Genetics of asthma: current research paving the way for development of personalized drugs

Asthma is a complex genetic disorder involving the interplay between various environmental and genetic factors. In this review, efforts have been made to provide information on the recent advances in these areas and to discuss the future perspective of research in the area of developing personalized drugs using pharmacogenomic approach. Atopic asthma is found to be strongly familial, however the mode of inheritance is controversial. A large number of studies have been carried out and a number of candidate genes have been identified. In addition, a number of chromosomal regions have been identified using genome-wide scans, which might contain important unknown genes. It has been shown in studies carried out in different populations that the genetic predisposition varies with ethnicity. In other words, genes that are associated with asthma in one population may not be associated with asthma in another population. In addition to the involvement of multiple genes, gene-gene interactions play a significant role in asthma. The importance of environmental factors in asthma is beyond doubt. However, it remains controversial whether a cleaner environment or increased pollution is a trigger for asthma. Despite the increasing prevalence of the disorder, only a limited number of therapeutic modalities are available for the treatment. A number of novel therapeutic targets have been identified and drugs are being developed for better efficacy with less side-effects. With the rapid progress in the identification of genes involved in various ethnic populations combined with the availability in future of well-targeted drugs, it will be possible to have appropriate medicine as per the genetic make-up of an individual

Role of vaginal progesterone in reducing the rate of preterm labour in women with a sonographic short cervix

Background: Preterm labour is responsible for not only neonatal morbidity and mortality but also has long term consequences .Till now there is no effective method of prevention. Progesterone has shown promising result. But ideal candidate, ideal route and when to start the treatment are still in dilemma. The present study was undertaken to know the role of progesterone on pregnant women with sonographically short cervix.Methods: This prospective case control study was started on 100 pregnant women with sonographic short cervix (≤2.5 cm) and between 19 – 29 weeks of gestation. 60 women, some with history of midtrimester abortion or preterm labour and some without this history were treated as cases and were given vaginal progesterone pessary 200 mg once daily till rupture of membrane or onset of labour or up to 36 weeks of gestation whichever is earlier. 40 women without any history of midtrimester abortion or preterm labour were treated as control and followed up.Results: Among the cases 18.3%, delivered preterm and 81.7% were term deliveries. Respective proportions among control were 40% and 60% respectively. 26 among the cases and all women of control group did not have history of preterm labour and mid trimester abortion. In the case group 26.9% and in the control group 40% had preterm deliveries. Though the proportion of labour was lower among the cases it is not statistically significant (p = 0.276). There is mean prolongation of gestational age by 8.4± 1.29 weeks in case group in present pregnancy compared the previous one in cases with history of preterm labour and midtrimester abortion which was statistically significant .When neonatal complication are compared there is no significant difference between the two groups.Conclusions: Vaginal progesterone started from midtrimester in pregnant ladies with short cervix with previous history of midtrimester abortion or preterm labour is effective in reducing the rate of preterm birth

Cerebrospinal fluid adenosine deaminase level as a diagnostic marker in adult tuberculous meningitis: a study conducted in a tertiary care hospital of Eastern India

Background: Tubercular meningitis is one of the highly prevalent form of meningitis in the world and is a significant cause of morbidity and mortality in developing countries like India. Lack of early and timely diagnosis and subsequent initiation of treatment makes the fatality rate even higher. Cerebrospinal fluid (CSF) analysis is most important aspect of lab diagnosis in tuberculous meningitis (TBM) worldwide. The objective of this study was to study the cerebrospinal fluid CSF adenosine deaminase (ADA) levels in TBM and non-TBM meningitis cases and to determine its diagnostic significance as a biochemical marker of TBM infection.Methods: The study population comprised three different patient groups. TBM (n=36), pyogenic meningitis (n=17) and aseptic meningitis group (n=12). Total 75 subjects were enrolled consecutively in the study and CSF specimens were collected from them. ADA and other cytological and biochemical estimation were carried out using standard protocol.Results: ADA level in TBM in compare to non-TBM was more and mean ADA level of TBM, AM and PM are 26.423±3.8, 2.602±0.5 and 6.29±0.3 respectively. There are highly significant differences between the TBM and non-TBM groups and also in compare with individual groups.Conclusions: CSF ADA levels are elevated in the TBM cases as compared to the non-TBM - meningitis cases.  Results are statistically significant. It is a simple and inexpensive diagnostic adjunctive test in the rapid and early diagnosis of TBM

Resveratrol Regulates Antioxidant Status, Inhibits Cytokine Expression and Restricts Apoptosis in Carbon Tetrachloride Induced Rat Hepatic Injury

Recent studies indicate the chemopreventive role of resveratrol in many animal models like ischemia, rheumatoid arthritis, human cancer, and diabetes. The present study was designed to investigate the chemopreventive potential of resveratrol in rat hepatic injury model by carbon tetrachloride. Male Wistar rats were treated with carbon tetrachloride (0.4 g/kg body weight) intraperitoneally daily for 8 weeks. Resveratrol (100 mg/kg, 200 mg/kg body weight) was given orally from first day until the last day of experiment. The investigation assesses the effect of resveratrol on morphological, oxidative status, histopathological, immunohistochemical, and apoptotic analysis in carbon tetrachloride-challenged liver tissue. The study indicated that the inflammatory cytokines TNF-α and IL-6 were profoundly expressed in experimental rats, whereas resveratrol decreases the immunopositivity of TNF-α and IL-6 and restored the altered architectural structure of challenged hepatic tissue. Resveratrol also protects liver cells by suppressing oxidative stress and apoptosis

Is there any difference in efficacy of oral sildenafil therapy in primary vs secondary Pulmonary Arterial Hypertension?

Objective: Oral sildenafil, a phosphodiesterase 5 inhibitor,is now accepted mode of therapy for symptomatic Pulmonary arterial hypertension(PAH).As the pathobiologic mechanisms are different in primary and secondary PAH, we undertook this study to find out any significant difference in efficacy of oral sildenafil therapy in primary versus secondary PAH. Methods: It was an unicentric parallel group longitudinal study. After selection and baseline investigations,all the patients of primary and secondary PAH were given sildenafil in fixed doses (50 mg thrice daily). Study parameters: 1. Distance covered in 6 minute walk test (6MWT), 2.Pulmonary arterial pressure (PAP) by trans-thoracic Doppler echocardiography, 3.quality of life (QOL) score assessed by Minnesota living with heart disease questionnaire. At the end of 6 weeks, 6 MWT, PAP, QOL were compared to the baseline value. Results: 42 subjects completed the study.20 subjects had primary PAH and 22 had secondary PAH. Sildenafil therapy was effective in both groups in reducing PAP, increase in distance covered in 6 minute walk and reducing QOL score. Reduction of PAP is significantly more in primary PAH than secondary PAH but no such difference was found in 6 MWT and QOL score. Conclusion: Though lowering of pulmonary arterial pressure in primary PAH is significantly lower than secondary PAH, this is not translated in better symptomatic relief. Key words: primary pulmonary hypertension, secondary pulmonary hypertension, sildenafil, pulmonary arterial pressure, 6 minute walk test

AN LC-MS/MS BASED BIOANALYTICAL APPROACH TO RESOLVE PHARMACOKINETIC INVESTIGATION OF ACOTIAMIDE HYDROCHLORIDE AND ITS APPLICATION TO BIOEQUIVALENCE STUDY

Objective: Acotiamide, a prokinetic drug used to treat Functional Dyspepsia, which acts by modulating gastric motility. However, in this present study, a simple and accurate bioanalytical method was developed for the estimation of Acotiamide in human plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and validated according to US-FDA guideline. Methods: The method was developed in blank human blood plasma; propranolol was used as internal standard (IS). Protein Precipitation technique was followed for the extraction of the drug from the plasma sample. In liquid chromatography, the C18 analytical column (50 x 3 mm, particle size-5 μm) was used; as a mobile phase, 0.1% formic acid in Mili Q water, and ACN with methanol (1:1) used, at 0.50 ml/min flow rate. Detection was done by positive electrospray ionization (ESI) with a run time of 7 min in multiple reaction monitoring (MRM) mode. Eight calibration concentrations were taken, ranging from 1.5625-200 ng/ml for Acotiamide. Different stability studies were performed and obtained results found within the acceptable range. Moreover, a comparative pharmacokinetic analysis was done in 24 healthy human volunteers in a single dose, randomized, crossover study. Results: The precursor to production reaction was; m/z 451.200 → 271.200 for Acotiamide and m/z 260.300 → 116.100 m/z for IS. The obtained calibration curve was linear, with a mean r2value 0.9953. Among the pharmacokinetic parameters, Cmax and Tmax were 25.71±2.31,23.61±2.32 ng/ml; 2.54±0.12, 2.43±0.21 h for reference and test samples, respectively. Conclusion: No major adverse events were noted in the clinical phase, the developed method was accurate and linear; obtained pharmacokinetic parameters hence represented

Altered expression and editing of miRNA-100 regulates iTreg differentiation

RNA editing ofmiRNAs, especially in the seed region, adds another layer to miRNA mediated gene regulation which can modify its targets, altering cellular signaling involved in important processes such as differentiation. In this study, we have explored the role of miRNA editing in CD4+ T cell differentiation. CD4+ T cells are an integral component of the adaptive immune system. Na¨ıve CD4+ T cells, on encountering an antigen, get differentiated either into inflammatory subtypes like Th1, Th2 or Th17, or into immunosuppressive subtype Treg, depending on the cytokine milieu. We found C-to-U editing at fifth position of mature miR-100, specifically in Treg. The C-to-U editing of miR-100 is functionally associated with at least one biologically relevant target change, from MTOR to SMAD2. Treg cell polarization by TGFβ1 was reduced by both edited and unedited miR-100 mimics, but percentage of Treg in PBMCs was only reduced by edited miR-100 mimics, suggesting a model in which de-repression of MTOR due to loss of unedited mir-100, promotes tolerogenic signaling, while gain of edited miR-100 represses SMAD2, thereby limiting the Treg. Such delicately counterbalanced systems are a hallmark of immune plasticity and we propose that miR-100 editing is a novel mechanism toward this end

Identification of Small Molecules that Enhance Synaptogenesis Using Synapse Microarrays

Synaptic function is affected in many brain diseases and disorders. Technologies for large-scale synapse assays can facilitate identification of drug leads. Here we report a “synapse microarray” technology that enables ultra-sensitive, high-throughput, and quantitative screening of synaptogenesis. Our platform enables the induction of synaptic structures in regular arrays by precise positioning of non-neuronal cells expressing synaptic proteins, while allowing neurites to grow freely around these cells. The technology increases by tenfold the sensitivity of the traditional assays, and simultaneously decreases the time required to capture synaptogenic events by an order of magnitude. It is readily incorporated into multiwell formats compatible with industrial high-throughput screening platforms. Using this technology, we screened a chemical library and identified novel histone deacetylase inhibitors that improve neuroligin-1 induced synaptogenesis via modulating class-I histone deacetylases. We also found a structure-activity relationship for designing novel potent histone deacetylase inhibitors, which can be applied towards development of new therapeutics