensitive to cytosolic cytochrome c microinjection. However, differentiated C2C12 cells (myotube-like cells) and primary myotubes are markedly resistant. This resistance is due to endogenous X-linked inhibitor of apoptotic protein (XIAP). Importantly, the selective difference in the ability of XIAP to block myotube but not myoblast apoptosis is not due to a change in XIAP but rather a decrease in Apaf-1 expression. This decrease in Apaf-1 links XIAP to caspase activation and death. Our findings suggest that in order for myotubes to die, they may degrade XIAP, functionally inactivate XIAP or upregulate Apaf-1. Importantly, we identify a role for endogenous Smac in overcoming XIAP to allow myotube death. However, in postmitotic cardiomyocytes, where XIAP also restricts apoptosis, endogenous Smac was not capable of overcoming XIAP to cause death. These results show that as skeletal muscle differentiate, they become resistant to apoptosis because of the ability of XIAP to regulate caspase activation. The increased restriction of apoptosis in myotubes is presumably important to ensure the long term survival of these postmitotic cells as they play a vital role in the physiology of organisms

Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE

Universal Alcohol/Drug Screening in Prenatal Care: A Strategy for Reducing Racial Disparities? Questioning the Assumptions

Agencies and organizations promoting universal screening for alcohol and drug use in prenatal care argue that universal screening will reduce White versus Black racial disparities in reporting to Child Protective Services (CPS) at delivery. Yet, no published research has assessed the impact of universal screening on reporting disparities or explored plausible mechanisms. This review defines two potential mechanisms: Equitable Surveillance and Effective Treatment and identifies assumptions underlying each mechanism. It reviews published literature relating to each assumption. Research relating to assumptions underlying each mechanism is primarily inconclusive or contradictory. Thus, available research does not support the claim that universal screening for alcohol and drug use in prenatal care reduces racial disparities in CPS reporting at delivery. Reducing these reporting disparities requires more than universal screening

Rogdi Defines GABAergic Control of a Wake-promoting Dopaminergic Pathway to Sustain Sleep in Drosophila

Kohlschutter-Tonz syndrome (KTS) is a rare genetic disorder with neurological dysfunctions including seizure and intellectual impairment. Mutations at the Rogdi locus have been linked to development of KTS, yet the underlying mechanisms remain elusive. Here we demonstrate that a Drosophila homolog of Rogdi acts as a novel sleep-promoting factor by supporting a specific subset of gamma-aminobutyric acid (GABA) transmission. Rogdi mutant flies displayed insomnia-like behaviors accompanied by sleep fragmentation and delay in sleep initiation. The sleep suppression phenotypes were rescued by sustaining GABAergic transmission primarily via metabotropic GABA receptors or by blocking wake-promoting dopaminergic pathways. Transgenic rescue further mapped GABAergic neurons as a cell-autonomous locus important for Rogdi-dependent sleep, implying metabotropic GABA transmission upstream of the dopaminergic inhibition of sleep. Consistently, an agonist specific to metabotropic but not ionotropic GABA receptors titrated the wake-promoting effects of dopaminergic neuron excitation. Taken together, these data provide the first genetic evidence that implicates Rogdi in sleep regulation via GABAergic control of dopaminergic signaling. Given the strong relevance of GABA to epilepsy, we propose that similar mechanisms might underlie the neural pathogenesis of Rogdi-associated KTS

Optimal delivery of follow-up care after surgery for Crohn’s disease: current perspectives

James P Campbell, Byron P Vaughn Department of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, MN, USA Abstract: Despite improvements in medical therapies for Crohn’s disease (CD), up to 70% of patients require surgery within 10 years of diagnosis. Surgery is not curative, and almost all patients will experience endoscopic recurrence, and many will go on to clinical recurrence. Identifying patients at high-risk of endoscopic recurrence and standardizing postoperative assessments are essential in preventing clinical recurrence of CD. In this review, we discuss the assessment, monitoring, and treatment of postoperative CD patients. We address the various individual risk factors as well as composite risk factors. Medications used for primary CD treatment can be used in the postoperative setting to prevent endoscopic or clinical recurrence with varying efficacy, although the cost-effectiveness of these approaches are not fully understood. Future directions for postoperative CD management include evaluation of newer biologic agents such as anti-integrin therapy and fecal microbiota transplant for prevention of recurrence. Development of a standard preoperative risk assessment tool to clearly stratify those at high-risk of recurrence is necessary to guide empiric therapy. Lastly, the incorporation of noninvasive testing into disease monitoring will likely lead to early detection of endoscopic recurrence that will allow for tailored treatment to prevent clinical recurrence. Keywords: Crohn’s disease, postoperative care, postoperative recurrenc

Volunteer patients and small groups contribute to abdominal examination's success

Helen M Shields,1 Nielsen Q Fernandez-Becker,2 Sarah N Flier,2 Byron P Vaughn,2 Melissa H Tukey,2 Stephen R Pelletier,3 Douglas A Horst2 1Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 2Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 3Center for Evaluation, Harvard Medical School, Boston, MA, USA Background: Prior to 2007, we taught the abdominal examination in a hospital based group to 40 students, at one hospital. We used volunteer patients, small groups, repetition, and required faculty development sessions. In 2007, our medical school changed its “Introduction to Physical Examination” session so that the entire class was to be taught in a geographically central session. Our hospital was selected to lead the abdominal examination portion of the session. Aim: Our aim was to answer three questions. First, could we quadruple the recruitment of volunteer patients, and faculty? Second, was it volunteer patients, small groups, repetition, or faculty training that was most valued by the students? Third, would volunteer patients and/or faculty agree to participate a second time? Methods: A total of 43-46 patients and 43-46 faculty were recruited and 43-46 examining rooms were obtained for each of the 5 years of this study. Teachers were required to attend a 1-hour faculty development session. The class of about 170 students was divided into 43–46 groups each year. The teacher demonstrated the abdominal examination and each student practiced the examination on another student. Each student then repeated the full abdominal examination on a volunteer patient. Results: Over the 5-year time period (2008–2012), the abdominal examination ranked first among all organ systems’ “Introductory Sessions”. The abdominal examination ratings had the best mean score (1.35) on a Likert scale where 1 is excellent and 5 is poor. The students gave the most positive spontaneous comments to having volunteer patients, with small groups coming in as the second most appreciated educational element. Conclusion: We successfully quadrupled the number of faculty, patients, and examining rooms and created a highly rated educational program as measured by anonymous student evaluations, patient and faculty participation, and the medical school’s selecting the abdominal examination methods as an “Advanced Examination” for the Pathways Curriculum. Keywords: abdominal examination, volunteer patients, small groups, repetition, faculty developmen