Type 1 diabetes-induced hyper-responsiveness to 5-hydroxytryptamine in rat pulmonary arteries via oxidative stress and induction of cyclooxygenase-2

Recent epidemiological data suggest that diabetes is a risk factor for pulmonary arterial hypertension. The aim of the present study was to analyze the link between type 1 diabetes and pulmonary arterial dysfunction in rats. Male Sprague-Dawley rats were randomly divided into a control group (saline) and a diabetic group (70 mg/kg streptozotocin). After 6 weeks, diabetic animals showed a down-regulation of the lung bone morphogenetic protein receptor type 2, up-regulation of 5-hydroxytryptamine (5-HT) 2A receptors and cyclooxygenase-2 (COX-2) proteins as measured by Western blot analysis, and increased contractile responses to 5-HT in isolated intrapulmonary arteries. The hyper-responsiveness to 5-HT was endothelium-independent and unaffected by inhibition of nitric-oxide synthase but prevented by indomethacin, the selective COX-2 inhibitor N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398), superoxide dismutase, and the NADPH oxidase inhibitor apocynin or chronic treatment with insulin. However, diabetic rats at 6 weeks did not develop elevated right ventricular pressure or pulmonary artery muscularization, whereas a longer exposure (4 months) to diabetes induced a modest, but significant, increase in right ventricular systolic pressure. In conclusion, type 1 diabetes mellitus in rats induces a number of changes in lung protein expression and pulmonary vascular reactivity characteristic of clinical and experimental pulmonary arterial hypertension but insufficient to elevate pulmonary pressure. Our results further strengthen the link between diabetes and pulmonary arterial hypertension.     

The limitations of gastro-jejunal (G-J) feeding tubes in children: a 9-year pediatric hospital database analysis

BACKGROUND: A gastro-jejunal (G-J) feeding tube is a safe and useful temporizing method of providing enteral access in children. Although G-J tubes are often used to obviate the need for a surgical jejunostomy, their long-term use is often associated with mechanical failure. AIM: To review the clinically effective durability of G-J feeding tubes in providing enteral access in children. METHODS: We performed a retrospective review of 102 patients at the Johns Hopkins Children's Center from 1994-2003 whose underlying diagnosis necessitated the need for postpyloric enteral access. RESULTS: Long-term follow-up was obtained in 85 (48 M; 37 F) patients with a median (range) age of 2.0 (0.1-18.0) yr. The most common indication for G-J tube placement was gastroesophageal reflux with aspiration in 51 patients and feeding intolerance and vomiting in 19 patients. The mean (range) number of tube replacements was 2.2 (1-14) over a median (range) duration of follow-up of 39 (2-474) days. The indication for G-J tube replacement included: tube displacement (58), a clogged tube (41), and a cracked tube or ruptured balloon (35). In 52 cases, the cause for G-J tube replacement was undetermined. CONCLUSIONS: G-J feeding tubes are associated with the frequent need for tube maintenance and replacement and may not be the most feasible clinical option in providing long-term (>1 month) enteral access in children intolerant to gastrostomy tube feeds. Future studies are needed to develop innovative percutaneous jejunostomy tube placement techniques that facilitate long-term enteral access.     

Acute Chagas' disease: immunohistochemical characteristics of T cell infiltrate and its relationship with T. cruzi parasitic antigens

OBJECTIVE: The present work analysed endomyocardial biopsies of patients with acute Chagas' disease in order to evaluate the frequency and intensity of T. cruzi antigens, CD4+ and CD8+ T cells to determine the characteristics of this recurrent disease in Venezuela. MATERIAL AND METHODS: Twelve endomyocardial biopsies of patients with Chagas' disease, 12 to 51 years old, (7M and 5F) were analysed. T. cruzi antigens and CD4+ (helper) and CD8+ (cytotoxic-suppressor) T cells were detected by the immunoperoxidase technique.The presence and intensity of lymphocytic myocarditis was evaluated according to the degree of myocardial fibre injury caused by inflammatory infiltrate. RESULTS: Myocarditis was present in 100% of the cases. The mean numbers of CD4+ T cell and CD8+ T cell were 11.00 (+/- 10.29); 14.69 (+/- 13.08) and the CD4/CD8 T cell ratio was 0.75. T. cruzi antigens were detected in 58%. There was a good correlation between the numbers of CD4 and CD8 T cells of each case and a lack of correlation with the amount of T. cruzi antigens. CONCLUSION: All patients with acute Chagas' disease show some degree of myocarditis that seems to be directly related to the presence of parasitic antigens. Both CD4 and CD8 T cells participate in this process.We are following these patients to see if patients with severe myocarditis and more parasite antigens in the acute phase will develop chronic heart failure.     

Effect of simvastatin in familial hypercholesterolemia on the affinity of electronegative low-density lipoprotein subfractions to the low-density lipoprotein receptor

The effect of simvastatin therapy on the biologic characteristics of the electronegative low-density lipoprotein (LDL) subfraction of patients with familial hypercholesterolemia (FH) was studied. Total LDL, isolated from FH plasma at 0, 3 and 6 months of simvastatin treatment, was subfractionated into electropositive LDL (LDL[+]) and electronegative LDL (LDL[-]) by anion exchange chromatography. LDL isolated from healthy normolipemic (NL) subjects was used as a control. The LDL(-) proportion was twofold higher in patients with FH than in NL subjects (17.6 +/- 1.6% vs 7.8 +/- 1.5%, respectively; p <0.05) and was progressively reduced by simvastatin therapy (15.7 +/- 1.6% at 3 months; 13.8 +/- 2.5% at 6 months; p <0.05). Both LDL subfractions from patients with FH had a higher relative cholesterol content and decreased apolipoprotein B and triglycerides than NL subfractions. Simvastatin progressively induced changes in lipid content of both LDL subfractions in patients with FH, and lipid composition was closer to these subfractions in NL subjects after 6 months of therapy. Binding displacement experiments in human fibroblasts demonstrated that LDL(-) from both groups of subjects had a lower affinity of binding to the LDL receptor that LDL(+). In addition, LDL(+) in patients with FH presented an intermediate binding affinity between LDL(-) and LDL(+) in NL subjects. Simvastatin-induced changes in LDL composition were accompanied by a progressive increase in affinity of LDL(+) and LDL(-) in patients with FH. After 6 months of therapy, LDL(+) in FH had an affinity similar to that of LDL(+) in NL subjects. The LDL(-)-induced release of chemokines interleukin-8 and monocyte chemotactic protein-1 from cultured endothelial cells was twofold higher compared with that of LDL(+). No difference in chemokine release between patients with FH and NL subjects or the effect of simvastatin were observed. We conclude that simvastatin therapy was able to modify LDL subfraction composition in subjects with FH and increase their affinity to the LDL receptor. This improvement could contribute to the observed reduction in LDL(-) proportion induced by simvastatin.     

Kir6.2 is required for adaptation to stress

Reaction to stress requires feedback adaptation of cellular functions to secure a response without distress, but the molecular order of this process is only partially understood. Here, we report a previously unrecognized regulatory element in the general adaptation syndrome. Kir6.2, the ion-conducting subunit of the metabolically responsive ATP-sensitive potassium (K(ATP)) channel, was mandatory for optimal adaptation capacity under stress. Genetic deletion of Kir6.2 disrupted K(ATP) channel-dependent adjustment of membrane excitability and calcium handling, compromising the enhancement of cardiac performance driven by sympathetic stimulation, a key mediator of the adaptation response. In the absence of Kir6.2, vigorous sympathetic challenge caused arrhythmia and sudden death, preventable by calcium-channel blockade. Thus, this vital function identifies a physiological role for K(ATP) channels in the heart.     

Predictive parameters for weaning from mechanical ventilation

The use of predictive parameters for weaning from mechanical ventilation is a rather polemic topic, and the results of studies on this topic are divergent. Regardless of the use of these predictive parameters, the spontaneous breathing trial (SBT) is recommended. The objective of the present study was to review the utility of predictive parameters for weaning in adults. To that end, we searched the Medline, LILACS, and PubMed databases in order to review articles published between 1991 and 2009, in English or in Portuguese, using the following search terms: weaning/desmame, extubation/extuba??o, and weaning indexes/indices de desmame. The use of clinical impression is an inexact means of predicting weaning outcomes. The most widely used weaning parameter is the RR/tidal volume (V T) ratio, although this parameter presents heterogeneous results in terms of accuracy. Other relevant parameters are MIP, airway occlusion pressure (P0.1), the P0.1/MIP ratio, RR, V T, minute volume, and the index based on compliance, RR, oxygenation, and MIP. An index created in Brazil, the integrative weaning index, has shown high accuracy. Although recommended, the SBT is inaccurate, approximately 15% of extubation failures going unidentified in SBTs. The main limitations of the weaning indexes are related to their use in specific populations, the cut-off points selected, and variations in the types of measurement. Since the SBT and the clinical impression are not 100% accurate, the weaning parameters can be useful, especially in situations in which the decision as to weaning is difficult.