Peroral Cholangioscopy with Intracorporeal Electrohydraulic Lithotripsy for Choledocholithiasis

Five patients with choledocholithiasis refractory to standard extraction methods after endoscopic sphincterotomy underwent peroral cholangioscopy with the "mother-daughter" endoscopy system. Electrohydraulic lithotripsy of nine stones was performed successfully and without complication, other than minor transient bleeding in one patient. The outer sheath of the "daughter scope" sustained a linear burn in one instance. This method of stone fragmentation is a useful adjunct to achieve ductal clearance in difficult cases.     

Escaping from Flatland: Antimalarial Activity of sp3-Rich Bridged Pyrrolidine Derivatives

We utilized synthetic photochemistry to generate novel sp³-rich scaffolds and report the design, synthesis, and biological testing of a diverse series of amides based on the 1-(amino-methyl)-2-benzyl-2-aza-bicyclo[2.1.1]hexane scaffold. Preliminary antimalarial screening of the library provided promising compounds with activity in the 1–5 μM range with an enhanced hit rate. Further evaluation (solubility, drug metabolism and pharmacokinetics (DMPK), and toxicity) of a selected compound (9) suggested that this series represents an excellent opportunity for further optimization with the framework offering multiple opportunities for the addition of uniquely vectorally positioned extra functionality.     

ERCC1 mutations impede DNA damage repair and cause liver and kidney dysfunction in patients

ERCC1-XPF is a multifunctional endonuclease involved in nucleotide excision repair (NER), interstrand cross-link (ICL) repair, and DNA double-strand break (DSB) repair. Only two patients with bi-allelic ERCC1 mutations have been reported, both of whom had features of Cockayne syndrome and died in infancy. Here, we describe two siblings with bi-allelic ERCC1 mutations in their teenage years. Genomic sequencing identified a deletion and a missense variant (R156W) within ERCC1 that disrupts a salt bridge below the XPA-binding pocket. Patient-derived fibroblasts and knock-in epithelial cells carrying the R156W substitution show dramatically reduced protein levels of ERCC1 and XPF. Moreover, mutant ERCC1 weakly interacts with NER and ICL repair proteins, resulting in diminished recruitment to DNA damage. Consequently, patient cells show strongly reduced NER activity and increased chromosome breakage induced by DNA cross-linkers, while DSB repair was relatively normal. We report a new case of ERCC1 deficiency that severely affects NER and considerably impacts ICL repair, which together result in a unique phenotype combining short stature, photosensitivity, and progressive liver and kidney dysfunction.     

Depressive symptoms and serum lipid levels in young adult women

Accumulating data suggest that depression is associated with risk factors for cardiovascular disease, but few studies have investigated potential behavioral mediators of such associations, particularly among women. In this study of healthy young adult women (n = 225), we examined associations among depressive symptoms, health behaviors, and serum lipid levels. Depressive symptoms were assessed with the 20-item Center for Epidemiologic Studies-Depression scale, and a fasting blood sample was obtained for serum lipid levels, including total cholesterol, high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C). Diet was measured using 24-h recalls, and other health behaviors (physical activity, smoking) were assessed via self-report questionnaire. Results indicated a modest negative association between depressive symptoms and LDL-C levels. Higher levels of depressive symptoms were also associated with lower total and insoluble dietary fiber intake, both of which were associated with HDL-C and LDL-C. Mediational analyses indicated a significant indirect effect of depressive symptoms on LDL-C via total and insoluble dietary fiber in unadjusted analyses, but not in adjusted analyses. The present findings suggest that depressive symptoms are inversely associated with serum LDL-C levels in young adult women, but that these associations are not likely mediated by adverse lifestyle behaviors.     

Why semantic dementia drives you to the dogs (but not to the horses): A theoretical account

This paper describes a patient (IH) with semantic dementia and severe impairment in all semantic categories except for numerical knowledge, which was preserved. IH showed a severe deficit in reading and writing non-number words (e.g., candle, juice) and nonwords, and preservation of reading and writing number words (e.g., one, forty) and numerals (e.g., 1, 40). IH's pattern of performance can be explained by the combination of a selective sparing of one semantic category--i.e., numbers--with a total deficit of nonsemantic processes for mapping letters and sounds. As number was the only spared semantic category in the presence of these other nonsemantic deficits, it follows that the semantic route is sufficient for accurate reading and spelling. Our data clarify the nature of reading and writing processes and support the functional and neuroanatomical independence of the number domain.