Midlife obesity and long-term risk of nursing home admission

Objective: Obesity is a growing problem among middle‐aged individuals. We investigated whether obesity in middle‐aged individuals influences the need for future nursing home care and whether the risk of nursing home admission associated with obesity is greater in whites than in blacks. Research Methods and Procedures: The study population (N = 8804) consisted of long‐term members of the Kaiser Permanente Medical Care Plan ages 75 to 85 years in 1995 who had completed a standardized, multiphasic health checkup while in their 50s. The multiphasic health checkup examinations were performed as part of routine medical care between the years 1964 and 1973 and included standardized measurements of BMI. We used health plan records to assess incident nursing home admissions from 1995 to 2002. The risk of nursing home admission associated with standard categories of midlife BMI was estimated using Cox proportional hazard analysis. Results: During an average follow‐up of 5.1 years, the nursing home admission rate was 6.8 per 100 person‐years of observation. After adjustment for comorbidities, midlife obesity predicted incident nursing home admission ～25 years later [hazard ratio (HR), 1.30; 95% confidence interval (CI), 1.15 to 1.46; p < 0.001]. Overweight BMI at midlife was not associated with future nursing home admission (HR, 1.05; 95% CI, 0.97 to 1.14; p = 0.23). The risk of nursing home admission associated with midlife obesity was higher in whites (HR, 1.34; 95% CI, 1.17 to 1.54; p < 0.001) than in blacks (HR 1.15; 95% CI, 0.87 to 1.52; p = 0.32), but the difference between races was not significant (p for interaction = 0.65). Discussion: Obesity among middle‐aged individuals is associated with an increased risk of nursing home admission in late life and may be an important target for reducing the future societal burden of nursing home care.     

A glucose sensor in Candida albicans

The Hgt4 protein of Candida albicans (orf19.5962) is orthologous to the Snf3 and Rgt2 glucose sensors of Saccharomyces cerevisiae that govern sugar acquisition by regulating the expression of genes encoding hexose transporters. We found that HGT4 is required for glucose induction of the expression of HGT12, HXT10, and HGT7, which encode apparent hexose transporters in C. albicans. An hgt4Delta mutant is defective for growth on fermentable sugars, which is consistent with the idea that Hgt4 is a sensor of glucose and similar sugars. Hgt4 appears to be sensitive to glucose levels similar to those in human serum ( approximately 5 mM). HGT4 expression is repressed by high levels of glucose, which is consistent with the idea that it encodes a high-affinity sugar sensor. Glucose sensing through Hgt4 affects the yeast-to-hyphal morphological switch of C. albicans cells: hgt4Delta mutants are hypofilamented, and a constitutively signaling form of Hgt4 confers hyperfilamentation of cells. The hgt4Delta mutant is less virulent than wild-type cells in a mouse model of disseminated candidiasis. These results suggest that Hgt4 is a high-affinity glucose sensor that contributes to the virulence of C. albicans.     

Vinegar: medicinal uses and antiglycemic effect

Vinegar folklore is as colorful as it is practical. Legend states that a courtier in Babylonia (c. 5000 BC) "discovered" wine, formed from unattended grape juice, leading to the eventual discovery of vinegar and its use as a food preservative. Hippocrates (c. 420 BC) used vinegar medicinally to manage wounds. Hannibal of Carthage (c. 200 BC), the great military leader and strategist, used vinegar to dissolve boulders that blocked his army's path. Cleopatra (c. 50 BC) dissolved precious pearls in vinegar and offered her love potion to Anthony. Sung Tse, the 10th century creator of forensic medicine, advocated hand washing with sulfur and vinegar to avoid infection during autopsies. Based on the writings of US medical practitioners dating to the late 18th century, many ailments, from dropsy to poison ivy, croup, and stomachache, were treated with vinegar, and, before the production and marketing of hypoglycemic agents, vinegar "teas" were commonly consumed by diabetics to help manage their chronic aliment. This review examines the scientific evidence for medicinal uses of vinegar, focusing particularly on the recent investigations supporting vinegar's role as an antiglycemic agent. Epidemiologic studies and clinical trials were identified by a MEDLINE title/abstract search with the following search terms: vinegar, glucose; vinegar, cancer; or vinegar, infection. All relevant randomized or case-control trials were included in this review.     

Rhodamine 123 permeability through the catfish intestinal wall: Relationship to thermal acclimation and acute temperature change

Temperature is known to influence xenobiotic retention in fish. The effect of acute and acclimatory temperature change upon Rhodamine 123 (Rho123) permeability through an in vitro catfish multi-segment (3) everted sac intestinal wall model was examined in a 9 cell matrix of acclimation and assay temperatures (10, 20 and 30 degrees C). Changes in Rho123 permeability were examined in context with membrane fluidity, xenobiotic solubility and intestinal morphology. When assayed at the acclimation temperature greater Rho123 permeability was noted at warmer acclimation temperatures for the proximal and middle intestinal segments, while the distal segment exhibited little change and apparent compensation across temperatures. Rho123 permeability was increased as assay temperatures were elevated above the acclimation temperature for most comparisons. Cold acclimation significantly increased total intestinal length (43.2%) and proximal intestine weights while total body weights did not differ. Brush border membranes (BBM) increased fluidity with increased assay temperatures, however, composite anisotropy lines were not significantly different between acclimation treatments. In an additive manner, the membrane probe DPH exhibited increased solubility in BBM with increases in acclimation and assay temperatures. Compositely, these results suggest that acclimation and acute temperature change may differentially influence xenobiotic permeability among intestinal segments with interacting mechanisms.     

The Gcs1 Arf-GAP mediates Snc1,2 v-SNARE retrieval to the Golgi in yeast

Gcs1 is an Arf GTPase-activating protein (Arf-GAP) that mediates Golgi-ER and post-Golgi vesicle transport in yeast. Here we show that the Snc1,2 v-SNAREs, which mediate endocytosis and exocytosis, interact physically and genetically with Gcs1. Moreover, Gcs1 and the Snc v-SNAREs colocalize to subcellular structures that correspond to the trans-Golgi and endosomal compartments. Studies performed in vitro demonstrate that the Snc-Gcs1 interaction results in the efficient binding of recombinant Arf1Delta17N-Q71L to the v-SNARE and the recruitment of purified coatomer. In contrast, the presence of Snc had no effect on Gcs1 Arf-GAP activity in vitro, suggesting that v-SNARE binding does not attenuate Arf1 function. Disruption of both the SNC and GCS1 genes results in synthetic lethality, whereas overexpression of either SNC gene inhibits the growth of a distinct subset of COPI mutants. We show that GFP-Snc1 recycling to the trans-Golgi is impaired in gcs1Delta cells and these COPI mutants. Together, these results suggest that Gcs1 facilitates the incorporation of the Snc v-SNAREs into COPI recycling vesicles and subsequent endosome-Golgi sorting in yeast.     

Heparin binding directs activation of T cells against adeno-associated virus serotype 2 capsid

Activation of T cells to the capsid of adeno-associated virus (AAV) serotype 2 vectors has been implicated in liver toxicity in a recent human gene therapy trial of hemophilia B. To further investigate this kind of toxicity, we evaluated T-cell responses to AAV capsids after intramuscular injection of vectors into mice and nonhuman primates. High levels of T cells specific to capsids of vectors based on AAV2 and a phylogenetically related AAV variant were detected. Vectors from other AAV clades such as AAV8 (ref. 3), however, did not lead to activation of capsid-specific T cells. Through the generation of AAV2-AAV8 hybrids and the creation of site-directed mutations, we mapped the domain that directs the activation of T cells to the RXXR motif on VP3, which was previously shown to confer binding of the virion to heparan sulfate proteoglycan (HSPG). Evaluation of natural and engineered AAV variants showed direct correlations between heparin binding, uptake into human dendritic cells (DCs) and activation of capsid-specific T cells. The role of heparin binding in the activation of CD8(+) T cells may be useful in modulating the immunogenicity of antigens and improving the safety profile of existing AAV vectors for gene therapy.     

Role of deficient type III interferon-lambda production in asthma exacerbations

Rhinoviruses are the major cause of asthma exacerbations, and asthmatics have increased susceptibility to rhinovirus and risk of invasive bacterial infections. Here we show deficient induction of interferon-lambdas by rhinovirus in asthmatic primary bronchial epithelial cells and alveolar macrophages, which was highly correlated with severity of rhinovirus-induced asthma exacerbation and virus load in experimentally infected human volunteers. Induction by lipopolysaccharide in asthmatic macrophages was also deficient and correlated with exacerbation severity. These results identify previously unknown mechanisms of susceptibility to infection in asthma and suggest new approaches to prevention and/or treatment of asthma exacerbations.     

Ligation of the hairpin ribozyme in cis induced by freezing and dehydration

Although reducing the temperature slows most chemical reactions, freezing can stimulate some reactions by mechanisms that are only partially understood. Here we show that freezing stimulates the self-ligation (circularization) of linear forms of the hairpin ribozyme (HPR) containing 2',3'-cyclic phosphate and 5'-OH termini. Divalent metal ions (M2+) are not required, but monovalent cations and anions at millimolar concentrations can have various effects on this reaction depending on the specific ion. Under optimal conditions, the observed rate of M2+-independent self-ligation reaches a peak (0.04 min(-1)) at -10 degrees C with a yield of -60% after 1 h. In contrast, no ligation occurs either at above 0 degrees C or in solutions that remain unfrozen when supercooled to subzero temperatures. Under freezing conditions, the cleavage-ligation equilibrium strongly favors ligation. Besides freezing, evaporation of the aqueous solvent as well as the presence of ethanol at levels of 40% or above can also induce M2+-independent HPR ligation at 25 degrees C. We argue that partial RNA dehydration, which is a common feature of freezing, evaporation, and the presence of ethanol, is a key factor supporting HPR ligation activity at both above- and below-freezing temperatures. In the context of the RNA world hypothesis, freezing-induced ligation is an attractive mechanism by which complex RNAs could have evolved under conditions in which RNA was relatively protected against degradation.