Antioxidant treatment of hindlimb-unloaded mouse counteracts fiber type transition but not atrophy of disused muscles

Oxidative stress was proposed as a trigger of muscle impairment in various muscle diseases. The hindlimb-unloaded (HU) rodent is a model of disuse inducing atrophy and slow-to-fast transition of postural muscles. Here, mice unloaded for 14 days were chronically treated with the selective antioxidant trolox. After HU, atrophy was more pronounced in the slow-twitch soleus muscle (Sol) than in the fast-twitch gastrocnemius and tibialis anterior muscles, and was absent in extensor digitorum longus muscle. In accord with the phenotype transition, HU Sol showed a reduced expression of myosin heavy chain type 2A (MHC-2A) and increase in MHC-2X and MHC-2B isoforms. In parallel, HU Sol displayed an increased sarcolemma chloride conductance related to an increased expression of ClC-1 channels, changes in excitability parameters, a positive shift of the mechanical threshold, and a decrease of the resting cytosolic calcium concentration. Moreover, the level of lipoperoxidation increased proportionally to the degree of atrophy of each muscle type. As expected, trolox treatment fully prevented oxidative stress in HU mice. Atrophy was not prevented but the drug significantly attenuated Sol phenotypic transition and excitability changes. Trolox treatment had no effect on control mice. These results suggest possible benefits of antioxidants in protecting muscle against disuse.     

Influence of age and sex on five human plasma lysosomal enzymes assayed by automated procedures

Automated fluorimetric procedures for the assay of five lysosomal glycohydrolases—β-N-acetylglucosaminidase; β-galactosidase; β-glucuronidase; α-mannosidase; α-fucosidase—in human plasma were set up. A Carlo Erba autoanalyser CLA 1500, provided with a sampler refrigerating unit and connected with a recording Turner Mod 111 fluorimeter was employed. The automated procedures, under the established optimal conditions, proved to be highly accurate and reproducible.Using the automated assay procedures the effect of sex and age on the plasma levels of the same enzymes was studied. 1273 randomly selected healthy subjects were studied. No sex differences were observed for all the enzymes studied with the exception of β-glucuronidase which displayed higher values (about 30%) in males from 25 to 60 years. The developmental profiles of all enzymes in females and males were similar and characterised by: (a) absolute maximum level in the umbilical cord blood; (b) absolute minimum level at 10–14 years; (c) decrease to a second minimum occurring around 35 years (not displayed by β-galactosidase and by β-glucuronidase in males); (e) slow further increase up to the elderly level which was then maintained till the oldest age examined, 74 years.     

Alagille syndrome: prenatal sonographic findings

We report a case of Alagille syndrome in which sonographic examination revealed the presence of angulation of the fetal spine due to vertebral fusion as well as tetralogy of Fallot. Histologic examination after pregnancy termination revealed the presence of agenesis of the gallbladder with a paucity of intrahepatic bile ducts, leading to the diagnosis of Alagille syndrome. In the presence of cardiac and axial skeletal anomalies, attention should be paid to the fetal gallbladder, whose absence would signal a diagnosis of Alagille syndrome.     

Bariatric Surgery to Reduce Mortality in US Adults. A Public Health Perspective from the Analysis of the American National Health and Nutrition Examination Survey Linked to the US Mortality Register

Background

Type II obesity represents a major pandemic and public health threat in high-income countries. Type II obesity increases the risk of all-cause and specific-cause mortality, and it is widely acknowledged that bariatric surgery represents the only effective therapeutic option in these patients. The aim of the present study was to estimate US population attributable risk for all-cause and cause-specific mortality in type II obese subjects undergoing weight loss as resulting from bariatric surgery alone and supplemented with behavioral intervention.

Methods

The American National Health and Nutrition Examination Survey linked to the US death registry updated to 2011 was used to estimate type II obesity prevalence and all-cause and specific cause of death for type II obese adults undergoing weight loss. Multivariate adjusted proportional hazard Cox models were used to estimate mortality risks. Statistical analyses were performed on the most updated version of the database (June 2017).

Results

A monotone positive trend for type II obesity was observed during the period 1999–2014 (p < 0.001). According to trend analysis, the rate of type II obesity in US adults is expected to rise up to 8.5%. Two- to sevenfold increased risk of all-cause and specific-cause mortality was observed for type II obese participants when compared to type I obese and overweight participants. Population attributable risk for all-cause and specific-cause mortality for type II obese subjects undergoing weight loss was ranging between 6 and 34%.

Conclusions

Bariatric surgery supplemented with behavioral intervention can result in a relevant reduction of mortality if extensively applied to the US population.

     

Soluble interleukin-2 receptor in hairy-cell leukemia: a reliable marker of disease

Summary The CD25 molecule, which corresponds to the p55 α chain of the interleukin-2 receptors, is strongly expressed by neoplastic cells in hairy-cell leukemia and is released in large amounts in the soluble form which is detectable in serum. In order to assess the reliability of the soluble interleukin-2 receptor as a disease marker in the management of patients with hairy-cell leukemia, we investigated serum levels in 35 untreated patients and in 2 patients with the hairy-cell leukemia variant. In 21 of 35 patients soluble receptor levels were also monitored during and after recombinant interferon-α therapy. Clinical and hematological parameters were also assessed. Soluble interleukin-2 receptor levels were extremely high at the time of diagnosis in patients with typical hairy-cell leukemia [32,722±27,001 vs. 331±145 units/ml in controls (mean±SD)], but not in patients with the leukemia variant. A progressive decrease in soluble interleukin-2 receptor levels paralleled the clinical response to treatment, although normal values were never detected, even in patients who achieved an apparent complete remission. After recombinant interferon-α discontinuation, disease recurrence was accompanied by a progressive increase to pre-treatment soluble receptor levels. Overall, a close correlation was found between soluble interleukin-2 receptor values and total tumor burden (r=0.84,P<0.001). On the basis of these data, soluble interleukin-2 receptor should be regarded as a key marker in the management of patients with hairy-cell leukemia.     

Inhibition of the antithrombotic effects of clopidogrel by proton pump inhibitors: Facts or fancies?

Clopidogrel plus aspirin is considered the antiplatelet treatment of choice in patients with acute coronary syndrome, whether or not they are undergoing a percutaneous coronary intervention (PCI). The same treatment is mandatory in all patients undergoing a PCI with stent implantation. Clopidogrel is a pro-drug that needs metabolic activation through a cytochrome P450-dependent pathway, with an extensive involvement of the CYP 2C19 isoenzyme. Proton pump inhibitors (PPIs) reduce the risk of gastrointestinal bleeding in patients receiving dual antiplatelet therapy. In the past two years some scientific evidences have suggested a possible negative interference of PPIs on antiplatelet effect of clopidogrel because of the competitive inhibition of the CYP 2C19 isoenzyme. Few studies testing platelet reactivity in patients receiving both clopidogrel and a PPI have demonstrated a reduced inhibitory effect of the association on platelet aggregation. Moreover, results from retrospective observational studies have shown a higher incidence of major cardiovascular events in patients receiving both clopidogrel and PPIs. These data have not been confirmed neither by the only prospective randomized study comparing clopidogrel plus omeprazole with clopidogrel alone, nor by the retrospective analysis of the TRITON TIMI 38 trial, where PPIs did not affect the clinical outcome of patients given clopidogrel or prasugrel. Nevertheless both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) have discouraged the concomitant use of clopidogrel and PPIs. Important questions concerning a true interference between the two classes of drugs still remain unanswered and need to be addressed by adequately powered studies.     

Preservation of Endothelium Nitric Oxide Release by Pulsatile Flow Cardiopulmonary Bypass When Compared With Continuous Flow

The aim of this work is to analyze endothelium nitric oxide (NO) release in patients undergoing continuous or pulsatile flow cardiopulmonary bypass (CPB). Nine patients operated under continuous flow CPB, and nine patients on pulsatile flow CPB were enrolled. Plasma samples were withdrawn for the chemiluminescence detection of nitrite and nitrate. Moreover the cellular component was withdrawn for the detection of nitric oxide synthase (NOS) activity in the erythrocytes, and an estimation of systemic inflammatory response was carried out. Significant reduction in the intraoperative concentration with respect to the preoperative was observed only under continuous flow CPB for both nitrite and NO_x (nitrite + nitrate) concentration (P = 0.010 and P = 0.016, respectively). Significant difference in intraoperative nitrite concentration was also observed between the groups (P = 0.012). Finally, erythrocytes showed a certain endothelial NOS activity, which did not differ between the groups, and no differences in the inflammatory response were pointed out. The significant reduction of NO₂^‐ concentration under continuous perfusion revealed the strong connection among perfusion modality, endothelial NO release, and plasmatic nitrite concentration. The similar erythrocyte eNOS activity between the groups revealed that the differences in blood NO metabolites are mainly ascribable to the endothelium release.     

Phylogeny of human T cell lymphotropic virus type 1 in Peru: a high degree of evolutionary relatedness with South African isolates

We investigated the prevalence and molecular epidemiology of human T cell lymphotropic virus type 1 in Peruvian HIV-1-positive subjects, and found a 10.1% prevalence in a consecutive series of 318 HIV-1-positive patients living in Lima. Phylogenetic analysis of the long terminal repeat of 10 patient isolates showed that all of them belonged to the HTLV-1aA (Transcontinental) subgroup. Although the majority of the Peruvian sequences included in the analysis formed a clade with other Latin American sequences, the isolates of three patients clustered significantly with South African strains. These data show a high prevalence of HTLV-1 infection in HIV-1-positive subjects living in Lima and confirm the presence in Latin America of HTLV-1 strains probably arising from South Africa.