Organochlorine pesticides residue in placenta and their influence on anthropometric measures of infants.

The objective of this study is to evaluate the influence of placental concentrations of some organochlorine pesticides on newborn's anthropometric measurements (height, weight, head circumference & ponderal index). For this study, we have collected 90 placental tissue samples for the measurement of Dichlorodiphenyltrichloroethane (DDT) & Hexachlocyclohexane (HCH) by Gas Chromatography equipped with Electron Capture Detector (GC-ECD). Regression analysis were performed between outcome variables such as birth weight, birth height, head circumference, ponderal index and independent variable i.e., organochlorine pesticide concentrations. In case of birth weight, there was a substantial decrease of 5.81, 1.94, 4.71, and 2.64 g for 1 ppb (µg/L) increase in placental α-HCH, ß-HCH, γ-HCH, and total HCH concentrations respectively. Significant decrease of 2.02 and 0.43 kg/m3 in ponderal index was found with 1 µg/L increase of total-HCH and total DDT concentrations in placenta. The results of this study support an association between environmental exposure to organochlorine pesticides and anthropometric development of the fetus leading to a significant reduction in its birth weight and ponderal index, slight and non-significant reduction in birth height and head circumference. Efforts should be made to reduce exposure of women of reproductive age in relation to long-term impact on health.

Pesticides exposure through environment and risk of pre-term birth: a study from Agra city.

Pre-term birth is an increasingly prevalent complex condition with multiple risk factors including environmental pollutants. Evidences linking organochlorine pesticides with adverse pregnancy outcomes are inconsistent for link between organochlorine pesticides and adverse pregnancy outcomes. We performed a case-control study of 50 cases of full-term births and 40 cases of pre-term births in this study. Placental organochlorine pesticides like metabolites of dichlorodiphenyltrichloroethane that is, (p,p-DDE, p,p-DDT and o,p-DDD) and isomers of hexachlorocyclohexane (α, ß, γ and δ HCH) were analyzed by gas chromatography. Although the mean levels of pesticide were found higher in the placenta of the women with pre-term delivery cases placentas, but only α-HCH, total-HCH, p,p-DDE and total-DDT were found statistically significant. It was observed that pesticide exposed women were approximately 1.7 times more likely to deliver pre-term baby as compare to pregnant women that were not exposed to any pesticides. We also observed that increasing maternal age reduced the risk of having pre-term birth (OR = 0.99). Among all pesticides, α-HCH was found to be strongest isomer to induce premature baby birth (p < 0.001). This study found that pregnant women's age and chronic disease, baby's weight at the time of birth and α-HCH were important risk factors for pre-term births.

Challenges in translational drug research in neuropathic and inflammatory pain: the prerequisites for a new paradigm.

AIM: Despite an improved understanding of the molecular mechanisms of nociception, existing analgesic drugs remain limited in terms of efficacy in chronic conditions, such as neuropathic pain. Here, we explore the underlying pathophysiological mechanisms of neuropathic and inflammatory pain and discuss the prerequisites and opportunities to reduce attrition and high-failure rate in the development of analgesic drugs. METHODS: A literature search was performed on preclinical and clinical publications aimed at the evaluation of analgesic compounds using MESH terms in PubMed. Publications were selected, which focused on (1) disease mechanisms leading to chronic/neuropathic pain and (2) druggable targets which are currently under evaluation in drug development. Attention was also given to the role of biomarkers and pharmacokinetic-pharmacodynamic modelling. RESULTS: Multiple mechanisms act concurrently to produce pain, which is a non-specific manifestation of underlying nociceptive pathways. Whereas these manifestations can be divided into neuropathic and inflammatory pain, it is now clear that inflammatory mechanisms are a common trigger for both types of pain. This has implications for drug development, as the assessment of drug effects in experimental models of neuropathic and chronic pain is driven by overt behavioural measures. By contrast, the use of mechanistic biomarkers in inflammatory pain has provided the pharmacological basis for dose selection and evaluation of non-steroidal anti-inflammatory drugs (NSAIDs). CONCLUSION: A different paradigm is required for the identification of relevant targets and candidate molecules whereby pain is coupled to the cause of sensorial signal processing dysfunction rather than clinical symptoms. Biomarkers which enable the characterisation of drug binding and target activity are needed for a more robust dose rationale in early clinical development. Such an approach may be facilitated by quantitative clinical pharmacology and evolving technologies in brain imaging, allowing accurate assessment of target engagement, and prediction of treatment effects before embarking on large clinical trials.

Semi-mechanistic modelling of the analgesic effect of gabapentin in the formalin-induced rat model of experimental pain.

PURPOSE: The formalin-induced rat model of nociception involves moderate continuous pain. Formalin-induced pain results in a typical repetitive flinching behaviour, which displays a biphasic pattern characterised by peaks of pain. Here we described the time course of pain response and the analgesic effect of gabapentin using a semi-mechanistic modelling approach. METHODS: Male Sprague-Dawley rats received gabapentin (10-100 mg/kg) or placebo 1 h prior to the formalin injection, as per standard protocol. A reduction in the frequency of the second peak of flinching was used as a behavioural measure of gabapentin-mediated anti-nociception. The flinching response was modelled using a mono-exponential function to characterise the first peak and an indirect response model with a time variant synthesis rate for the second. PKPD modelling was performed using a population approach in NONMEM v.7.1.2. RESULTS: The time course of the biphasic response was adequately described by the proposed model, which included separate expressions for each phase. Gabapentin was found to reversibly decrease, but not suppress the flinching frequency of the second response peak only. The mean IC50 estimate was 7,510 ng/ml, with relative standard error (RSE%) of 40%. CONCLUSIONS: A compartmental, semi-mechanistic model provides the basis for further understanding of the formalin-induced flinching response and consequently to better characterisation of the properties of gabapentin, such as the potency in individual animals. Moreover, despite high exposure levels, model predictions show that gabapentin does not completely suppress behavioural response in the formalin-induced pain model.

Efficacy of patient-initiated follow-up clinics in secondary care: a systematic review.

Patient-initiated follow up (PIFU) is an initiative that allows patients to initiate hospital follow-up appointments on an 'as required' basis compared with the traditional 'physician-initiated' model. The main principle is to reduce inappropriate regular follow-up appointments. In this systematic review, we attempt to address its efficacy for outpatient secondary level care. Using Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, an electronic literature search was performed independently by two authors using pre-defined search terms across EMBASE, Ovid MedLine, PubMed, PSYCINFO and the Cochrane Library databases. Articles were included if they specifically evaluated any aspect of PIFU. Studies evaluating non-outpatient-based, primary level-based and nurse-led clinic appointments were excluded. A total of 747 articles was reviewed, and six were finally included for the systematic review. Three studies analysed efficacy of PIFU with regards to rheumatological disease and found that there was no deleterious clinical effect and a trend towards increased satisfaction and quality of life including lower costs in the PIFU group. Two studies looked at PIFU and inflammatory bowel disease and identified some clinical benefit and lower costs and equivalent satisfaction and QoL with the PIFU group. A further study looked at PIFU in stage 1 breast cancer and did not find any significant differences in outcomes. There is evidence to suggest that PIFU systems result in fewer overall outpatient appointments in secondary care led services while maintaining equivalent if not better patient satisfaction, quality of life and clinical outcomes across a range of chronic conditions.

Optimised protocol design for the screening of analgesic compounds in neuropathic pain.

We have previously shown how screening experiments for neuropathic pain can be optimised taking into account parameter and model uncertainty. Here we demonstrate how optimised protocols can be used to screen and rank candidate molecules. The concept is illustrated by pregabalin as a new chemical entity and gabapentin as a reference compound. ED-optimality was applied to a logistic regression model describing the relationship between drug exposure and response to evoked pain in the complete Freund's adjuvant (CFA) model in rats. Design variables for optimisation of the experimental protocol included dose levels and sampling times. Prior information from the reference compound was used in conjunction with relative in vitro potency as priors. Results from simulated scenarios were then combined with fitting of experimental data to estimate precision and bias of model parameters for the empirical and optimised designs. The pharmacokinetics of pregabalin was described by a two-compartment model. The expected value of EC(50) of pregabalin was 637.5 ng ml(-1). Model-based analysis of the data yielded median (range) of EC(50) values of 1,125 (898-2412) ng ml(-1) for the empirical protocol and 755 (189-756) ng ml(-1) for the optimised design. In contrast to current practice, optimal design entails different sampling schedule across dose levels. ED-optimised designs should become standard practice in the screening of candidate molecules. It ensures lower bias when estimating the drug potency, facilitating accurate ranking and selection of compounds for further development.

Application of ED-optimality to screening experiments for analgesic compounds in an experimental model of neuropathic pain.

In spite of the evidence regarding high variability in the response to evoked pain, little attention has been paid to its impact on the screening of drugs for inflammatory and neuropathic pain. In this study, we explore the feasibility of introducing optimality concepts to experimental protocols, enabling estimation of parameter and model uncertainty. Pharmacokinetic (PK) and pharmacodynamic data from different experiments in rats were pooled and modelled using nonlinear mixed effects modelling. Pain data on gabapentin and placebo-treated animals were generated in the complete Freund's adjuvant model of neuropathic pain. A logistic regression model was applied to optimise sampling times and dose levels to be used in an experimental protocol. Drug potency (EC(50)) and interindividual variability (IIV) were considered the parameters of interest. Different experimental designs were tested and validated by SSE (stochastic simulation and estimation) taking into account relevant exposure ranges. The pharmacokinetics of gabapentin was described by a two-compartment PK model with first order absorption (CL = 0.159 l h(-1), V(2) = 0.118 l, V(3) = 0.253 l, Ka = 0.26 h(-1), Q = 1.22 l h(-1)). Drug potency (EC(50)) for the anti-allodynic effects was estimated to be 1400 ng ml(-1). Protocol optimisation improved bias and precision of the EC50 by 6 and 11.9. %, respectively, whilst IIV estimates showed improvement of 31.89 and 14.91 %, respectively. Our results show that variability in behavioural models of evoked pain response leads to uncertainty in drug potency estimates, with potential impact on the ranking of compounds during screening. As illustrated for gabapentin, ED-optimality concepts enable analysis of discrete data taking into account experimental constraints.

Hemoadsorption by extracorporeal cytokine adsorption therapy (CytoSorb®) in the management of septic shock: A retrospective observational study.

INTRODUCTION: Sepsis results in immunologic disturbances with the release of various inflammatory mediators such as cytokines. Cytokines can damage the cells, and the continuous release of inflammatory mediators leads to severely impaired immunity. Therefore, the reduction in cytokine levels by hemoadsorption represents a new concept for blood purification. CytoSorb® as a hemoadsorption device is a detoxification system, which aims to decrease the cytokines levels. This study was conducted to understand any beneficial effects of CytoSorb® therapy in septic patients. METHODOLOGY: This was a retrospective and observational study, approved by the scientific and ethics committee of Max Super Specialty Hospital, Patparganj, Delhi, India and conducted in compliance with current International Council for Harmonization, Good Clinical Practice, Schedule Y, and Indian Council of Medical Research guidelines. Subjects of either gender (age > 18 year) were included in the study. The data were presented as mean ± standard deviation and categorical as frequency and percentage (%). A p value less than 0.05 (p < 0.05) was considered to be statistically significant. RESULTS: A total number of 36 patients were included in the study. Majority of the patients were male with mean age (56.36 ± 14.83). After therapy, procalcitonin and total leucocyte count levels decreased within 24 h. Post therapy, sepsis-related organ failure assessment (SOFA) score of Day (D)1, D2, and D3 reduced to 10.4 ± 3.63, 8.7 ± 4.02, and 7.8 ± 3.67, respectively. The Acute Physiology and Chronic Health Evaluation (APACHE) II score and predicted mortality were lower in the survivor group as compared to the non-survivor group. CONCLUSION: Hemoadsorption using the extracorporeal adsorption device (CytoSorb®) might be an effective rescue therapy in stabilizing septic shock patients.

Stability of an underactuated bipedal gait.

A self-excited biped walking mechanism consisting of two legs that are connected in series at the hip joint through a servomotor is studied as a cyclic system with collisions. A torque proportional to angle between the shank of the swinging leg and the vertical is seen to sustain a gait. Each leg has a thigh and a shank connected at a passive knee joint that has a knee stopper restricting hyperextension similar to the human knee. A mathematical model for the dynamics of the system including the impact equations is used to analyse the stability of the system through examination of phase plane plots. Attractor lines along which the system approaches stability have been identified. A leg length for optimal stability has been identified. The biological basis for the proposed system has been identified by comparison with human gait.

Admission ECG predicts long-term outcome in acute coronary syndromes without ST elevation.

BACKGROUND: Acute coronary syndromes (ACS) without ST elevation are a frequent cause of hospital admission, myocardial infarction and death. AIM: To explore the role of the ECG in stratifying ACS patients. DESIGN: Prospective, centrally-coordinated multicentre registry involving 56 centres throughout the UK. METHODS: Consecutive patients admitted with ACS without ST elevation on the presenting ECG (n = 1046) were followed for 6 months. A subgroup (n = 653) were flagged with the UK Office for National Statistics and followed-up for death over 4 years. RESULTS: Mean follow-up for the group as a whole was 2.4 years. In the first 6 months, the death rate was 7.3%. Survival at 1 year was 90.8% (95%CI 88.2%-92.8%); at 45 months it was 77.8% (95%CI 74.1%-81.1%). We compared data in those with ST depression or bundle branch block on the admission ECG (n = 304, 29%) with those with T wave inversion, Q waves and minor ST segment changes (n = 576, 55%) and those with a normal ECG (n = 166, 16%). Their respective incidences of death were 15%, 5% and 2% (p < 0.01) at 6 months, and 38%, 22% and 7% (p < 0.01) at 4 years. DISCUSSION: Rates of adverse events are high in patients admitted to UK hospitals with ACS without ST elevation. The ECG remains a very important and simple discriminator of both short- and long-term risk, enabling more aggressive, proven therapies to be targeted towards those at highest risk.

Long term prognosis of heart failure after acute coronary syndromes without ST elevation.

BACKGROUND: Information about long term outcomes of patients with acute coronary syndromes (ACS) who have clinically diagnosed heart failure is scarce. METHODS: In a UK registry, this study evaluated patients with non-ST elevation ACS, recording treatment, and clinical outcomes for six months. In a subgroup, a four year mortality follow up was performed to estimate the impact of the clinical diagnosis of heart failure on survival. RESULTS: Of 1046 patients, 139 (13%) had a history of clinically diagnosed heart failure. At discharge, ACE inhibitors were prescribed for 58% and 28%, of those with and without a history of heart failure respectively (p<0.001). Rates of angiography, percutaneous intervention, and coronary artery bypass graft were 17.3% and 29.2% (p = 0.003), 5.0% and 8.4% (p = 0.17), and 5.0% and 7.5% (p = 0.3) for these groups respectively. Death or new myocardial infarction at six months occurred in 22% and 10% (p<0.001) and at four years death occurred in 60% and 20% of these groups respectively (p<0.001). In a multivariate analysis prior heart failure carried an odds ratio of 2.0 (p = 0.001) for death or myocardial infarction at six months and 2.4 (p<0.001) for death over four years. New heart failure was associated with an increased risk of death at six months (20% compared with 5%, p<0.001). CONCLUSION: A clinical history of heart failure carries a substantial risk of death in patients admitted with ACS without ST elevation. Nearly 60% of those with prior heart failure are dead after four years. After adjustment for confounding factors, prior heart failure more than doubles the risk compared with those with no history.

Personal and ambient PM2.5 exposure assessment in the city of Agra.

Human exposure to fine particles can have significant harmful effects on the respiratory and cardiovascular system. To investigate daily exposure characteristics to PM2.5 with ambient concentrations in an urban environment, a personal exposure measurements were conducted for school children, office workers and at their residents, in the city of Taj 'Agra', India. In order to account for all the sources of particulate matter exposure, measurements on several different days during December 2013 to February 2014 were carried out. Personal environment monitors (PEM) and APM 550 were used to measure PM2.5 concentration. The research findings provide insight into possible sources and their interaction with human activities in modifying the human exposure levels.

N,N'-Dialkylbis(dichlorophenyl)ethylenediamines and -imidazolidines: relationship between structure and estradiol receptor affinity.

Diastereomeric N,N'-dialkylbis(dichlorophenyl)ethylenediamines and the corresponding imidazolidines with chlorine in the 2,4, 2,6, 3,4, and 3,5 positions were synthesized. Only the stereoisomers of the 2,6-dichloro-substituted compounds exhibit for N-CH3 (2e, 3e), N-C2H5 (2f, 3f), and N-C3H7 (2g, 3g) an affinity to the estradiol receptor (Ka values ranging from 9.1 X 10(4) to 9.1 X 10(6)), because the nitrogen atoms are shielded by the ortho-located chlorine atoms; therefore, a binding interaction with hydrophobic receptor areas is possible. These substances show weak uterotrophic activity and no significant effect on the growth of the DMBA-induced hormone-dependent mammary adenocarcinoma of the rat.

Effect of incorporation of isabgol husk in a low fibre diet on faecal excretion and serum levels of lipids in adolescent girls.

The effect of consumption of isabgol husk for 3 weeks on faecal excretion and serum levels of lipids was investigated in 11 adolescent girls. The consumption of isabgol husk lowered serum lipids and increased faecal fat.

Extraction & assay of fibronectin from stored plasma.

Fibronectin was extracted from 20 units of 3 days old plasma by the heparin cold precipitation technique using 15 or 30 units of sodium heparin per ml of plasma. Immunoelectrophoresis of the extracted fibronectin showed it to be 131.37 +/- 24.73 times concentrated over fibronectin levels in standard plasma, with a mean recovery of 73.99 +/- 18.40 per cent. Corresponding figures by ELISA were 118.95 +/- 27.99 (concentration) and 73.99 +/- 18.40 (per cent).

Alloimmunisation to platelet transfusions in the Indian patients.

Twenty nine patients of acute and chronic leukemia undergoing chemotherapy and receiving blood transfusions (BT) and platelet transfusions (PT) from random donors (3-20 PT from 4-56 donors) were followed up for alloimmunisation using the platelet immunofluorescence test. Two women patients aged 65 and 28 yr reacted positive. Both patients had received multiple BT but no PT at the time of testing. Both were parous women. Our results point to the need to test for alloimmunisation prior to starting PT in parous women who have received multiple BT, although a study on larger number of patients is necessary for confirmation.

Fibronectin levels in Indian neonates in health & disease.

Cord blood samples were estimated for serum fibronectin (Fn) by immunoelectrophoresis (IE) and enzyme linked immuno sorbent assay (ELISA) in 250 newborn healthy and sick infants classified into 6 categories: i.e., term appropriate for date (TAFD), preterm appropriate for date (PTAFD), term small for date (TSFD), preterm small for date (PTSFD), birth asphyxia (BA) and septicemia (SEP). TAFD infants were assayed for plasma Fn in addition. Comparison of Fn levels in the different groups by the Wilcoxan rank sum test indicated no significant difference between term and preterm infants, between PTAFD and PTSFD, TAFD and TSFD and in infants with and without birth asphyxia. Babies with septicemia had a significantly (P < 0.01) lower Fn level (29.97 +/- 29.03 mg/l) than those with no septicemia (42.77 +/- 30.20 mg/l). TAFD infants had Fn levels (serum 41.44 +/- 31.08 mg/l, plasma 85.20 +/- 33.38 mg/l) that are less than half the levels reported in the Western literature for newborn term infants. A possible cause could be the associated medical problems in mothers as 41 per cent of mothers of TAFD infants had conditions such as pregnancy induced hypertension, gestational diabetes, rheumatic heart disease, infection etc.

Treatment of vitiligo.

Vitiligo, particularly in darker skinned individuals, is a psychosocial disaster. With patient education, proper therapeutic selection and persistence, favorable repigmentation can be achieved in the majority of individuals with vitiligo. Attention to the activity state of the disease, the type, location and extent of the vitiligo must be carefully balanced against the patient's expectations, time commitment and assumption of risks. In this review, Dr Taneja succinctly summarizes the wide range of therapeutic options available today for the vitiligo patient.