HLA class II and class I polymorphism in Venezuelan patients with myasthenia gravis

Oligotyping performed among ethnically mixed Venezuelan patients with myasthenia gravis (MG) and controls has revealed positive associations of HLA class I A*31, B*08, B*39, B*40, C*15, C*17, and class II DRB1*09 and negative associations of DQB1*06 and DQA1*02 with the disease. Sequential removal of human leukocyte antigen B (HLA-B) alleles when relative predispositional effects (RPEs) were looked for demonstrated that B*08 is the allele group with the largest contribution in the overall MG patients followed by B*39 and B*40. Several specificities (A*31, B*08, C*17, DRB1*03, DQA1*05, and DQB1*02) indicated increased frequencies among patients with thymic hyperplasia versus patients without hyperplasia or controls. Tests to identify alleles with the strongest association to MG in our patients detected DRB1*13 and B*38 as possible predisposing secondarily associated alleles in patients with hyperplasia. The associations observed disappear after Bonferoni correction of probability values and have been described in patients of Caucasian and/or Oriental ethnic background. Thus, our results reflect the heterogeneity of our population and of the patients tested and suggest a limited influence of several HLA genes in this heterogeneous disease or that these might be only markers of nearby non-HLA genes responsible for the susceptibility or resistance effect.     

Mapping of maurotoxin binding sites on hKv1.2, hKv1.3, and hIKCa1 channels

Maurotoxin (MTX) is a potent blocker of human voltage-activated Kv1.2 and intermediate-conductance calcium-activated potassium channels, hIKCa1. Because its blocking affinity on both channels is similar, although the pore region of these channels show only few conserved amino acids, we aimed to characterize the binding sites of MTX in these channels. Investigating the pH(o) dependence of MTX block on current through hKv1.2 channels, we concluded that the block is less pH(o) - sensitive than for hIKCa1 channels. Using mutant cycle analysis and computer docking, we tried to identify the amino acids through which MTX binds to hKv1.2 and hIKCa1 channels. We report that MTX interacts with hKv1.2 mainly through six strong interactions. Lys(23) from MTX protrudes into the channel pore interacting with the GYGD motif, whereas Tyr(32) and Lys(7) interact with Val(381), Asp(363), and Glu(355), stabilizing the toxin onto the channel pore. Because only Val(381), Asp(363), and the GYGD motif are conserved in hIKCa1 channels, and the replacement of His(399) from hKv1.3 channels with a threonine makes this channel MTX-sensitive, we concluded that MTX binds to all three channels through the same amino acids. Glu(355), although important, is not essential in MTX recognition. A negatively charged amino acid in this position could better stabilize the toxin-channel interaction and could explain the pH(o) sensitivity of MTX block on current through hIKCa1 versus hKv1.2 channels.     

Demineralising osteopathies: new aspects of diagnostic imaging

The wide use of multimodal radiologic analysis of bone tissue has led to a new concept of the term osteopenia towards grouping the various osteopathies as demineralizing osteopathies. With bone densitometry measurements both high precision and accuracy can be achieved, whereas conventional radiographs provide insights into the architecture of the bone to better advantage. By using both modalities discrepancies of the radiological reports with the final diagnosis may be avoided. Despite ongoing success in techniques of semi-automated data analysis and reporting the radiological and the clinical assessment of bone diseases are still an indispensable part of establishing the diagnosis.     

Alpha(1)-adrenoceptor-mediated depolarization and beta-mediated hyperpolarization in cultured rat dorsal root ganglion neurones

The effect of excitotoxic injury on the production of monocyte chemoattractant protein-1 (MCP-1) was examined in rat cortico-striatal slice cultures. Treatment with 50 microM N-methyl-D-aspartate (NMDA) for 4 h, which caused severe damage in neurons, induced the production of MCP-1 in astrocytes. Production levels were markedly elevated immediately after the treatment, peaked at 4-8 h, and had decreased to nearly the basal level by 72 h. Since the treatment promoted the release of MCP-1 in the slice cultures, but not in the enriched astrocyte cultures, it is unlikely that NMDA directly acted on the astrocytes. These results suggest that information on neuronal injury induced by NMDA is transmitted to astrocytes to induce the production of MCP-1. Organotypic slice cultures are useful for investigating the inflammatory responses of astrocytes in the process of neuronal injury.     

Nitrosation, nitration, and autoxidation of the selective estrogen receptor modulator raloxifene by nitric oxide, peroxynitrite, and reactive nitrogen/oxygen species

The regulation of estrogenic and antiestrogenic effects by selective estrogen receptor modulators (SERMs) provides the basis for use in long-term therapy in cancer chemoprevention and postmenopausal osteoporosis. However, the evidence for carcinogenic properties within this class requires study of potential pathways of toxicity. There is strong evidence for the elevation of cellular levels of NO in tissue treated with SERMs, including the benzothiophene derivative, raloxifene, in part via up-regulation of nitric oxide synthases. Therefore, the reactions of 17beta-estradiol (E(2)), raloxifene, and an isomer with NO, peroxynitrite, and reactive nitrogen/oxygen species (RNOS) generated from NO(2)(-)/H(2)O(2) systems were examined. Peroxynitrite from bolus injection or slow release from higher concentrations of 3-morpholinosydnonimine (SIN-1) reacted with the benzothiophenes and E(2) to give aromatic ring nitration, whereas peroxynitrite, produced from the slow decomposition of lower concentrations of SIN-1, was relatively unreactive toward E(2) and yielded oxidation and nitrosation products with raloxifene and its isomer. The oxidation and nitrosation products formed were characterized as a dimer and quinone oxime derivative. Interestingly, the reaction of the benzothiophenes with NO in aerobic solution efficiently generated the same oxidation products. Stable quinone oximes are not unprecedented but have not been previously reported as products of RNOS-mediated metabolism. The reaction of glutathione (GSH) with the quinone oxime gave both GSH adducts from Michael addition and reduction to the corresponding o-aminophenol. The ready autoxidation of raloxifene, observed in the presence of NO, is the first such observation on the reactivity of SERMs and is potentially a general phenomenon of significance to SERM chemical toxicology.     

Obese Patients Have Inadequate Protein Intake Related to Protein Intolerance Up to 1 Year Following Roux-en-Y Gastric Bypass

Background: Inadequate protein intake is a concern following Roux-en-Y gastric bypass (RYGBP). The small gastric pouch and bypass restrict energy intake and may lead to insufficient protein intake and absorption, and excess loss of lean tissue. Methods:We evaluated protein intake in 93 (77 F,16 M) morbidly obese individuals (BMI = 52.0±12.9 [SD]) who underwent RYGBP at our medical center. Participants completed 24-hr food recalls and received nutritional counseling at 3, 6, and 12 months following surgery. Results: Daily energy intake (kcal/day) increased from 849±329 (SD) at 3 months to 1,101±400 at 12 months (P=.009). Protein intake also increased (g/day) from 45.6±14.2 at 3 months to 58.5±17.1 at 12 months (P=.04), and as a percentage of goal protein intake from 55.1%±23.0 at 3 months to 73.5%±38.0 at 12 months (P=.02). Although energy and protein intake increased significantly over the 12-month period, protein intake at 12 months remained significantly lower (P=.01) than the daily recommended guidelines (1.5 g/kg IBW) for a low-energy restrictive diet. Energy intake did not differ in those who reported food intolerances at 3 months (P=.77) or 6 months (P=.65), but was lower in them at 12 months (trend, P=.06). Also at 12 months, protein intake (P=.02) and percentage of protein intake goal (P=.04) were significantly lower in those with protein intolerance. Conclusions: These results suggest that postoperative patients consume insufficient amounts of protein, possibly mediated by protein intolerance. Protein supplementation following RYGBP deserves further consideration.     

Retroperitoneal Castleman's disease

We present 2 cases of retroperitoneal localisation of Castleman's disease--hyalino-vascular histologic type. A 65 years old woman and a 67 years old man were admitted with the diagnosis of retroperitoneal tumour. The clinical findings were not specific. Surgical removal of the tumour is the treatment of choice. Focal recurrences didn't occur.     

Alcohol and hemorrhagic stroke in Santiago, Chile. A case-control study

BACKGROUND AND PURPOSE: Hemorrhagic stroke (HS) is a major cause of disability and death worldwide. There is a dearth of information on HS from geographically defined populations in Latin America. In this study we assessed the importance of alcohol consumption as a risk factor for HS in Chile. METHODS: Case-control study in Santiago, Chile, of 140 consecutive patients with CT-confirmed HS, matched by sex and age with 140 hospital controls. Alcohol consumption was measured in grams (ethanol) per week, using a questionnaire administered to the patients or caregivers or both. We defined four categories of alcohol consumption: nondrinkers (0.0 g/week), light (0.1-115 g/week), moderate (116-402.5 g/week) and heavy drinkers (>402.5 g/week). Other variables measured included diabetes mellitus (DM), cigarette smoking, arterial hypertension, liver disease and chronic use of nonsteroidal anti-inflammatory drugs (NSAID). Statistical analysis was performed with STATA 6.0 software. RESULTS: A total of 280 subjects with a mean age of 65.5 years were studied over a 3-year period, 122 men (43.5%) and 158 women (56.5%). Alcohol intake was 394.1 g/week among cases and 174.5 g/week in controls (p=0.01). The following odds ratios (OR) with 95% confidence intervals (CI) were found: hypertension 4.89 (2.86-10.3) and chronic use of NSAID 3.44 (2.15-12.9). Using conditional logistic regression analysis high alcohol intake was found to have a statistically significant OR of 4.47 (CI 1.14-17.2). CONCLUSIONS: In Chile, a high alcohol intake (>402.5 g/week) increased more than 4 times the risk of HS and remained a significant risk factor for HS after controlling for hypertension, cigarette smoking, liver disease, blood cholesterol levels, and chronic use of NSAID. The risk was higher in younger patients (<65 years of age).