A randomized,double-blind,placebo-controlled trial of dexamethasone in severe respiratory syncytial virus (RSV) infection: effects on RSV quantity and clinical outcome

Forty-one previously healthy children <2 years of age who required mechanical ventilation for respiratory syncytial virus (RSV) infection were randomized to receive dexamethasone (0.5 mg/kg; n=22) or saline placebo (n=19) intravenously every 12 h for 4 days. RSV quantity was measured by quantitative plaque assay in fresh tracheal and nasal aspirates obtained at intervals of 24+/-3 h on days 0, 1, 2, 5, and 7 following entry. Analysis by linear mixed-effects modeling demonstrated a significantly greater decline in mean tracheal RSV quantity in the placebo group than in the dexamethasone group from day 0 to day 1 (0.82 vs. 0.21 log pfu/mL; P=.01) and from day 0 to day 2 (1.45 vs. 0.53 log pfu/mL; P=.03). No differences were found between groups in nasal RSV quantity, white blood cell counts in tracheal or nasal aspirates, serum neutralizing antibody titers during convalescence, or duration of mechanical ventilation, intensive care unit stay, or hospital stay.     

Mechanisms of disease: genetic insights into the etiology of type 2 diabetes and obesity

Until recently, progress in identification of the genetic variants influencing predisposition to common forms of diabetes and obesity has been slow, a sharp contrast to the large number of genes implicated in rare monogenic forms of both conditions. Recent advances have transformed the situation, however, enabling researchers to undertake well-powered scans able to detect association signals across the entire genome. For type 2 diabetes, the six high-density genome-wide association studies so far performed have extended the number of loci harboring common variants implicated in diabetes susceptibility into double figures. One of these loci, mapping to the fat mass and obesity associated gene (FTO), influences diabetes risk through a primary effect on fat mass, making this the first common variant known to influence weight and individual risk of obesity. These findings offer two main avenues for clinical translation. First, the identification of new pathways involved in disease predisposition-for example, those influencing zinc transport and pancreatic islet regeneration in the case of type 2 diabetes-offers opportunities for development of novel therapeutic and preventative approaches. Second, with continuing efforts to identify additional genetic variants, it may become possible to use patterns of predisposition to tailor individual management of these conditions.     

Nuclear medicine dynamic investigations of diffuse chronic liver diseases and portal hypertension

Radio-isotopic techniques may be useful in diagnosis and staging of chronic diffuse liver diseases. Liver angioscintigraphy (LAS) and per-rectal portal scintigraphy (PRPS) are at well discriminating portal hypertension (PHT), very early cirrhosis hemodynamic failure and compensatory arterialisation of liver perfusion. Supplied information is related to PHT, liver morphology and mesenchimal activity in liver, spleen and bone marrow. Correlation of LAS and PRPS may diagnose installing of PHT earlier than any actual morphologic imagistic method. Our experience (after more than 300 PRPS and 500 LAS) suggests that PHT and portal-cave shunts (PCS) may be classified in five functional stages. These five patterns (types) are characteristic for portal dynamics, supporting disease staging and follow-up of evolution to cirrhosis. All five dynamics may be assessed by PRPS and LAS. Scintigraphic techniques also explore portal thromboses, perfusion differences between the lobes of cirrhotic liver, betablockers effect in PHT, earliest stages of PHT, malignant tumours occurring on cirrhosis, the different characteristics of alcoholic liver comparing to viral etiology.     

Low circulating IGF-I levels in hyperthyroidism are associated with decreased GH response to GH-releasing hormone

OBJECTIVE Several abnormalities In the GH response to pharmacological stimuli have been described in hyperthyroidism. Both normal and high serum IGF-I levels have been reported, as well as a decrease in IGF-I bioactivity. We have evaluated the GH response to GH-releasing hormone (GHRH) in hyperthyroid patients and the effects of hyperthyroidism on serum IGF-I levels. The possible relations between nutritional status, thyroid hormones and IGF-I levels were also investigated. We also studied the influence of long-term β-adrenoceptor blockade on the GH response to GHRH In these patients. DESIGN In 18 hyperthyroid patients and In 12 control subjects, GHRH (100μg) was administered as an i.v. bolus injection. Eight hyperthyroid patients and 8 control subjects received 50 μg GHRH i.v. Seven hyperthyroid patients were reevaluated after β-adrenoceptor blockade. IGF-I and albumin levels were measured Initially in all hyperthyroid patients and control subjects. Body composition was determined in 11 hyperthyroid patients and in a group of 33 matched normal controls. PATIENTS Hyperthyroid patients were compared to control subjects. MEASUREMENTS GH, TSH and free 14 were measured by Immunofluorometric assay. IGF-I, total T3 and total T4 were measured by radioimmunoassay. Body composition was determined using a dual-energy X-ray absorptfometer. RESULTS The GH response to 100 μg GHRH in hyper thyroid patients was blunted compared to control subjects. The mean peak GH levels and the area under the curve were significantly lower in hyperthyroid patients compared to control subjects (11 ± 1 vs 27 ± 5 μg/l and 820 ± 113 vs 1879 ± 355 μg/l 120 min, respectively; P <0.01). IGF-I levels were significantly reduced in hyperthyroid patients compared to controls (131 ± 10 vs 201 ± 16 μg/l, respectively; P <0.01). Ideal body weight, serum albumin levels and the lean body mass were also reduced In hyperthyroid patients. After β-adrenoceptor blockade there were no changes in the blunted GH response to GHRH in hyperthyroid patients. CONCLUSION Our data suggest that the blunted GH response to GHRH In hyperthyroidism is apparently not related to circulating IGF-I levels. It is possible that nutritional factors could play a role in the reduced circulating IGF-I levels found In these patients.     

Glucagon induces the plasma membrane insertion of functional aquaporin-8 water channels in isolated rat hepatocytes

Although glucagon is known to stimulate the cyclic adenosine monophosphate (cAMP)-mediated hepatocyte bile secretion, the precise mechanisms accounting for this choleretic effect are unknown. We recently reported that hepatocytes express the water channel aquaporin-8 (AQP8), which is located primarily in intracellular vesicles, and its relocalization to plasma membranes can be induced with dibutyryl cAMP. In this study, we tested the hypothesis that glucagon induces the trafficking of AQP8 to the hepatocyte plasma membrane and thus increases membrane water permeability. Immunoblotting analysis in subcellular fractions from isolated rat hepatocytes indicated that glucagon caused a significant, dose-dependent increase in the amount of AQP8 in plasma membranes (e.g., 102% with 1 micromol/L glucagon) and a simultaneous decrease in intracellular membranes (e.g., 38% with 1 micromol/L glucagon). Confocal immunofluorescence microscopy in cultured hepatocytes confirmed the glucagon-induced redistribution of AQP8 from intracellular vesicles to plasma membrane. Polarized hepatocyte couplets showed that this redistribution was specifically to the canalicular domain. Glucagon also significantly increased hepatocyte membrane water permeability by about 70%, which was inhibited by the water channel blocker dimethyl sulfoxide (DMSO). The inhibitors of protein kinase A, H-89, and PKI, as well as the microtubule blocker colchicine, prevented the glucagon effect on both AQP8 redistribution to hepatocyte surface and cell membrane water permeability. In conclusion, our data suggest that glucagon induces the protein kinase A and microtubule-dependent translocation of AQP8 water channels to the hepatocyte canalicular plasma membrane, which in turn leads to an increase in membrane water permeability. These findings provide evidence supporting the molecular mechanisms of glucagon-induced hepatocyte bile secretion.     

Treatment with statins in general medicine: dosage and effectiveness. Results of the observational study STATIMED

Using a retrospective study in general medicine, we observed the rates of achieving targets for LDL-cholesterol as recommended by the French Agency for the Safety of Health care Products (AFSSAPS) in 2000, according to the types of statin prescribed and the dosages used. Out of 64 961 individuals treated with a statin between 31 July 2001 and 1 August 2002, we identified 22 065 patients treated with monotherapy, having had an LDL-cholesterol level performed at least 6 weeks after starting treatment or after changing statin or dosage, and no longer than 6 months before the start of our study in the other cases. In primary prevention, 81.9% of patients attained their objectives. The success rates became less impressive with increasing levels of cardiovascular risk: 95.6%, 86.9%, 72.0% and 56.3% for 0, 1, 2 and 3 or more risk factors respectively (p < 0.0001). For secondary prevention, the targets were only met for 62.8% of patients. In total, only 77.8% of the entire sample met their targets. For each type of statin, higher doses were used for patients with higher cardiovascular risk, but the percentage of patients reaching their LDL-cholesterol targets diminished. In conclusion, under the current conditions of managing lipid risk, the LDL-cholesterol targets are not sufficiently met. Extrapolating from the data obtained in this study, about 300 000 patients in France require better management than recommended in the 2000 AFSSAPS guidelines.     

Relationship of SARS-CoV-2–specific CD4 response to COVID-19 severity and impact of HIV-1 and tuberculosis coinfection

T cells are involved in control of coronavirus disease 2019 (COVID-19), but limited knowledge is available on the relationship between antigen-specific T cell response and disease severity. Here, we used flow cytometry to assess the magnitude, function, and phenotype of SARS coronavirus 2–specific (SARS-CoV-2–specific) CD4⁺ T cells in 95 hospitalized COVID-19 patients, 38 of them being HIV-1 and/or tuberculosis (TB) coinfected, and 38 non–COVID-19 patients. We showed that SARS-CoV-2–specific CD4⁺ T cell attributes, rather than magnitude, were associated with disease severity, with severe disease being characterized by poor polyfunctional potential, reduced proliferation capacity, and enhanced HLA-DR expression. Moreover, HIV-1 and TB coinfection skewed the SARS-CoV-2 T cell response. HIV-1–mediated CD4⁺ T cell depletion associated with suboptimal T cell and humoral immune responses to SARS-CoV-2, and a decrease in the polyfunctional capacity of SARS-CoV-2–specific CD4⁺ T cells was observed in COVID-19 patients with active TB. Our results also revealed that COVID-19 patients displayed reduced frequency of Mycobacterium tuberculosis–specific CD4⁺ T cells, with possible implications for TB disease progression. These results corroborate the important role of SARS-CoV-2–specific T cells in COVID-19 pathogenesis and support the concept of altered T cell functions in patients with severe disease.