Severe hypoleptinaemia associated with insulin resistance in patients with common variable immunodeficiency

Objective Common variable immunodeficiency (CVI) is a primary immunodeficiency syndrome characterized by impaired production of antibodies and recurrent infections. Delay in diagnosis leads to metabolic wastage and low body weight. Leptin, a hormone produced by white adipose tissue, modulates insulin action by signal transduction cross‐talk and by direct action on pancreatic beta‐cells. We hypothesized that patients with CVI might present a defective regulation of leptin production and insulin resistance. Patients Thirteen CVI patients (39 ± 11 years) under gammaglobulin replacement were evaluated in parallel with 13 gender‐, age‐, body weight‐ and body mass index (BMI)‐matched healthy voluntaries, and with data from two large population series, the Bruneck and the Hoorn Studies. Measurements Serum leptin and insulin levels, homeostasis model assessment – insulin resistance (HOMA‐IR), body composition, haematological, biochemical and immunoglobulin measurements were obtained. Data were analysed by a one‐way analysis of variance (anova ) and by Pearson's rank analysis. The institutional ethics committee approved the study, and informed consent was obtained from patients and controls. Results No differences were found between CVI and the control group when comparing gender distribution, age, body weight, BMI, waist/hip ratio, relative body fat and fasting glucose levels. Leptin levels were lower (P < 0·05) in CVI patients than in controls and lower than fasting leptin levels detected in a large population study. CVI patients’ serum leptin levels did not correlate with BMI (r = 0·074, P = 0·8) and their high HOMA‐IR indicated insulin resistance. Conclusions CVI patients are relatively hypoleptinaemic and insulin resistant, and their serum leptin levels are not correlated to their BMI.     

Effect of Ki‐67 on Immunohistochemical Classification of Luminal A to Luminal B Subtypes of Breast Carcinoma

It has recently been proposed to include an immunohistochemical marker of cell proliferation, Ki‐67, as an element with which to classify the molecular subtypes of breast cancer. The objective of this study was to evaluate the effect of the introduction of the Ki‐67 marker on the molecular classification of breast cancer by immunohistochemistry. This study was performed on 234 cases of invasive ductal carcinoma of the breast submitted to two immunohistochemical classification panels, one including Ki‐67 and the other not. The data obtained with the two classifications were correlated with well‐established prognostic factors such as histologic grade, the number of lymph nodes affected and tumor size. The molecular classification without Ki‐67 identified: 136 cases of luminal A (58.1%), 19 cases of luminal B (8.1%), 27 cases of human epidermal growth‐factor receptor 2 overexpressing (11.5%), 27 cases of basal‐like (11.5%), and 25 cases of nonbasal‐like triple‐negative tumors (10.7%). When Ki‐67 was included, this situation changed significantly, with the following cases being identified: 72 cases of luminal A (30.8%) and 83 cases of luminal B tumors (35.5%), resulting in a Kappa score of 0.216. Evaluation of correlations between the luminal A and luminal B tumor subtypes and the selected prognostic factors showed a statistically significant difference only when Ki‐67 was included and only with respect to histologic grade (p < 0.001). The new classification with Ki‐67 significantly altered the prevalence of the luminal A and luminal B subtypes and improved correlation with the histologic grade.     

Retinal lesions induce differential changes in the expression of flip and flop isoforms of the glutamate receptor subunit GluR1 in the chick optic tectum

A sensitive RNase protection assay was employed to determine the levels of mRNA encoding the GluR1 subunit flip and flop isoforms in the chick optic tectum and forebrain. We found that the flip GluR1 mRNA predominates in the forebrain, whereas the flop variant is more strongly expressed in the optic tectum. A temporal analysis of GluR1 variants in the embryonic and adult chick brain revealed that the flip isoform is more highly expressed at E12 than at P15-21, whereas mRNA levels of the flop isoform are higher at P15-21 than at E12. To study the effect of deafferentation on GluR1 expression, unilateral retinal lesions were performed. Two days later the mRNA levels of GluR1 flip and flop variants were decreased in the deafferented tectum, especially for the flop isoform. However, 7 days after the lesion, the mRNA levels of both GluR1 isoforms were increased, especially for the flip isoform. These results reveal an important control of the retinal input upon the expression of the different GluR1 isoforms. Furthermore, they indicate a differential spatial and temporal regulation of the flip and flop splice variants, suggesting the existence of a mechanism regulating differential splicing or possibly differential RNA stability.     

Effects of the tumour necrosis factor-alpha inhibitors pentoxifylline and thalidomide in short-term experimental oral mucositis in hamsters

Oral mucositis is a frequent side-effect of cancer therapy. A definitive method of prophylaxis or treatment is not yet available. As pentoxifylline (PTX) and thalidomide (TLD) have been shown to inhibit cytokine synthesis, we studied the effects of these cytokine inhibitors in an experimental oral mucositis model. Oral mucositis was induced in Golden hamsters by the administration of 5-fluorouracil (5-FU) followed by mechanical trauma of the cheek pouch. On days 4, 5, 10, 12, 14 and 16, lesions induced by 5-FU were examined macroscopically and microscopically, and the presence and intensity of hyperemia, erythema, edema, inflammatory cell infiltration, hemorrhagic areas, ulcers and abscesses were recorded. Saline (control), PTX (5, 15, 45 mg kg(-1)) or TLD (10, 30, 90 mg kg(-1)) were administered daily and animals were killed on day 10 for macroscopic and histological analysis and assay of myeloperoxidase (MPO) activity. Animals were weighed daily, and total and differential leukocyte counts were performed on peripheral blood. PTX and TLD were found to reduce the macroscopic and histological parameters of oral mucositis and MPO activity. PTX and TLD also reversed peripheral neutrophilia, but only PTX prevented weight loss. The results indicate a protective effect of PTX and TLD, suggesting an important role for tumour necrosis factor-alpha (TNF-alpha) in the pathophysiology of 5-FU induced-oral mucositis in hamsters.     

Down-regulation of Na+ transporters and AQP2 is responsible for acyclovir-induced polyuria and hypophosphatemia

BACKGROUND: Acyclovir (ACY) is a useful therapeutic agent for the systemic treatment of herpes virus infection. An increase in urinary phosphate excretion and polyuria has been described. The objective of this study was to analyze the exact mechanism of the urinary-concentrating dysfunction and the increase in phosphaturia associated with ACY. METHODS: We first analyzed 7 (adult and pediatric) non-AIDS cases of encephalitis receiving 15 mg/kg bw/d of intravenous ACY. Fractional phosphate and sodium excretion, urinary potassium volume, and plasma phosphate concentrations were analyzed. Additional studies in rats treated with intraperitoneal ACY (100 mg/kg bw) were also conducted. Animals were maintained in metabolic cages and 24-hour urine samples were collected to measure volume, osmolality, and sodium/potassium/phosphate excretion. Treated rats were also evaluated after 24 hours and 48 hours of water deprivation. Northern hybridization and semiquantitative immunoblotting were performed to evaluate (in both control and treated animals) expression of the cotransporters Na-Pi type IIa (Na-Pi-IIa) and Na-K-2Cl (NKCC2). Semiquantitative immunoblotting was carried out in the kidneys of ACY rats and control rats in order to analyze aquaporin 2 (AQP2) protein expression. RESULTS: Patients started on ACY developed polyuria and hyperphosphatemia after 48 hours. In rats, ACY-induced hyperphosphaturia and hypophosphatemia were accompanied by increased excretion of sodium, potassium, and magnesium, increased urine output, lower urinary osmolality, and a partial urinary concentrating defect. Concurrent downregulation of Na-Pi-IIa and NKCC2 expression was observed. There was also a decrease in medullar expression of the AQP2 collecting duct water channel. CONCLUSION: Downregulation of Na-Pi-IIa appears to play a crucial role in the downregulation of ACY-induced hyperphosphaturia. The accompanying polyuria and urinary-concentrating defect can in part be explained by the downregulation of NKCC2 and AQP2.     

Estimating the gasoline components and formulations toxicity to microalgae (Tetraselmis chuii) and oyster (Crassostrea rhizophorae) embryos: an approach to minimize environmental pollution risk

Even though petrochemical contamination frequently occurs in the form of oil spills, it is thought that a greater danger to coastal habitats is posed by chronic petrochemical toxicity associated with urban run-off, in which gasoline water-soluble-fraction (WSF) plays an important role. The hypothesis of the entrepreneurs, who were associated to the scientists uncharged of this research, was that recycled petrochemical waste may provide different gasoline formulations, having different toxic properties; the correlation between the gasoline formulations and their components' toxicological effects might contribute to the reformulation of the products, in such a way that the gasoline generated could be less toxic and less harmful to the environment. The aim of this research was to determine the toxic effects of 14 different types of gasoline (formulated, in accordance with National Petroleum Agency standards, from petrochemical waste), on Tetraselmis chuii (microalgae culture) and Crassostrea rhizophorae (embryos). Microalgae and oyster embryos were exposed to different gasoline formulations water-soluble fractions (WSF) at a range of concentrations (0%, 4.6%, 10.0%, 22.0%, 46.0%, and 100%), for 96 and 24h, respectively. The tests were carried out under controlled conditions. End-points have been CI50-96h (concentration causing 50% growth inhibition in microalgae cultures) and EC50-24h (concentration causing abnormalities on 50% of the exposed embryos). Through these procedures, gasoline formulations, which represent the lowest environmental risk, were selected. Bioassays carried out on the 8 different gasoline components aimed to correlate gasoline toxicity with the toxic potential of its components. The analysis of principal components showed that the C9DI, a mixture of aromatic hydrocarbons of 9 carbon atoms, had the highest level of toxic potential, followed by C9S (a mixture of aromatics with 9-11 carbon atoms) and heavy naphtha. The results showed gasoline formulations 1-4 (monoaromatic hydrocarbons being the most conspicuous components) to be the least toxic, whilst formulations 12-14 (having higher content of C9DI, C9S and naphtha) were found to be the most harmful to organisms. This study led to the identification of the most toxic WSF gasoline components (C9DI and C9S), and to the possibility of developing more eco-compatible gasoline formulations.     

Job satisfaction and work impact among providers of a mental health service

OBJECTIVE: To assess job satisfaction and work impact among providers of a mental health service and their potential association with sociodemographic and job-related variables. METHODS: A cross-sectional study was carried out in 321 employees of a long-stay mental health service in Rio de Janeiro, Southeastern Brazil, in 2005. The following instruments were applied: the WHO Mental Health Services Satisfaction and Work Impact scales, and a questionnaire on sociodemographic and job features. Variable associations were analysed using the Mann-Whitney, Kruskal-Wallis, Chi-square tests and multiple linear regression. RESULTS: The mean score of satisfaction was 3.29 (SD=0.64) and the mean score for work impact was 1.77 (SD=0.62). Of all respondents, 61.8% reported a moderate level of satisfaction. Job satisfaction was positively associated with increasing age, lower schooling, being a non-governmental organization employee, developing non-patient-related activities, being involved in an innovative project. The highest levels of work impact were observed among civil servants, young people and females. CONCLUSIONS: Most features associated to the lowest levels of job satisfaction were associated to the highest levels of work impact. Despite the moderate level of satisfaction among providers, there is an evident need for policy changes, mainly those related to increasing availability of supplies and human resources and building restoration.