Ever since the introduction of the first disease modifying therapies, the concept of multiple sclerosis treatment algorithms developed ceaselessly. The increasing number of available drugs is paralleled by impelling issue of ensuring the most appropriate treatment to the right patient at the right time. The purpose of this review is to describe novel agents recently approved for multiple sclerosis treatment, namely teriflunomide, alemtuzumab and dimethylfumarate, focusing on mechanism of action, efficacy data in experimental setting, safety and tolerability. The place in therapy of newer treatment implies careful balancing of risk-benefit profile as well as accurate patient selection. Hence the widening of therapeutic arsenal provides greater opportunity for personalized therapy but also entails a complex trade-off between efficacy, tolerability, safety and eventually patient preference.

Delirium is an acute disorder of attention and cognition seen relatively commonly in people aged 65 yr or older. The prevalence is estimated to be between 11 and 42 per cent for elderly patients on medical wards. The prevalence is also high in nursing homes and long term care (LTC) facilities. The consequences of delirium could be significant such as an increase in mortality in the hospital, long-term cognitive decline, loss of autonomy and increased risk to be institutionalized. Despite being a common condition, it remains under-recognised, poorly understood and not adequately managed. Advanced age and dementia are the most important risk factors. Pain, dehydration, infections, stroke and metabolic disturbances, and surgery are the most common triggering factors. Delirium is preventable in a large proportion of cases and therefore, it is also important from a public health perspective for interventions to reduce further complications and the substantial costs associated with these. Since the aetiology is, in most cases, multfactorial, it is important to consider a multi-component approach to management, both pharmacological and non-pharmacological. Detection and treatment of triggering causes must have high priority in case of delirium. The aim of this review is to highlight the importance of delirium in the elderly population, given the increasing numbers of ageing people as well as increasing geriatric age.

Combination therapy with three drug regimens for human immunodeficiency virus (HIV) infection significantly suppresses the viral replication. However, this therapeutic impact is restricted by adverse drug events and response in terms of short and long term efficacy. There are multiple factors involved in different responses to antiretrovirals (ARVs) such as age, body weight, disease status, diet and heredity. Pharmacogenomics deals with individual genetic make-up and its role in drug efficacy and toxicity. In depth genetic research has provided evidence to predict the risk of developing certain toxicities for which personalized screening and surveillance protocols may be developed to prevent side effects. Here we describe the use of pharmacogenomics for optimal use of HAART (highly active antiretroviral therapy).

Background & objectives: Interleukin 4 (IL4) and IL13 genes are believed to be responsible for inflammation of the airways in asthmatics. These share a common receptor component called IL4Rα which is another potentially important candidate gene linked to asthma phenotypes. Another gene Toll-like receptor 4 (TLR4) might affect the incidence or progression of asthma through the expression of proinflammatory genes. Several single nucleotide polymorphisms (SNPs) in IL4, IL13, IL4Rα and TLR4 have been reported to be linked to asthma or related phenotypes in several ethnic populations using linkage studies and association studies. However, the results have not been consistent. We investigated five SNPs (C-589T and C-33T of IL4, G+2044A of IL13, A+1902G of IL4Rα, and A+896G of TLR4) in patients with adult onset asthma to evaluate their role in manifestation and severity of asthma. Methods: Adult (>18 yr of age) patients with asthma (n=100) and healthy controls (n=50) were included in the study. Genotyping was performed using sequenom MassARRAY technology. Results: The mutant alleles of the C-589T and C-33T SNPs in the promoter region of IL4 were present in 4 per cent patients with asthma but absent from the control group suggesting that the variations in IL4 may contribute to asthma occurrence. The SNPs of other genes were seen in both controls and patients. Interpretation & conclusions: The results suggest the possible association between the genetic distribution of C-589T and C-33T SNPs of IL4 with asthma in Indian adults.

Background & objectives: Leprosy type 1 reactions (T1R) are acute episodes of immune exacerbation that are a major cause of inflammation and nerve damage. T1R are diagnosed clinically and supported by histopathology. No laboratory marker is currently available that can accurately predict a T1R. Increased plasma and tissue expression of inducible nitric oxide synthase (i-NOS) and chemokine CXCL10 have been demonstrated in T1R. We studied the gene expression and immunoexpression of i-NOS, CXCL10 and its receptor CXCR3 in clinically and histopathologically confirmed patients with T1R and compared with non-reactional leprosy patients to understand which biomarker has better potential in distinguishing reaction from non-reaction. Methods: Gene expression of i-NOS, CXCL10 and CXCR3 was studied in 30 skin biopsies obtained from patients with borderline tuberculoid (BT), mid-borderline (BB) and borderline lepromatous (BL) leprosy with and without T1R by real-time PCR. Further validation was done by immunhistochemical expression on 60 borderline leprosy biopsies with and without T1R. Results: Of the 120 patients histopathological evaluation confirmed T1R in 65 (54.2%) patients. CXCR3 gene expression was significantly (P<0.05) higher in BT- and BB-T1R patients compared to those without T1R. The CXCL10 gene expression was significantly higher (P<0.05) in BB leprosy with T1R but the difference was not significant in patients with BT with or without T1R. Immunoexpression for CXCR3 was significant in both BB-T1R and BB (P<0.001) and BT and BT-T1R (P<0.001). Immunoexpression of CXL10 was significant only in differentiating BB from BB-T1R leprosy (P<0.01) and not the BT cases. i-NOS immunoexpression was not useful in differentiating reactional from non-reactional leprosy. Interpretation & conclusions: Both CXCL10 and CXCR3 appeared to be useful in differentiating T1R reaction in borderline leprosy while CXCR3 alone differentiated BT from BT-T1R. CXCR3 may be a potentially useful immunohistochemical marker to predict an impending T1R.

Background & objectives: Abnormal endothelial function represents a preclinical marker of atherosclerosis. This study was conducted to evaluate associations between anthropometry, cardiometabolic risk factors, and early life factors and adult measures of endothelial function in a young urban Indian cohort free of clinical cardiovascular disease. Methods: Absolute changes in brachial artery diameter following cuff inflation and sublingual nitroglycerin (400 µg) were recorded to evaluate endothelium-dependent and -independent measures of endothelial function in 600 participants (362 men; 238 women) from the New Delhi Birth Cohort (2006-2009). Data on anthropometry, cardiometabolic risk factors, medical history, socio-economic position, and lifestyle habits were collected. Height and weight were recorded at birth, two and 11 yr of age. Age- and sex-adjusted linear regression models were developed to evaluate these associations. Results: The mean age of participants was 36±1 yr. Twenty two per cent men and 29 per cent women were obese (BMI th > 30 kg/m ^[2] ). Mean systolic blood pressure (SBP) was 131±14 and 119±13 mmHg, and diabetes prevalence was 12 and 8 per cent for men and women, respectively. Brachial artery diameter was higher for men compared with women both before (3.48±0.37 and 2.95±0.35 cm) and after hyperaemia (3.87±0.37 vs. 3.37±0.35 cm). A similar difference was seen before and after nitroglycerin. Markers of increased adiposity, smoking, SBP, and metabolic syndrome, but not early life anthropometry, were inversely associated with endothelial function after adjustment for age and sex. Interpretation & conclusions: The analysis of the current prospective data from a young urban Indian cohort showed that cardiometabolic risk factors, but not early life anthropometry, were associated with worse endothelial function.

Background & objectives: Cytogenetic microarray (CMA) is now recommended as a first-tier clinical diagnostic test in cases with idiopathic intellectual disability and/or developmental delay (ID/DD). Along with clinically relevant variants, CMA platforms also identify variants of unknown significance (VUS). This study was done to look for utility and various issues in interpretation of copy number variants (CNVs) in Indian patients with ID/DD. Methods: The CMA was performed in 86 Indian patients with idiopathic ID/DD with or without dysmorphic features. CNV was reported if copy number gain was >400 kb in size and copy number loss was > 200 kb in size. Results: Pathogenic CNVs were found in 18 of 86 (20.9%) patients. One large (14 Mb size) de novo heterozygous copy number gain was found in one patient. VUS (total 31) were present in 17 of 86 (19.7%) patients. Five novel recurrent benign CNVs were also present in our patients. Interpretation & conclusions: Our findings highlight the difficulties in interpretation of CNVs identified by CMA. More Indian data on VUS and recurrent benign CNVs will be helpful in the interpretation of CMA in patients with ID/DD.

Background & objectives: Diabetic peripheral neuropathy (DPN) is a major complication of type 2 diabetes and have long term complications on the postural control of the affected population. The objectives of this study were to evaluate postural stability in patients with DPN and to examine correlation of Michigan Neuropathy Screening Instrument (MNSI) with duration of diabetes, age and postural stability measures. Methods: Participants were included if they had clinical neuropathy which was defined by MNSI. Sixty one patients gave their consent to participate in the study and were evaluated on posturography for postural stability measures in four conditions. Repeated measures of analysis of variance (RANOVA) was used to analyze the changes in postural stability measures in different conditions. Results: An increase in mean value of postural stability measures was observed for velocity moment 20.4±1.3, 24.3±2.2, 42.3±20.7, 59±43.03, mediolateral displacement 0.21±0.10, 0.22±0.18, 0.03±0.11, 0.34±0.18, and anteroposterior displacement 0.39 ± 0.09, 0.45±0.12, 0.47±0.13, 0.51±0.20 from EO to EC, EOF, and ECF, respectively. There was a significant difference (P<0.05) in participants with DPN, with greater sway amplitude on firm and foam surface in all the conditions. Moderate correlation of MNSI with age (r=0.43) and postural stability measures were also observed. Interpretation & conclusions: Evaluation of postural stability in Indian DPN population suggests balance impairments on either firm and foam surfaces, with greater likelihood of fall being on foam or deformable surfaces among elderly adults with neuropathy (CTRI/2011/07/001884).

Background & objectives: There is a growing concern over the radiation exposure of patients from undergoing ¹⁸FDG PET/CT (¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography) whole body investigations. The aim of the present study was to study the kinetics of ¹⁸FDG distributions and estimate the radiation dose received by patients undergoing ¹⁸FDG whole body PET/CT investigations. Methods: Dynamic PET scans in different regions of the body were performed in 49 patients so as to measure percentage uptake of ¹⁸FDG in brain, liver, spleen, adrenals, kidneys and stomach. The residence time in these organs was calculated and radiation dose was estimated using OLINDA software. The radiation dose from the CT component was computed using the software CT-Expo and measured using computed tomography dose index (CTDI) phantom and ionization chamber. As per the clinical protocol, the patients were refrained from eating and drinking for a minimum period of 4 h prior to the study. Results: The estimated residence time in males was 0.196 h (brain), 0.09 h (liver), 0.007 h (spleen), 0.0006 h (adrenals), 0.013 h (kidneys) and 0.005 h (stomach) whereas it was 0.189 h (brain), 0.11 h (liver), 0.01 h (spleen), 0.0007 h (adrenals), 0.02 h (kidneys) and 0.004 h (stomach) in females. The effective dose was found to be 0.020 mSv/MBq in males and 0.025 mSv/MBq in females from internally administered ¹⁸FDG and 6.8 mSv in males and 7.9 mSv in females from the CT component. For an administered activity of 370 MBq of ¹⁸FDG, the effective dose from PET/CT investigations was estimated to be 14.2 mSv in males and 17.2 mSv in females. Interpretation & conclusions: The present results did not demonstrate significant difference in the kinetics of ¹⁸FDG distribution in male and female patients. The estimated PET/CT doses were found to be higher than many other conventional diagnostic radiology examinations suggesting that all efforts should be made to clinically justify and carefully weigh the risk-benefit ratios prior to every ¹⁸FDG whole body PET/CT scan.

Background & objectives: Studies involving animal models of experimental tuberculosis have elucidated the predominant role of cytokines secreted by T cells and macrophages to be an essential component of the immune response against Mycobacterium tuberculosis infection. The immune activities of CD4+ T cells are mediated in part by Th1 cytokine interferon gamma (IFN-γ) which is produced primarily by T cells and natural killer (NK) cells and critical for initiating the immune response against intracellular pathogen such as M. tuberculosis. Nuclear matrix protein SMAR1 plays an important role in V(D)J recombination, T helper cell differentiation and inflammatory diseases. In this study a transgenic mouse model was used to study the role of SMAR1 in M. tuberculosis infection. Methods: Wild type BALB/c, C57BL/6, BALB/c-EGFP-SMAR1 and C57BL/6-SMAR1 transgenic mice were infected with M. tuberculosis (H37Rv). A dose of 100 bacilli was used for infection via respiratory route. Bacterial load in lung and spleen of infected mice was determined at 2, 4, 6 and 8 wk post-infection. Gene expression analysis for Th1 cytokines and inducible nitric oxide synthase (iNOS) was performed in infected lung tissues by quantitative reverse transcription (RT)-PCR. Results: SMAR1 transgenic mice from both BALB/c and C57BL/6 genetic background displayed higher bacillary load and susceptibility to M. tuberculosis infection compared to wild type mice. This susceptibility was attributed due to compromised of Th1 response exhibited by transgenic mice. Interpretation & conclusions: SMAR1 transgenic mice exhibited susceptibility to M. tuberculosis infection in vivo irrespective of genetic background. This susceptibility was attributed to downregulation of Th1 response and its hallmark cytokine IFN-γ. Hence, SMAR1 plays an important role in modulating host immune response after M. tuberculosis infection.

Background & objectives: Infantile diaper dermatitis is a common, acute inflammatory reaction of the skin around diaper among infants. This study was undertaken to compare the effect of topical application of Bentonite and Calendula creams on the improvement of infantile diaper dermatitis. Methods: This double blind randomized controlled trial was undertaken on 100 patients of infantile diaper dermatitis. The 100 participants were randomly assigned into two groups of 50 each, and were prescribed the coded medicine. The mothers were trained to apply the cream and level of improvement was judged by observing the affected area on the first visit and then after three days of receiving treatment. Results: The mean age of infants was 6.45±5.53 months in Calendula group and 7.35±6.28 months in Bentonite group. Overall, 88 per cent of lesions in the Bentonite group started improving in the first six hours while this rate was 54 per cent in Calendula group (P<0.001). The risk ratio for the improvement in the first six hours was 2.99 folds in the Bentonite group. Also, lesions in 86 per cent infants in the Bentonite group and 52 per cent in the Calendula group were completely improved in the first three days after treatment (P<0.001). Interpretation & conclusions: Our results showed that in comparison with Calendula, Bentonite had faster healing effect and was more effective on the improvement of infantile diaper dermatitis (IRCT ID: IRCT 2012112811593N1).

Background & objectives: There is a significant bone tissue loss in patients from diseases and traumatic injury. The current autograft transplantation gold standard treatment has drawbacks, namely donor site morbidity and limited supply. The field of tissue engineering has emerged with a goal to provide alternative sources for transplantations to bridge this gap between the need and lack of bone graft. The aim of this study was to prepare biocomposite scaffolds based on chitosan (CHT), polycaprolactone (PCL) and hydroxyapatite (HAP) by freeze drying method and to assess the role of scaffolds in spatial organization, proliferation, and osteogenic differentiation of human mesenchymal stem cells (hMSCs) in vitro, in order to achieve bone graft substitutes with improved physical-chemical and biological properties. Methods: Pure chitosan (100CHT) and composites (40CHT/HAP, 30CHT/HAP/PCL and 25CHT/HAP/PCL scaffolds containing 40, 30, 25 parts per hundred resin (phr) filler, respectively) in acetic acid were freeze dried and the porous foams were studied for physicochemical and in vitro biological properties. Results: Scanning electron microscope (SEM) images of the scaffolds showed porous microstructure (20-300 μm) with uniform pore distribution in all compositions. Materials were tested under compressive load in wet condition (using phosphate buffered saline at pH 7.4). The in vitro studies showed that all the scaffold compositions supported mesenchymal stem cell attachment, proliferation and differentiation as visible from SEM images, [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay, alkaline phosphatase (ALP) assay and quantitative reverse transcription (qRT)-PCR. Interpretation & conclusions: Scaffold composition 25CHT/HAP/PCL showed better biomechanical and osteoinductive properties as evident by mechanical test and alkaline phosphatase activity and osteoblast specific gene expression studies. This study suggests that this novel degradable 3D composite may have great potential to be used as scaffold in bone tissue engineering.