In Silico-Based High-Throughput Screen for Discovery of Novel Combinations for Tuberculosis Treatment

There are currently 18 drug classes for the treatment of tuberculosis, including those in the development pipeline. An in silico simulation enabled combing the innumerably large search space to derive multidrug combinations. Through the use of ordinary differential equations (ODE), we constructed an in silico kinetic platform in which the major metabolic pathways in Mycobacterium tuberculosis and the mechanisms of the antituberculosis drugs were integrated into a virtual proteome. The optimized model was used to evaluate 816 triplets from the set of 18 drugs. The experimentally derived cumulative fractional inhibitory concentration (∑FIC) value was within twofold of the model prediction. Bacterial enumeration revealed that a significant number of combinations that were synergistic for growth inhibition were also synergistic for bactericidal effect. The in silico-based screen provided new starting points for testing in a mouse model of tuberculosis, in which two novel triplets and five novel quartets were significantly superior to the reference drug triplet of isoniazid, rifampin, and ethambutol (HRE) or the quartet of HRE plus pyrazinamide (HREZ).     

Diffusion tensor imaging observation in Pott's spine with or without neurological deficit

Background:Diffusion tensor imaging (DTI) is based upon the phenomenon of water diffusion known as “Brownian motion.” DTI can detect changes in compressed spinal cord earlier than magnetic resonance imaging and is more sensitive to subtle pathological changes of the spinal cord. DTI observation in compressed and noncompressed spinal cord in tuberculosis (TB) spine is not described. This study presents observations in Pott''s spine patients with or without neural deficit.Results:The mean canal encroachment in group A was 39.60% and group B 44.4% (insignificant). Group A mean FA values above SOL, at the lesion and below SOL were 0.608 ± 0.09, 0.554 ± 0.14, and 0.501 ± 0.16 respectively. For group B mean FA values above SOL, at the lesion and below SOL were 0.628 ± 0.09, 0.614 ± 0.12 and 0.487 ± 0.15 respectively. There was a significant difference in mean FA above the SOL as compared to the mean FA at and below SOL. P value above versus below the SOL was statistically significant for both groups (0.04), but P value for at versus below the SOL (0.01) was statistically significant only in group B. On tractography, disruption of fiber tract at SOL was found in 14/15 (93.3%) cases of group A and 14/15 cases (93.3%) of group B (6/6 grade 4, 3/3 grade 3 and 5/6 grade 2 paraplegic cases).Conclusion:The FA and MD above the lesion were same as reported for healthy volunteer hence can be taken as control. FA increases, and MD decreases at SOL in severe grade of paraplegia because of epidural collection while in milder grade, both decrease. In group A (without neurological deficit), mean FA and MD in patients with and without canal encroachment was similar. On tractography, both groups A and B (with or without neurological deficit) showed disruption of fiber tract at SOL and thickness of distally traced spinal cord was appreciably less than the upper cord. FA and MD could not differentiate between various grades of paraplegia. Although the number of patients in each group are small.     

GLP-1 Agonists and Blood Pressure: A Review of the Evidence

Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease. The presence of concomitant hypertension in diabetics is a major driver of excess cardiovascular risk. Glucagon-like peptide-1 receptor agonists (GLP-1a) act on numerous pathways that intersect glycemic, weight, and blood pressure (BP) control. BP-lowering effects have been observed in mouse models of hypertension with a variety of GLP-1a. Acute administration of GLP-1a in humans has been shown to no effects and sometimes increased BP in humans. Chronic administration of GLP-1a, however, reduces clinic systolic BP (≈2 mmHg) at least when evaluated as a secondary end point in glycemia-lowering studies while simultaneously increasing heart rate. BP lowering has not been consistently observed in two recent double-blind controlled clinical trials evaluating ambulatory BP as the primary end point. While a number of mechanisms including vascular, myocardial, renal, and central nervous system pathways have been suggested in animal studies, these mechanistic pathways have not been sufficiently detailed in humans and it is unclear if the same pathways are operational. Further studies need to be conducted to unravel the full spectrum of effects of this drug class. An understanding of their effects on BP may help provide an explanation for the ability of GLP-1a to influence cardiovascular (CV) events in ongoing event-driven CV trials.     

In silico study on indole derivatives as anti HIV-1 agents: a combined docking,molecular dynamics and 3D-QSAR study

The HIV-1 envelope glycoprotein gp120 plays a vital role in the entry of virus into the host cells and is a potential antiviral drug target. Recently, indole derivatives have been reported to inhibit HIV-1 through binding to gp120, and this prevents gp120 and CD4 interaction to inhibit the infectivity of HIV-1. In this work, molecular docking, molecular dynamics (MD) and three-dimensional quantitative structure–activity relationship studies were carried out. Molecular docking studies of the most active and the least active compounds were performed to identify important residues in the binding pocket. We refined the docked poses by MD simulations which resulted in conformational changes. After equilibration, the structure of the ligand and receptor complex was stable. Therefore, we just took the last snapshot as the representative binding pose for this study. This pose for the most active inhibitor was used as a template for receptor-based alignment which was subsequently used for comparative molecular field analysis. Resultant 3D contour maps suggested smaller substituents are desirable at the 7-position of indole ring to avoid steric interactions with Ser375, Phe382 and Tyr384 residues in the active site. These results can be exploited to develop potential leads and for structure-based drug design of novel HIV-1 inhibitors.     

CONGENITAL PARVOVIRUS INFECTION

Congenital parvovirus infection was diagnosed in two liveborn premature infants born at 24 and 35 weeks of gestational age. The illnesses were associated with placentomegaly, petechial rash, edema, hepatomegaly, anemia and thrombocytopenia, respiratory insufficiency, and death at 5 and 6 days of age. The syndromes exhibited by these cases shared common but nonspecific features with other life-threatening congenital infections. Serological studies in one case supported the diagnosis of parvoviral infection. Postmortem examination of both revealed nuclear inclusions in erythroid precursor cells characteristic of parvovirus infection. Use of the polymerase chain reaction confirmed the presence of parvovirus DNA in one of the cases. Intrauterine parvovirus B19 infection is most commonly associated with hydrops fetalis, "transient" hydrops, or a favorable outcome in infants found to be viremic after birth. These and previously reported examples of congenital B19 disease exemplify an exceptional form of human parvovirus infection.     

Blood flow in pulmonary veins: I. Studies in dog and man

The pattern of blood flow in the large extra parenchymal pulmonary veins is pulsatile in both dog and man. This pulsatility is dominated by the changes in left atrial pressure taking place throughout the cardiac cycle. No pulsatile component of low in the large pulmonary veins could be attributed to forward transmission of a flow pulse conducted from the lung capillaries. The findings suggest that there must be a region of considerable compliance in the pulmonary venous system which can absorb pulsations from the lung capillaries and eliminate their transmission to the left atrium.     

Skeletal muscle metabolism in patients with congestive heart failure: relation to clinical severity and blood flow

We and others have previously demonstrated excessive phosphocreatine (PCr) depletion and acidosis in skeletal muscle during exercise in patients with congestive heart failure (CHF). In the present study, we performed serial measurements of PCr and pH during gradually incremental flexor digitorum superficialis exercise in 22 patients with CHF and 11 age-matched controls to determine: (1) whether abnormalities were present at the same relative workloads (a comparison that would at least partially compensate for differences in muscle mass), (2) the temporable course of the metabolic changes, (3) the relationship of the metabolic findings to clinical variables, and (4) the relationship of the metabolic abnormalities to forearm blood flow. The patients with CHF had significantly lower [PCr] and pH at all submaximal levels of exercise, and these abnormalities were apparent from the onset of low-level exercise. There was considerable heterogeneity among the patients with CHF with respect to the metabolic findings, with 14 of 22 exhibiting either PCr or pH values more than 2 SDs below normal. Patients whose capacity was more limited during the protocol had lower [PCr], and especially pH, at low loads than did other patients with CHF or the control subjects. The more symptomatic patients and those with more limited bicycle exercise tolerance also had lower pH values. In contrast, there were no significant differences in forearm blood flow between the patients and controls and no relationship between forearm blood and either clinical variables or the metabolic findings. These results indicate that skeletal muscle metabolic abnormalities are present in many patients with CHF and that they are not primarily due to either muscle atrophy or impaired blood flow. These changes may explain in part the marked heterogeneity of symptom status and exercise capacity of patients with similar degrees of cardiac dysfunction.