Abnormal Intracellular Accumulation and Extracellular Aβ Deposition in Idiopathic and Dup15q11.2-q13 Autism Spectrum Disorders

<div><h3>Background</h3><p>It has been shown that amyloid ß (Aβ), a product of proteolytic cleavage of the amyloid β precursor protein (APP), accumulates in neuronal cytoplasm in non-affected individuals in a cell type–specific amount.</p> <h3>Methodology/Principal Findings</h3><p>In the present study, we found that the percentage of amyloid-positive neurons increases in subjects diagnosed with idiopathic autism and subjects diagnosed with duplication 15q11.2-q13 (dup15) and autism spectrum disorder (ASD). In spite of interindividual differences within each examined group, levels of intraneuronal Aβ load were significantly greater in the dup(15) autism group than in either the control or the idiopathic autism group in 11 of 12 examined regions (p<0.0001 for all comparisons; Kruskall-Wallis test). In eight regions, intraneuronal Aβ load differed significantly between idiopathic autism and control groups (p<0.0001). The intraneuronal Aβ was mainly N-terminally truncated. Increased intraneuronal accumulation of Aβ_17–40/42 in children and adults suggests a life-long enhancement of APP processing with α-secretase in autistic subjects. Aβ accumulation in neuronal endosomes, autophagic vacuoles, Lamp1-positive lysosomes and lipofuscin, as revealed by confocal microscopy, indicates that products of enhanced α-secretase processing accumulate in organelles involved in proteolysis and storage of metabolic remnants. Diffuse plaques containing Aβ_1–40/42 detected in three subjects with ASD, 39 to 52 years of age, suggest that there is an age-associated risk of alterations of APP processing with an intraneuronal accumulation of a short form of Aβ and an extracellular deposition of full-length Aβ in nonfibrillar plaques.</p> <h3>Conclusions/Significance</h3><p>The higher prevalence of excessive Aβ accumulation in neurons in individuals with early onset of intractable seizures, and with a high risk of sudden unexpected death in epilepsy in autistic subjects with dup(15) compared to subjects with idiopathic ASD, supports the concept of mechanistic and functional links between autism, epilepsy and alterations of APP processing leading to neuronal and astrocytic Aβ accumulation and diffuse plaque formation.</p> </div

Posterior component separation/transversus abdominis release

The Rives-Stoppa technique for ventral hernia repair is commonly utilized due to well-proven outcomes with low overall morbidity. However, this approach is limited by the amount of myofascial advancement and sublay space available for a wide mesh overlap. Thus, anterior component separation was developed to allow further myofascial advancement. Some limitations were noted, which led to the subsequent study, utilization, and refinement of the posterior component separation (PCS) technique. PCS continues to demonstrate low hernia recurrence, surgical site occurrences, and improvement in rectus muscle function. Continued adoption of this technique has expanded to minimally invasive approaches for hernia repair. This paper is a comprehensive review of the evolution of PCS, technique, and outcomes

Nontyphoidal cardiac salmonellosis: two case reports and a review of the literature

Nontyphoidal Salmonella, especially Salmonella enterica, is a rare cause of endocarditis and pericarditis that carries a high mortality rate. Proposed predisposing conditions include immunodeficiency states, congenital heart defects, and cardiac valve diseases. We present 2 cases of cardiovascular salmonellosis. The first case is that of a 73-year-old woman with mechanical mitral and bioprosthetic aortic valves who died from sequelae of nontyphoidal Salmonella mitral valve vegetation, aortic valve abscess, and sepsis. The second case is that of a 62-year-old man with a recent systemic lupus erythematosus exacerbation treated with oral steroids, who presented with obstructive features of tamponade and sepsis secondary to a large S. enteritidis purulent pericardial cyst. He recovered after emergent pericardial drainage and antibiotic therapy. Identifying patients at risk of cardiovascular salmonellosis is important for early diagnosis and treatment to minimize sequelae and death. We reviewed the literature to identify the predisposing risk factors of nontyphoidal Salmonella cardiac infection

Characterizing hospitalist practice and perceptions of critical care delivery

BACKGROUND: Intensivist shortages have led to increasing hospitalist involvement in critical care delivery. OBJECTIVE: To characterize the practice of hospitalists practicing in the intensive care unit (ICU) setting. DESIGN: Survey of hospital medicine physicians. SETTING: This survey was conducted as a needs assessment for the ongoing efforts of the Critical Care Task Force of the Society of Hospital Medicine Education Committee. PARTICIPANTS: Hospitalists in the United States. INTERVENTION: An iteratively developed, 25-item, webbased survey. MEASUREMENTS: Results were compiled from all respondents then analyzed in subgroups. Various items were examined for correlations. RESULTS: A total of 425 hospitalists completed the survey. Three hundred and twenty-five (77%) provided critical care services, and 280 (66%) served as primary physicians in the ICU. Hospitalists were significantly more likely to serve as primary physicians in rural ICUs (85% of rural respondents vs 62% of nonrural; P \u3c .001 for association). Half of the rural hospitalists who were primary physicians for ICU patients felt obliged to practice beyond their scope, and 90% at least occasionally perceived that they had insufficient support from board-certified intensivists. Among respondents serving as primary physicians for ICU patients, 67% reported at least moderate difficulty transferring patients to higher levels of ICU care. Difficulty transferring patients was the only item significantly correlated with the perception of being expected to practice beyond one\u27s scope (P \u3c .05 for association). CONCLUSIONS: Hospitalists frequently deliver critical care services without adequate training or support, most prevalently in rural hospitals. Without major changes in intensivist staffi ng or patient distribution, this is unlikely to change

Impact of defects on the electrical transport, optical properties and failure mechanisms of GaN nanowires.

We present the results of a three year LDRD project that focused on understanding the impact of defects on the electrical, optical and thermal properties of GaN-based nanowires (NWs). We describe the development and application of a host of experimental techniques to quantify and understand the physics of defects and thermal transport in GaN NWs. We also present the development of analytical models and computational studies of thermal conductivity in GaN NWs. Finally, we present an atomistic model for GaN NW electrical breakdown supported with experimental evidence. GaN-based nanowires are attractive for applications requiring compact, high-current density devices such as ultraviolet laser arrays. Understanding GaN nanowire failure at high-current density is crucial to developing nanowire (NW) devices. Nanowire device failure is likely more complex than thin film due to the prominence of surface effects and enhanced interaction among point defects. Understanding the impact of surfaces and point defects on nanowire thermal and electrical transport is the first step toward rational control and mitigation of device failure mechanisms. However, investigating defects in GaN NWs is extremely challenging because conventional defect spectroscopy techniques are unsuitable for wide-bandgap nanostructures. To understand NW breakdown, the influence of pre-existing and emergent defects during high current stress on NW properties will be investigated. Acute sensitivity of NW thermal conductivity to point-defect density is expected due to the lack of threading dislocation (TD) gettering sites, and enhanced phonon-surface scattering further inhibits thermal transport. Excess defect creation during Joule heating could further degrade thermal conductivity, producing a viscous cycle culminating in catastrophic breakdown. To investigate these issues, a unique combination of electron microscopy, scanning luminescence and photoconductivity implemented at the nanoscale will be used in concert with sophisticated molecular-dynamics calculations of surface and defect-mediated NW thermal transport. This proposal seeks to elucidate long standing material science questions for GaN while addressing issues critical to realizing reliable GaN NW devices