Generating induced pluripotent stem cells (iPSCs) requires massive epigenome reorganization. It is unclear whether reprogramming of female human cells reactivates the inactive X chromosome (Xi), like in mouse. Here we establish that human (h)iPSCs derived from several female fibroblasts under standard culture conditions carry an Xi. Despite the lack of reactivation, the Xi undergoes defined chromatin changes, and expansion of hiPSCs can lead to partial loss of XIST RNA. These results indicate that hiPSCs are epigenetically dynamic and do not display a pristine state of X-inactivation with two active X’s as found in some female human embryonic stem cells. Furthermore, while fibroblasts are mosaic for the Xi, hiPSCs are clonal for the Xi. This non-random pattern of X chromosome inactivation in female hiPSCs, which is maintained upon differentiation, has critical implications for clinical applications and disease modeling, and could be exploited for a unique form of gene therapy for X-linked diseases.

Metabolic syndrome comprises a cluster of related disorders that includes obesity, glucose intolerance, insulin resistance, dyslipidemia, and fatty liver. Recently, gut-derived chronic endotoxemia has been identified as a primary mediator for triggering the low-grade inflammation responsible for the development of metabolic syndrome. In the present study we examined the role of the small intestinal brush-border enzyme, intestinal alkaline phosphatase (IAP), in preventing a high-fat-diet-induced metabolic syndrome in mice. We found that both endogenous and orally supplemented IAP inhibits absorption of endotoxin (lipopolysaccharides) that occurs with dietary fat, and oral IAP supplementation prevents as well as reverses metabolic syndrome. Furthermore, IAP supplementation improves the lipid profile in mice fed a standard, low-fat chow diet. These results point to a potentially unique therapy against metabolic syndrome in at-risk humans.etabolic syndrome is a complex syndrome composed of a cluster of disorders that includes obesity, glucose intolerance, insulin resistance, abnormal lipid profile (dyslipidemia), fatty liver, and hypertension (1, 2). Metabolic syndrome leads to type 2 diabetes, atherosclerosis, and nonalcoholic fatty liver disease (1, 2). Approximately 35-39% of the US population suffers from the syndrome (3). This epidemic of metabolic syndrome has devastating consequences in terms of mortality, morbidity, and total healthcare expenditures (4).Recently, "metabolic endotoxemia" has been proposed to be central to the pathogenesis of metabolic syndrome. The Gramnegative bacterial cell wall component lipopolysaccharide (LPS) is known as endotoxin, and metabolic endotoxemia is defined as a two-to threefold persistent increase in circulating endotoxin concentrations above the normal levels (5). Metabolic endotoxemia leads to low-grade systemic inflammation as evidenced by increased serum levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1, and IL-6 (5). It is well recognized that chronic inflammation causes damage to pancreatic beta cells (6), hepatocytes (7), and vascular endothelial cells (8), and dysfunction of these cells is thought to contribute to metabolic syndrome.A high-fat diet (HFD) has been shown to cause metabolic endotoxemia in animals and humans (5, 9), but the underlying molecular mechanisms remain incompletely understood. Ghoshal et al. (10) demonstrated that intestinal epithelial cells (enterocytes) internalize LPS from the apical surface, which is then transported to the Golgi apparatus where it complexes with chylomicrons, the lipoproteins that transport the absorbed longchain fatty acids in enterocytes. The chylomicron-LPS complex is then secreted into mesenteric lymph and makes its way into the systemic circulation. Excess chylomicron formation during highfat feeding leads to prolonged chylomicronemia (complexed with LPS) that ultimately induces systemic inflammation. Also, it has been shown that an HFD causes local intestinal inflammation (11). Systemic and local inf...

Our large multicenter study indicates that LA-ERCP in patients with RYGB is feasible with a high procedure success rate comparable with that of standard ERCP in patients with normal anatomy. The ERCP-related adverse events rate is comparable with conventional ERCP, but the overall adverse event rate was higher because of the added laparoscopy-related events.