Replicative fitness of historical and recent HIV-1 isolates suggests HIV-1 attenuation over time

BACKGROUND: Changes in virulence during an epidemic are common among pathogens, but still unexplored in the case of HIV-1. Here we used primary human cells to study the replicative fitness of primary HIV-1 isolates from untreated patients, comparing historical (1986-1989) and recent samples (2002-2003). METHODS: Head-to-head dual virus infection/competition assays were performed in both peripheral blood mononuclear cells and human dendritic cell/T-cell co-cultures with pairs of 12 carefully matched historical and recent HIV-1 isolates from untreated patients. Sensitivity to inhibition by lamivudine (3TC) and TAK-779 of historical and recent R5 HIV-1 isolates was measured in a subset of samples. RESULTS: Overall, the historical HIV-1 out-competed the recent HIV-1 isolates in 176 of 238 competitions and in 9 of 12 competitions carefully matched for CD4 cell count. The mean relative replicative fitness (W) of all historical HIV-1 strains was significantly greater than that of recent HIV-1 isolates (W(1986-1989) = 1.395 and W(2002-2003) = 0.545, P < 0.001 (t test)). The more fit viruses (mean W > 1) from 1986-1989 appeared less sensitive to TAK-779 and 3TC than did the less fit (mean W < 1) 2002-2003 viruses. CONCLUSIONS: These findings suggest that HIV-1 replicative fitness may have decreased in the human population since the start of the pandemic. This 'attenuation' could be the consequence of serial bottlenecks during transmission and result in adaptation of HIV-1 to the human host.     

New prospects in myocardial surgical revascularization

Myocardial revascularization with coronary bypass graft surgery or angioplasty is the conventional treatment for ischaemic heart disease. The progressive refinement of both techniques (eg, use of arterial grafts and drug eluting stents) has improved clinical outcomes but the elucidation of which of the two treatments is more effective would require well designed randomised studies. While the utility of off-pump as compared to on-pump coronary bypass graft surgery is still debated, the evidence for the exclusive use of arterial conduits for surgical revascularization is compelling. Patients with diffuse coronary artery disease that cannot be treated by conventional revascularization treatments remain a challenge for the control of angina and a variety of alternative treatments, including transmyocardial laser revascularization and cardiac denervation, have been applied. However, these treatments do not eliminate angina and the benefit obtained is transient. The angiogenic therapy using stem cells and modification of gene expression is a new treatment which potential, in spite of the promising animal studies and the initial clinical trials, is still unclear. The introduction of less invasive surgical techniques and robotics could play an important role for the delivery of these treatments in the future.     

SR31747A is a sigma receptor ligand exhibiting antitumoural activity both in vitro and in vivo

SR31747A is a recently described sigma receptor ligand that binds SR31747A-binding protein 1 (SR-BP) and emopamil-binding protein (EBP) (also called the sigma 1 receptor and the human sterol isomerase (HSI), respectively), and has immunoregulatory and antiproliferative activities. To further investigate its antitumour activity and focusing on cancers, which are sensitive to the molecule, we measured the proliferation of different human epithelial breast or prostate cancer cell lines following in vitro and in vivo SR31747A treatment. Firstly, in vitro, we found that nanomolar concentrations of SR31747A dramatically inhibited cell proliferation in both hormono-responsive and -unresponsive cancer cell lines. Secondly, tumour development was significantly decreased in mice treated with SR31747A. In an attempt to decipher the SR31747A mode of action, we found that the two binding sites may not fully account for this activity. Indeed, while competitive experiments indicated that EBP prevails in mediating SR31747A antiproliferative activity, an analysis of the expression of both receptors indicated that the cellular sensitivity to SR31747A is not correlated with either EBP or SR-BP expression. These data suggest that additional binding sites may exist. Preliminary binding studies demonstrated that SR31747A also binds to sigma 2, a protein that has not yet been cloned, but which is considered as a potential marker of the proliferative status of tumour cells. Altogether, our data demonstrate the antitumoural activity of SR31747A both in vitro and in vivo in two different cancer models, broaden the spectrum of its binding proteins and enhance the potential for further therapeutic development of the molecule.     

Renal function in pediatric patients with β-thalassemia major

In patients with β-thalassemia major, the most important cause of mortality and morbidity is organ failure due to deposits of iron.. In this study, the nature of the kidney injury and possible pathogenetic factors were investigated. Seventy children with β-thalassemia major and 14 age and sex-matched healthy children were involved in the study. Blood and timed urine samples were obtained for hematological and biochemical tests. The mean values of blood urea nitrogen (BUN), serum creatinine, creatinine clearance, serum sodium, urine osmolality, fractional excretion of sodium, potassium, and uric acid were not statistically different between the groups. Serum levels of potassium, phosphorus, and uric acid and the urine volume, high urinary protein to creatinine (U_P/Cr), urinary N-acetyl-β-d-glucosaminidase to creatinine (U_NAG/Cr), and urinary malondialdehyde to creatinine, (U_MDA/Cr) and the tubular phosphate reabsorption (TRP) values were statistically different between two groups (P<0.05). Increased serum levels of potassium, phosphorus, and uric acid in the patient group were attributed to the rapid erythrocyte turnover. The presence of high U_P/Cr, U_NAG/Cr and U_MDA/Cr ratios shows that in these patients with proximal renal tubular damage may be secondary to oxidative lipid peroxidation mediated by the iron overload. Received: 30 September 1999 / Revised: 19 May 2000 / Accepted: 22 May 2000     

Efficacy and safety of prostate vaporesection using a 120-W 2-μm continuous-wave Tm:YAG laser (RevoLix 2) in patients on continuous oral anticoagulant or antiplatelet therapy

The aim of our current study was to demonstrate the efficacy and safety of vaporesection using a 120-W Tm:YAG laser (Revolix Duo) in patients with BPH receiving systemic anticoagulation or antiplatelet therapy. Between April 2010 and November 2011, a total of 76 patients using oral antiplatelet or anticoagulant (OA) agents affected by LUTS for BPH were underwent thulium vaporesection of the prostate (ThuVARP) using a 120-W 2-μm CW Tm:YAG laser and evaluated at 3- and 6-month follow-up. Of these, in 41 patients (group A) was performed vaporesection while receiving OA therapy. In 35 patients (group B), OA agents were discontinued 10 days before surgery. There were no significant differences in average vaporesection times, catheterization time, or hospital stay. There was no significant change in serum sodium level before and immediately after vaporesection in either group. Significant improvements compared to baseline were observed at each postoperative assessment in both groups for Qmax, PVR, IPSS, and QoL. More specifically, the IPSS score improved from 21.7 at baseline to 5.2 at 6 months in group A and from 20.7 to 4.5 in group B. At 6 months, Qmax increased 226 and 190 % for the 2 groups, respectively. The PVR decreased from 119 at baseline to 11 mL at 6 months in group A and from 125 to 11 mL in group B. ThuVARP is a safe and efficient procedure for patients with BPH, refractory to pharmacotherapy, who require active antiplatelet or anticoagulant therapy.     

Adenosine Monophosphate-Activated Protein Kinase (AMPK) as a New Target for Antidiabetic Drugs: A Review on Metabolic,Pharmacological and Chemical Considerations

In view of the epidemic nature of type 2 diabetes and the substantial rate of failure of current oral antidiabetic drugs the quest for new therapeutics is intensive. The adenosine monophosphate-activated protein kinase (AMPK) is an important regulatory protein for cellular energy balance and is considered a master switch of glucose and lipid metabolism in various organs, especially in skeletal muscle and liver. In skeletal muscles, AMPK stimulates glucose transport and fatty acid oxidation. In the liver, it augments fatty acid oxidation and decreases glucose output, cholesterol and triglyceride synthesis. These metabolic effects induced by AMPK are associated with lowering blood glucose levels in hyperglycemic individuals. Two classes of oral antihyperglycemic drugs (biguanidines and thiazolidinediones) have been shown to exert some of their therapeutic effects by directly or indirectly activating AMPK. However, side effects and an acquired resistance to these drugs emphasize the need for the development of novel and efficacious AMPK activators. We have recently discovered a new class of hydrophobic D-xylose derivatives that activates AMPK in skeletal muscles in a non insulin-dependent manner. One of these derivatives (2,4;3,5-dibenzylidene-D-xylose-diethyl-dithioacetal) stimulates the rate of hexose transport in skeletal muscle cells by increasing the abundance of glucose transporter-4 (GLUT-4) in the plasma membrane through activation of AMPK. This compound reduces blood glucose levels in diabetic mice and therefore offers a novel strategy of therapeutic intervention strategy in type 2 diabetes. The present review describes various classes of chemically-related compounds that activate AMPK by direct or indirect interactions and discusses their potential for candidate antihyperglycemic drug development.     

The radial hyperaemic response: a new and objective assessment of ulnar collateral supply to the hand.

The assessment of adequate ulnar collateral supply to the hand is mandatory prior to the harvest of the radial artery as a conduit for coronary artery bypass grafting. However, there is currently no one test which is widely used in all centres. We report a new and objective method of assessing ulnar collateral supply to the hand prior to harvest of the radial artery. This technique involves assessing the presence of a hyperaemic flow response to occlusion of the radial artery using an intraoperative transit time flowmeter. We found this technique to be objective and reliable, and would advocate its use in patients with a positive Allen's test.