Gaucher disease: expression and characterization of mild and severe acid beta-glucosidase mutations in Portuguese type 1 patients

Type 1 Gaucher disease (GD), the most prevalent lysosomal storage disease, results from the deficient activity of acid alpha-glucosidase. Molecular analysis of 12 unrelated Portuguese patients with type 1 GD identified three novel acid â-glucosidase mutations (F109V, W184R and R395P), as well as three previously reported, but uncharacterized, lesions (R359Q, G377S and N396T). The type 1 probands were either heteroallelic for the well-characterized common lesion, N370S, and the F109V, W184R, R359Q or N396T lesions or homoallelic for the G377S or N396T mutations. Expression of the W184R, R359Q, and R395P mutations revealed very low specific activities based on cross-reacting immunologic material (CRIM SAs of 0.0004, 0.016 and 0.045, respectively), consistent with their being found only in type 1 patients who had a neuroprotective N370S allele. In contrast, the F109V, G377S and N396T alleles had significant acid â-glucosidase activity (CRIM specific activities of 0.15, 0.17, 0.14, respectively), in agreement with their being mild type 1 alleles. Thus, these studies identified additional acid â-glucosidase mutations in the Portuguese population and demonstrated that the G377S and N396T mutations were neuroprotective, consistent with the mild clinical phenotypes of the type 1 patients who were homoallelic for the G377S and N396T lesions

Intrinsic high aerobic capacity protects against lipid induced hepatic insulin resistance [abstract]

Hepatic steatosis is commonly linked to hepatic insulin resistance. However, recent studies have found that increased hepatic triacylglycerol (TAG) accumulation is not always associated with impaired hepatic insulin signaling, leading to a hypothesis that partitioning of lipids into TAG in the liver matched with high rates of fatty acid oxidation (FAO) under high lipid exposure conditions may protect against hepatic insulin resistance. We examined this hypothesis in the livers of high and low capacity running (HCR/LCR) rats which were created by artificial selection based on differences in intrinsic aerobic capacity

Aural Foreign Bodies in Children

Background: Pediatric aural foreign bodies (FB) are relative medical emergencies. Primary care physicians, pediatricians, and otorhinolaryngologists commonly encounter them. Objective: The objective was to carry out a retrospective analysis of pediatric aural FB managed in otorhinolaryngology department of the University of Calabar Teaching Hospital, Nigeria. Materials and Methods: A total of 157 children with aural FB managed at the Department of Otorhinolaryngology, University of Calabar Teaching Hospital, Nigeria, from January 2015 to December 2018 were reviewed with regard to the type of FB, location, in the ear, methods of removal,  complications, age, and sex. Results: Of the 157 children, 54.1% were males and 45.9% females. Male: female ratio was 1.2:1. Ninety‑five (60.5%) were below the age of 5 years, 46 (29.3%) were 6–10 years of age, and 16 (10.2%) were in the age group of 11–15 years. The most common objects were beads, papers, and cotton. Most presentations (86%) were within 24 h. Seven patients (4.5%) required surgical removal under general anesthesia. Most of the patients (92.4%) had no complications. Morbidities include bleeding from the ear canal 6 (3.8%), canal abrasions/lacerations 4 (2.5%), and tympanic membrane perforations 2 (1.3%). Conclusion: Aural FBs are common conditions in children in our environment. Most of these can be successfully removed by skillful personnel,  adequate immobilization, and proper instrumentation. Pediatricians, family physicians, and other health workers should not hesitate to refer to otorhinolaryngologists, uncooperative/apprehensive children, those with a history of attempted removal by their parents or caregivers, or FB whose contour, composition and position in the canal cannot be fully assessed. Keywords: Aural, children, foreign bodie

Increased aerobic capacity reduces susceptibility to acute high‐fat diet‐induced weight gain

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134165/1/oby21564.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134165/2/oby21564_am.pd

GATA-2 and GATA-3 regulate trophoblast-specific gene expression in vivo.

We previously demonstrated that the zinc finger transcription factors GATA-2 and GATA-3 are expressed in trophoblast giant cells and that they regulate transcription from the mouse placental lactogen I gene promoter in a transfected trophoblast cell line. We present evidence here that both of these factors regulate transcription of the placental lactogen I gene, as well as the related proliferin gene, in trophoblast giant cells in vivo. Placentas lacking GATA-3 accumulate placental lactogen I and proliferi

Interdisciplinary Approach to Examine the Effects of Lifestyle Modifications on Nonalcoholic Fatty Liver Disease

Comparative Medicine - OneHealth and Comparative Medicine Poster SessionA critical complication of the obesity epidemic experienced in Westernized societies is nonalcoholic fatty liver disease (NAFLD). NAFLD, fatty liver not due to alcohol consumption, is the most common chronic liver disease and associated with increasing morbidity, mortality, and demand for liver transplantation. NAFLD is a progressive disease with a histological spectrum ranging from hepatic steatosis to nonalcoholic steatohepatitis, advanced fibrosis, and cirrhosis. Approximately one third of all US adults (90 million) have fatty livers, with prevalence rates as high as 75-100% in the obese and morbidly obese. With growing health problems associated with NAFLD, major questions facing research scientists and health care providers are what are the mechanisms responsible for NAFLD development and what is the best treatment strategy. Since drug interventions appear to be only marginally successful, the cornerstone therapy for NAFLD remains lifestyle modifications of exercise and weight loss. However, while recent cross-sectional observations suggest that being more physically active is inversely associated with NAFLD, studies which attempt to identify molecular mechanisms underlying the effects of lifestyle modifications on NAFLD are lacking. To address these clinical questions, we have taken an interdisciplinary approach with collaborations from experts in multiple departments and facilities at the University of Missouri, including Nutrition and Exercise Physiology, Hepatology, Veterinary Biomedical Sciences, and VA investigators. In addition, we have utilized a unique animal model, the hyperphagic Otsuka Long-Evans Tokushima Fatty (OLETF) rat that develops obesity, insulin resistance and overt type 2 diabetes, a model which we liken to overeating, sedentary, obese humans. Through a series of experiments, we found that the natural progression pattern of fatty liver disease in the sedentary OLETF rat closely resembles the human condition (progression from simple hepatic steatosis to hepatocyte ballooning, fibrosis, and inflammation). We also have compelling evidence that hepatic mitochondrial dysfunction is present at an early age and mitochondrial content, function, and mitochondrial health are disrupted with disease progression, suggesting a potential primary event in NAFLD in this animal model. However and perhaps even more important, when OLETF rats are given access to voluntary running wheels and allowed to exercise daily, the initiation and progression of NAFLD is completely prevented. These benefits occur through modification in both peripheral and hepatic factors, including maintenance of glycemic control and enhancement of hepatic mitochondrial content and function. We are currently in the process of translating these very exciting findings in a randomized, human clinical trial examining the impact of different lifestyle modifications in the treatment of NAFLD. Findings from our research group have important public health application, particularly for the 60-80% of Americans who overeat, who are overweight, and who are physically inactive

Erratum: "A Gravitational-wave Measurement of the Hubble Constant Following the Second Observing Run of Advanced LIGO and Virgo" (2021, ApJ, 909, 218)

[no abstract available

Narrowband Searches for Continuous and Long-duration Transient Gravitational Waves from Known Pulsars in the LIGO-Virgo Third Observing Run

Isolated neutron stars that are asymmetric with respect to their spin axis are possible sources of detectable continuous gravitational waves. This paper presents a fully coherent search for such signals from eighteen pulsars in data from LIGO and Virgo's third observing run (O3). For known pulsars, efficient and sensitive matched-filter searches can be carried out if one assumes the gravitational radiation is phase-locked to the electromagnetic emission. In the search presented here, we relax this assumption and allow both the frequency and the time derivative of the frequency of the gravitational waves to vary in a small range around those inferred from electromagnetic observations. We find no evidence for continuous gravitational waves, and set upper limits on the strain amplitude for each target. These limits are more constraining for seven of the targets than the spin-down limit defined by ascribing all rotational energy loss to gravitational radiation. In an additional search, we look in O3 data for long-duration (hours-months) transient gravitational waves in the aftermath of pulsar glitches for six targets with a total of nine glitches. We report two marginal outliers from this search, but find no clear evidence for such emission either. The resulting duration-dependent strain upper limits do not surpass indirect energy constraints for any of these targets. © 2022. The Author(s). Published by the American Astronomical Society