Sibutramine treatment in obesity: initial eating behaviour in relation to weight loss results and changes in mood.

The aim of the study was to study the role of initial eating behaviour for subsequent weight loss in treatment with sibutramine (Reductil, Meridia) an anti-obesity drug enhancing satiety, and also to assess changes in mood during the treatment. The participants were 36 obese patients with a mean BMI of 39 kg m(-2). Eating behaviour was assessed with the three factor eating questionnaire (TFEQ), and depressive features with the comprehensive psychopathological rating scale (CPRS). Sibutramine (15 mg) was administered daily. The TFEQ restraint scale was negatively related to 6 months weight loss. In particular, strategic dieting behaviour and a more controlled attitude towards self-regulation were negatively related to weight loss. A positive non-placebo controlled change in mood was found already after 2 months treatment. The changes in mood were not related to the weight loss. Patients with more unrestrained eating seem to have reduced their amount of food intake more radically with enhanced satiety, manifested by greater weight loss. Physiologically enhanced satiety could have the greatest weight loss effect for patients whose eating is more governed by hunger drives and appetite rather that by conscious efforts and cognitive control.     

DNA methylation in anal intraepithelial lesions and anal squamous cell carcinoma.

PURPOSE: Anal intraepithelial neoplasia is associated with human papillomavirus infection and may progress to invasive squamous cell carcinoma (SCC), which is increasing in immunocompromised patients. We hypothesize that anal intraepithelial neoplasia is associated with abnormal DNA methylation and that detection of these events may be used to improve screening programs. EXPERIMENTAL DESIGN: Seventy-six patients were identified who underwent anal cytology screening and subsequent biopsy at our institution between 1999 and 2004. The specimens from these patients included 184 anal biopsies [normal, n = 57; low-grade squamous intraepithelial lesion (LSIL), n = 74; high-grade squamous intraepithelial lesion (HSIL), n = 41; and invasive SCC, n = 12] and 37 residual liquid-based anal cytology specimens (normal, n = 11; LSIL, n = 12; HSIL, n = 14). The methylation status of the following genes was determined for each biopsy and cytology sample using real-time methylation-specific PCR: HIC1, RASSF1, RARB, CDKN2A, p14, TP73, APC, MLH1, MGMT, DAPK1, and IGSF4. RESULTS: Methylation-specific PCR analysis of biopsy samples revealed that DNA methylation was more common in SCC and HSIL than LSIL and normal mucosa. Specifically, methylation of IGSF4 and DAPK1 was prevalent in SCC (75% and 75% of cases, respectively) and HSIL (59% and 71%, respectively) but was absent in LSIL and normal biopsy samples. Methylation profiles of cytologic samples were similar to those found in the biopsy samples. CONCLUSIONS: Aberrant DNA methylation is a frequent event in anal HSIL and SCC. Methylation of IGSF4 and DAPK1 is specific for HSIL and SCC, and may serve as a useful molecular biomarker.     

Role of mouse CYP2E1 in the O-hydroxylation of p-nitrophenol: comparison of activities in hepatic microsomes from Cyp2e1(-/-) and wild-type mice.

Enzymatic activities are routinely used to identify the contribution of individual forms of cytochrome P450 in a particular biotransformation. p-Nitrophenol O-hydroxylation (PNPH) has been widely used as a measure of CYP2E1 catalytic activity. However, rat and human forms of CYP3A have also been shown to catalyze this activity. In mice, the contributions of CYP3A and CYP2E1 to PNPH activity are not known. Here we used hepatic microsomes from Cyp2e1(-/-) and wild-type mice to investigate the contributions of constitutively expressed and alcohol-induced murine CYP2E1 and CYP3A to PNPH activity. In liver microsomes from untreated mice, PNPH activity was much greater in wild-type mice compared with Cyp2e1(-/-) mice, suggesting a major role for CYP2E1 in catalyzing PNPH activity. Hepatic PNPH activities were not significantly different in microsomes from male and female mice, although the microsomes from females have dramatically higher levels of CYP3A. Treatment with a combination of ethanol and isopentanol resulted in induction of CYP3A proteins in wild-type and Cyp2e1(-/-) mice, as well as CYP2E1 protein in wild-type mice. The alcohol treatment increased PNPH activities in hepatic microsomes from wild-type mice but not from Cyp2e1(-/-) mice. Our findings suggest that in untreated and alcohol-treated mice, PNPH activity may be used as a specific probe for CYP2E1 and that constitutively expressed and alcohol-induced forms of mouse CYP3A have little to no role in catalyzing PNPH activity.     

Systematic Evidence Map for Over One Hundred and Fifty Per- and Polyfluoroalkyl Substances (PFAS)

Background: Per- and polyfluoroalkyl substances (PFAS) are a large class of synthetic (man-made) chemicals widely used in consumer products and industrial processes. Thousands of distinct PFAS exist in commerce. The 2019 U.S. Environmental Protection Agency (U.S. EPA) Per- and Polyfluoroalkyl Substances (PFAS) Action Plan outlines a multiprogram national research plan to address the challenge of PFAS. One component of this strategy involves the use of systematic evidence map (SEM) approaches to characterize the evidence base for hundreds of PFAS.Objective: SEM methods were used to summarize available epidemiological and animal bioassay evidence for a set of ∼150 PFAS that were prioritized in 2019 by the U.S. EPA’s Center for Computational Toxicology and Exposure (CCTE) for in vitro toxicity and toxicokinetic assay testing.Methods: Systematic review methods were used to identify and screen literature using manual review and machine-learning software. The Populations, Exposures, Comparators, and Outcomes (PECO) criteria were kept broad to identify mammalian animal bioassay and epidemiological studies that could inform human hazard identification. A variety of supplemental content was also tracked, including information on in vitro model systems; exposure measurement–only studies in humans; and absorption, distribution, metabolism, and excretion (ADME). Animal bioassay and epidemiology studies meeting PECO criteria were summarized with respect to study design, and health system(s) were assessed. Because animal bioassay studies with ≥21-d exposure duration (or reproductive/developmental study design) were most useful to CCTE analyses, these studies underwent study evaluation and detailed data extraction. All data extraction is publicly available online as interactive visuals with downloadable metadata.Results: More than 40,000 studies were identified from scientific databases. Screening processes identified 44 animal and 148 epidemiology studies from the peer-reviewed literature and 95 animal and 50 epidemiology studies from gray literature that met PECO criteria. Epidemiological evidence (available for 15 PFAS) mostly assessed the reproductive, endocrine, developmental, metabolic, cardiovascular, and immune systems. Animal evidence (available for 40 PFAS) commonly assessed effects in the reproductive, developmental, urinary, immunological, and hepatic systems. Overall, 45 PFAS had evidence across animal and epidemiology data streams.Discussion: Many of the ∼150 PFAS were data poor. Epidemiological and animal evidence were lacking for most of the PFAS included in our search. By disseminating this information, we hope to facilitate additional assessment work by providing the initial scoping literature survey and identifying key research needs. Future research on data-poor PFAS will help support a more complete understanding of the potential health effects from PFAS exposures. https://doi.org/10.1289/EHP10343     

Autosomal dominant cone-rod dystrophy due to a missense mutation (R838C) in the guanylate cyclase 2D gene (GUCY2D) with preserved rod function in one branch of the family

Autosomal recessive retinitis pigmentosa (ARRP) is a degenerative disorder of photoreceptors. Mutations in several genes encoding different proteins of the visual cascade are described. The inheritance of two intragenic markers within the interstitial retinol binding protein (IRBP) gene was established in 45 Spanish families with a history of ARRP. Homozygosity mapping and cosegregation analyses were positive in 19 families. Only one heterozygous T-C transition at position 3024 (exon 1) was detected in one consanguineous family. This variant was identified as a rare polymorphism and was present in 5% of the chromosomes analyzed.     

In diabetic retinopathy, foveal thickness of 300 μm seems to correlate with functionally significant loss of vision

Purpose To study the relationship between foveal thickness assessed by optical coherence tomography (OCT) and foveal function measured with multi focal electroretinography (mfERG) in patients with non-proliferative diabetic retinopathy, and with no previous laser treatment. Methods Twenty-six eyes from 18 diabetic patients (13 men), aged 59 years, (range 28–79 years), diabetes duration 15 years, (range 2–27 years), with a macular thickness between 200 and 600 μm were evaluated by mfERG, visual acuity (ETDRS score) and OCT. Mean amplitudes and implicit times of the mfERG responses were analyzed within the four innermost (14 degrees) of the six concentric rings. For comparison with the results from the OCT (diameter of measured area = 6 mm) we analyzed the summed response from the first and second ring (central zone), corresponding to the central area of the OCT. The third(zone 2) and fourth (zone 3)of the four innermost of the six concentric rings measured by the mfERG corresponding to the second and third area of OCT. Results An increased macular thickness in the central area of the OCT correlated to reduced amplitudes (r = −0.541; P = 0.004) and prolonged implicit times (r = 0.548; P = 0.004) in the central zone of the mfERG, and inversely correlated with visual acuity, −0.49; P = 0.045. Retinal thickness in the second area was correlated to prolonged implicit times in the second mfERG zone (r = −0.416; P = 0.034). No correlations were found for the third area of the OCT. When macular thickness exceeded 300 μm the decrease of amplitudes and prolonged implicit times, measured by mfERG, seemed to be more pronounced. Conclusion In conclusion increased macular thickness is correlated with reduced amplitudes and prolonged implicit times on the mf ERG and worse visual acuity.