Weight reduction improves biochemistry and histology in patients with chronic hepatitis C

Hepatitis C virus (HCV) is a major cause of chronic liver disease that may progress to cirrhosis. Antiviral treatment is successful in less than 50% of patients, is costly and causes debilitating side effects. For these reasons, additional therapies to limit the progression of liver disease are urgently required. Steatosis is found in 60% of patients with HCV and is strongly associated with more severe fibrosis. Improvements in biochemical parameters may be seen with weight reduction, however the effects on liver histology have not been investigated. We propose that in patients with chronic HCV and steatosis, obesity contributes to fat in the liver, which results in increased fibrosis and progression to cirrhosis. This study investigated the effect of weight reduction on liver biochemistry and histology in patients with HCV and the success of weight maintenance after an intensive intervention. We examined the effect of a 12 week diet and exercise program where all subjects were seen weekly by the Dietician, with the goal of achieving a 0.5 kg weight loss per week. Biochemistry was monitored monthly and a liver biopsy was performed prior to and 3-6 months after the intervention period. Patients then entered a 12 month weight maintenance program with monthly dietetic review. After 12 weeks there was a mean weight loss of 5.9 ± 3.2 kg and a mean reduction in waist circumference of 9.0 ± 5.0 cm. In 16 of the 19 patients, serum ALT levels fell progressively with weight loss. Mean fasting insulin fell from 16 to 11 mmol/L (p

Weight reduction in patients with chronic HCV reduces circulating insulin levels

Steatosis occurs in >50% of patients with chronic HCV. In patients with viral genotype 3, steatosis may be a cytopathic effect of the virus. However in many patients with HCV, the pathogenesis of steatosis appears to be the same as for patients with non-alcoholic fatty liver disease (NAFLD) ie related to increased body mass index (BMI). We studied the effect of a 12 week weight reduction program on metabolic parameters in subjects with chronic HCV genotype 1 (Group 1, n = 16), genotype 3 (Group 2, n = 13) and patients with NAFLD (Group 3, n = 13). A liver biopsy was performed prior to and 3-6 months after the intervention period in 15 patients. The mean (SD) BMI of subjects in groups 1, 2 and 3 was 30.7 (4.0), 29.0 (5.2) and 33.3 (7.7), respectively. There was no significant difference in the amount of weight loss, change in waist circumference, change in ALT or reduction in steatosis between the 3 groups. Mean (SD) weight loss was 5.1 (3.7) kg. In those patients who lost weight, serum insulin (mean (SD) mU/L) changed from 17.8 (7.8) to 11.5 (4.8) (p = 0.003), 12.4 (5.0) to 8.4 (4.3) (p = 0.02), and 16.9 (7.3) to 17.8 (8.1) (p = 0.76) in Groups 1, 2 and 3, respectively. A small amount of weight loss is associated with a reduction in circulating insulin levels in patients with chronic HCV, particularly in genotype 1. In patients with NAFLD, the lack of a significant decrease in circulating insulin with weight reduction may reflect the higher initial BMI or may be due to the pathogenesis of this disorder.

Equine laminitis: loss of hemidesmosomes in hoof secondary epidermal lamellae correlates to dose in an oligofructose induction model: an ultrastructural study

Reasons for performing study: Light microscopical studies show that the key lesion of laminitis is separation at the hoof lamellar dermal-epidermal interface. More precise knowledge of the damage occurring in the lamellar basement membrane zone may result if laminitis affected tissue is examined with the transmission electron microscope. This could lead to better understanding of the pathogenesis of lesions and the means of treatment or prevention. Objectives: To investigate the ultrastructure of acute laminitis as disease of greater severity is induced by increasing oligofructose (OF) dosage. Methods: Three pairs of normal horses, dosed with OF at 7.5, 10 and 12.5 g/kg bwt via nasogastric intubation, developed laminitis 48 h later. Following euthanasia, their forefeet were processed for transmission electron microscopy. Lamellar basal cell hemidesmosome (HD) numbers and the distance between the basal cell plasmalemma and the lamina densa of the basement membrane were estimated and compared to control tissue. Results: Increasing OF dosage caused greater HD loss and more severe laminitis. The characteristic separation of the basement membrane, cytoskeleton failure and rounded basal cell nuclei results from combined HD dysassembly and anchoring filament failure. Conclusions: Without properly assembled HDs, dysadhesion between the lamina densa of the basement membrane (BM) and epidermal basal cells occurs, emphasising the fundamental importance of HDs in maintaining attachment at the lamellar interface. Medical conditions that trigger lamellar matrix metalloproteinase (MMP) activation and/or compromise entry of glucose into lamellar basal cells appear to promote loss and failure of HDs and, therefore, laminitis development. Potential relevance: A correlation between lameness severity and escalating loss of lamellar HDs now exists. Therapy aimed at protecting the lamellar environment from haematogenous delivery of MMP activators or from glucose deprivation may control laminitis development.

Low prenatal vitamin D alters morphology, cell density and gene expression in adult rat brain: Correlations with schizophrenia

Statement of the study: Based on data from ecological and analytic epidemiological studies, we have proposed that low prenatal vitamin D is a candidate risk-modifying factor for schizophrenia. Previously, we demonstrated that low prenatal vitamin D adversely affected brain development in neonatal rats (Eyles et al, 2003). Here we examine the impact of both prenatal and early life hypovitaminosis D on various outcomes in the adult rat brain. Methods: Female Sprague-Dawley rats were made vitamin D deficient via the use of a special diet (Dyets CA) and lighting conditions that excluded UVB radiation. Animals were kept under these conditions for 6 weeks then mated with males kept under normal conditions. Vitamin deplete dams were kept under these conditions during pregnancy. Offspring from two test groups were examined. Offspring were either reared with dams repleted with vitamin D at birth or remained under deplete conditions till weaning. Both test groups were weaned under normal vitamin D conditions and remained so till testing at adulthood. We compared the brains of adult offspring kept under both test conditions with animals from control environments. Summary of results: We found a significant persistent dose-related increase in lateral ventricle volume and alterations in anterior cingulate and prefrontal cortical cell densities (consistent with the known prodifferentiation properties of this steroid). In both test groups we observed a reduced expression of NGF as well as a down-regulation of transcripts coding for GABAA alpha 4 receptor and two neuronal structural elements; MAP2 and Neurofilament L. Conclusion: These findings provide further evidence that vitamin D is involved in brain development. An increase in prefrontal cortical cell density, a reduction neuronal structural elements and persistent ventriculomegaly are all common anatomical findings in the brains of patients with schizophrenia. The specific reduction in transcripts for neuronal structural proteins but not GFAP is also in accordance with the proposal that frontal cortical architecture in schizophrenia reflects a reduction in connectivity rather than a reduction in glial processes(Goldman-Rakic and Selemon, 1997). These findings confirm the biological plausibility of early life hypovitaminosis D as a risk factor for schizophrenia.

Self-assembled naphthalenediimide derivative films for light-assisted electrochemical reduction of oxygen

This naphthalene diimide derivative, DC18, forms highly conjugated semiconducting stacked assemblies over electrodes after electrochemical conditioning. These molecular materials are very efficient towards electrochemical photoreduction of oxygen under visible light.

BUPROPION/NALTREXONE FIXED-DOSE COMBINATION FOR THE TREATMENT OF OBESITY

The combination of bupropion and naltrexone is one of the most promising new possibilities for the treatment of obesity in an era of increasing prevalence of this disease and decreasing options for its pharmacological management. Although approved by FDA panel members, it was temporally rejected by the FDA afterwards, who demanded more cardiovascular safety data for its commercialization. This monograph will focus on the physiology involved in its mechanisms of action and results of clinical trials.

Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia

Purpose Dasatinib is a BCR-ABL inhibitor, 325-fold more potent than imatinib against unmutated BCR-ABL in vitro. Phase II studies have demonstrated efficacy and safety with dasatinib 70 mg twice daily in chronic-phase (CP) chronic myelogenous leukemia (CML) after imatinib treatment failure. In phase I, responses occurred with once-daily administration despite only intermittent BCR-ABL inhibition. Once-daily treatment resulted in less toxicity, suggesting that toxicity results from continuous inhibition of unintended targets. Here, a dose-and schedule-optimization study is reported. Patients and Methods In this open-label phase III trial, 670 patients with imatinib-resistant or -intolerant CP-CML were randomly assigned 1: 1: 1: 1 between four dasatinib treatment groups: 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. Results With minimum follow-up of 6 months (median treatment duration, 8 months; range, = 1 to 15 months), marked and comparable hematologic (complete, 86% to 92%) and cytogenetic (major, 54% to 59%; complete, 41% to 45%) response rates were observed across the four groups. Time to and duration of cytogenetic response were similar, as was progression-free survival (8% to 11% of patients experienced disease progression or died). Compared with the approved 70-mg twice-daily regimen, dasatinib 100 mg once daily resulted in significantly lower rates of pleural effusion (all grades, 7% v 16%; P = .024) and grade 3 to 4 thrombocytopenia (22% v 37%; P = .004), and fewer patients required dose interruption (51% v 68%), reduction (30% v 55%), or discontinuation (16% v 23%). Conclusion Dasatinib 100 mg once daily retains the efficacy of 70 mg twice daily with less toxicity. Intermittent target inhibition with tyrosine kinase inhibitors may preserve efficacy and reduce adverse events.

Ocular toxicity of intravitreous adalimumab (Humira) in the rabbit

Purpose To evaluate the ocular toxicity of escalating doses of intravitreous adalimumab (Humira) in the rabbit eye. Methods Twelve New Zealand albino rabbits received unilateral intravitreous injections of 0.1 ml of adalimumab 0.25 mg (three eyes), 0.50 mg (three eyes), 1.0 mg (three eyes) or 0.1 ml balanced salt solution (BSS, threeeyes). Slit-lamp biomicroscopy and fundoscopy were carried out at baseline, day 1, 7 and 14 following intravitreous injection, while electroretinography (ERG) was carried out at baseline and day 14. Animals were euthanized on day 14, and histopathological examination of the eyes was performed. Results Slit-lamp biomicroscopy and fundoscopy were normal in eyes having received BSS, 0.25 mg or 0.50 mg adalimumab; however, inflammation was present in two of three eyes having received 1.0 mg adalimumab. Similarly, comparison of scotopic and photopic ERG light at baseline and day 14 demonstrated no changes in eyes receiving BSS, 0.25 mg or 0.50 mg adalimumab, but two of three eyes having received 1.0 mg adalimumab showed a greater than 30% reduction in a and b wave. Finally, histopathology demonstrated no differences between eyes receiving BSS, 0.25 mg or 0.50 mg of adalimumab, but two of three eyes injected with 1.0 mg demonstrated inflammatory cell infiltration of the vitreous and anterior chamber, with one of these eyes demonstrating retinal necrosis. Conclusions Escalating doses of intravitreous adalimumab in rabbit eyes caused no detectable functional or structural ocular toxicity up to a dose of 0.50 mg. Administration of 1.0 mg in 0.1 ml was associated with an inflammatory reaction and retinal necrosis.

Results of high dose-rate brachytherapy boost before 2D or 3D external beam irradiation for prostate cancer

Background and purpose: To evaluate biochemical control and treatment related toxicity of patients with localized adenocarcinoma of the prostate treated with high dose-rate brachytherapy (HDRB) combined with conventional 2D or 3D-conformal external beam irradiation (EBI). Material and methods: Four-hundred and three patients treated between December 2000 and March 2004. HDRB was delivered with three fractions of 5.5-7 Gy with a single implant, followed by 45 Gy delivered with 2D or 3D conformal EBI. Results: The median follow-up was 48.4 months. Biochemical failure (BF) occurred in 9.6% according to both ASTRO and Phoenix consensus criteria. Mean time to relapse was 13 and 26 months, respectively. The 5-year BF free survival using the ASTRO criteria was 94.3%, 86.9% and 86.6% for the low, intermediate and high risk groups, respectively; using Phoenix criteria, 92.4%, 88.0% and 85.3%, respectively. The only predictive factor of BF in the multivariate analysis by both ASTRO and Phoenix criteria was the presence of prostate nodules detected by digital palpation, and patients younger than 60 years presented a higher chance of failure using Phoenix criteria only. Conclusions: Treatment scheme is feasible and safe with good efficacy. (C) 2011 Elsevier Ireland Ltd All rights reserved. Radiotherapy and Oncology 98 (2011) 169-174

Thin superior medial pedicle reduction mammaplasty for severe mammary hypertrophy

Background There are multitudes of procedures in plastic surgery used to correct hypertrophic and pendulous breasts in patients with heavy and ptotic breasts who need great resections of breast tissue, where the suprasternal notch-to-nipple distance is long and the use of nipple-areola transposition techniques is a challenge for the plastic surgeon. The purpose of this study is to present a technique of reduction mammaplasty that could solve these problems based on the following principles: mammary reduction utilizing a thin superior medial pedicle (0.8-1.5 cm thick) and the resection performed in two steps: (1) the base excess at a plane perpendicular to the breast (this determines the cone`s height) and (2) central half keel (this determines the breast diameter reduction). Methods Ninety patients with mammary hypertrophy were operated on at the ""Hospital das Clinicas,"" Sao Paulo University Medical School, between January 2000 and November 2005. Inclusion in this study required a minimum of 12-cm change in nipple position and a 750-g breast resection. Results The mean change in nipple position was 16 cm (range = 12-21 cm). The mean weight of each breast was 1400 (range = 750-3000 g).Considering the great amount of volume removed and the size of the operated breasts, few complications were observed and were similar to those reported following other techniques described in the literature. Patient satisfaction following this procedure was high. Conclusion The results of this study clearly demonstrate that thin superior medial pedicle reduction mammaplasty is a safe and reliable technique in cases of severe mammary hypertrophy.

Correlation between the Body Mass Index (BMI) of Pregnant Women and the Development of Hypotension after Spinal Anesthesia for Cesarean Section

Nani FS, Torres MLA - Correlation between the Body Mass Index (BMI) of Pregnant Women and the Development of Hypotension after Spinal Anesthesia for Cesarean Section. Background and objectives: Very few publications correlate hypotension in obese pregnant women, and especially morbidly obese, after spinal anesthesia for cesarean section. The objective of the present study was to evaluate the incidence of hypotension according to the BMI. Methods: Forty-nine patients with pregestational BMI below 25 kg.m(-2) were included in the Eutrophia group, and 51 patients with BMI >= 25 kg.m(-2) were included in the Overweight group. After spinal anesthesia, blood pressure, volume of crystalloid infused, and dose of vasopressors used until delivery were recorded. A fall in systolic blood pressure below 100 mmHg or 10% reduction of the initial systolic blood pressure (SBP) was considered as hypotension and it was corrected by the administration of vasopressors. Results: Episodes of hypotension were fewer in the Eutrophia group (5.89 +/- 0.53 vs. 7.80 +/- 0.66, p = 0.027), as well as the amount of crystalloid administered (1,298 +/- 413.6 mL vs. 1,539 +/- 460.0 mL; p = 0.007), and use of vasopressors (5.87 +/- 3.45 bolus vs. 7.70 +/- 4.46 bolus; p = 0.023). As for associated diseases, we observed higher incidence of diabetes among obese pregnant women (29.41% vs. 9.76%, RR 1.60, 95%CI: 1.15-2.22, p = 0.036), however, differences in the incidence of pregnancy-induced hypertension (PIN) were not observe between both groups (overweight: 21.57%, normal weight: 12.20%, RR 1.30, 95%CI: 0.88-1.94, p = 0.28). Conclusions: In the study sample, pregestational BMI >= 25 kg.m(-2) was a risk factor for hypotension after spinal anesthesia in patients undergoing cesarean section. The same group of patients required higher doses of vasopressors. Those results indicate that the anesthetic techniques in those patients should be improved to reduce the consequences of post-spinal anesthesia hypotension, both in pregnant women and fetuses.