Dual targeted 2-Benzylideneindanone pendant hydroxamic acid group exhibits selective HDAC6 inhibition along with tubulin stabilization effect.

Abnormal epigenetics has been recognised as an early event in tumour progression and aberrant acetylation of lysine in particular has been understood in tumorigenesis. Therefore, it has become an attractive target for anticancer drug development. However, HDAC inhibitors have limited success due to toxicity and drug resistance concerns. Present study deals with design and synthesis of bivalent indanone based HDAC6 and antitubulin ligands as anticancer agents. Two of the analogues 9 and 21 exhibited potent antiproliferative activities (IC50, 0.36-3.27 µM) and high potency against HDAC 6 enzyme. Compound 21 showed high selectivity against HDAC 6 while 9 exhibited low selectivity. Both the compounds also showed microtubule stabilization effects and moderate anti-inflammatory effect. Dual targeted anticancer agents with concomitant anti-inflammatory effects will be more attractive clinical candidates in future.

Association of Child Neurology-Indian Epilepsy Society Consensus Document on Parental Counseling of Children with Epilepsy.

When a child is diagnosed with epilepsy, counseling regarding the same is done by the treating doctor. Most parents are frightened and have poor knowledge about epilepsy. Therapeutic advice including drug dosage, administration and side effects takes up the major part of physician's time, thereby neglecting important issues like home seizure management, follow up and others. These lacunae in knowledge require systematic patient and family education. To address these issues, an expert group meeting of pediatric neurologists and epileptologists in India along with social workers/epilepsy educators, legal experts, parents, and teachers was held. The various aspects regarding parental counseling in children with epilepsy were discussed and a consensus document was formulated. Here authors present the group consensus statement on counseling parents and caregivers of children with epilepsy. This document is intended to help physicians and pediatricians counsel the families when a child is diagnosed with epilepsy.

Disconnect of type 2 biomarkers in severe asthma; dominated by FeNO as a predictor of exacerbations and periostin as predictor of reduced lung function.

BACKGROUND: biomarkers of Type 2 (T2) inflammation may predict asthma control and exacerbation risk. However, the relationships between individual T2 biomarkers to exacerbations and lung function in severe asthma remain uncertain. OBJECTIVES: to explore the roles played by T2 biomarkers individually and as a composite score in predicting clinical outcomes in severe asthma. METHODS: unselected severe asthma patients were enrolled in this cross sectional real life study. Participants were clinically characterised and the following measurements were obtained: the frequency of exacerbations requiring oral corticosteroids (OCS), asthma control (Juniper ACQ6-7), lung function, Fraction exhaled Nitric Oxide (FeNO), peripheral blood eosinophils (PBE), and serum periostin. RESULTS: A total of 115 patients were recruited [mean age 45 years (range 18-70), 80 (69.6%) females, mean forced expiratory volume in first second (FEV1) %predicted was 68% ±â€¯24.7, mean inhaled corticosteroids (ICS) 1.96 ±â€¯0.82 mg/day. FeNO correlated significantly with PBE (r = 0.35, p = 0.0004), but not with periostin (r = 0.22, p = 0.065) and there was no significant correlation between PBE and periostin. FeNO correlation with exacerbations (r = 0.42, p = 0.0008) was stronger than PBE and periostin. A composite score of the 3 biomarkers correlated with exacerbations in a dose-dependent manner but multiple regression analysis did not confirm an added benefit. Only periostin demonstrated a significant correlation with FEV1%predicted (r = -0.34, p = 0.004) with ROC-AUC 0.7. CONCLUSION: FeNO demonstrated stronger correlation with asthma exacerbations than PBE or periostin with no definite added benefit from a composite score of the 3 biomarkers. Only periostin showed significant association with reduced lung function raising its potential as a biomarker of airway remodeling.

Mindfulness in the Context of Romantic Relationships: Initial Development and Validation of the Relationship Mindfulness Measure.

Trait mindfulness and mindfulness in the context of romantic relationships may not be completely overlapping constructs. This study adapted an existing measure of trait mindfulness to assess the tendency to be mindful in romantic relationships, the Relationship Mindfulness Measure (RMM). Using data from 185 young adults, the results supported the RMM's internal consistency, test-retest reliability, and concurrent and predictive validity. The RMM accounted for a significant portion of variance in positive relationship quality, negative relationship quality, and anxious and avoidant attachment, even after controlling for trait mindfulness. Based on these findings, assessing relationship mindfulness may improve research exploring the role of mindfulness in romantic relations and therefore facilitate the development and refinement of mindfulness training programs for couples.

Longterm clinical outcomes of omalizumab therapy in severe allergic asthma: Study of efficacy and safety.

Omalizumab has been shown to be an effective add-on therapy for patients with uncontrolled severe persistent allergic asthma. There has been a steady accumulation of evidence on the long-term effectiveness of omalizumab; however, data on real-life outcomes beyond one year of treatment is limited. In this study, we report on long-term outcomes of omalizumab treatment. We collected data from our severe asthma registry on hospitalisations, exacerbations, corticosteroid sparing, asthma control, lung function, biomarkers and side effects, to determine if the benefit was sustained and treatment was safe on the long term. Forty-five patients [mean age 44.9 years (range 19-69), females 37/45 (82%), mean duration of omalizumab treatment = 60.7 ± 30.9 months (range 23-121) were included in the analysis. We observed a reduction in the annual acute asthma related hospital admissions for the total population from 207 at baseline to 40 on treatment (80.7% reduction), whilst the per patient annual hospitalisations were reduced from a mean of 4.8 to 0.89 post-omalizumab treatment (p < 0.00001). There was a 76.7% reduction in daily mean maintenance OCS dose (prednisolone equivalent) from 25.8 mg (n = 43) to 6.0 mg (p < 0.0001), associated with clinically significant improvement in asthma control questionnaire (ACQ) from mean score of 4.1 (range 3.7-4.7) to 2.27 (range 0.5-4.1) p < 0.0001. The mean % predicted FEV1 has improved from 59.2% at baseline to 75.7% on treatment (p = 0.001). There was a statistically non-significant reduction in median peripheral blood eosinophils (PBE) from 300 cells/µl (range 40-1050) at baseline to 175 cells/µl (range 0-1500) post-treatment (p = 0.068), and statistically significant reduction of median fraction exhaled nitric oxide (FeNO) level from 37 parts per billion (range 12-178) to 24 ppb (range 7-50) (p = 0.0067). The work/school missed days were reduced in 17/19 patients who were at employment or school. The overall safety profile of the treatment seemed acceptable and was consistent with published experience. In conclusion, results from this real-life study demonstrate that improved outcomes in patients with severe allergic asthma are sustained with longer-term omalizumab therapy.

Secondary antibody deficiency - causes and approach to diagnosis.

Antibody deficiencies can occur in the context of primary disorders due to inherited genetic defects; however, secondary immune disorders are far more prevalent and can be caused by various diseases and their treatment, certain medications and surgical procedures. Immunoglobulin replacement therapy has been shown to be effective in reducing infections, morbidity and mortality in primary antibody deficiencies but secondary antibody deficiencies are in general poorly defined and there are no guidelines for the management of patients with this condition. Clinical decisions are based on experience from primary antibody deficiencies. Both primary and secondary antibody deficiencies can be associated with infections, immune dysregulation and end-organ damage, causing significant morbidity and mortality. Therefore, it is important to diagnose and treat these patients promptly to minimise adverse effects and improve quality of life. We focus on secondary antibody deficiency and describe the causes, diagnosis and treatment of this disorder.

Systemic reactions and anaphylaxis with an acute serum tryptase ≥14 µg/L: retrospective characterisation of aetiology, severity and adherence to National Institute of Health and Care Excellence (NICE) guidelines for serial tryptase measurements and specialist referral.

AIMS: To characterise patients with systemic reactions and anaphylaxis with an acute serum tryptase of ≥14 µg/L against recently published World Allergy Organisation (WAO) diagnostic criteria. To also perform a clinical audit to assess adherence to National Institute of Health and Care Excellence (NICE) guideline recommendations regarding serial tryptase measurements and specialist referral. METHODS: A systematic retrospective survey (2006-2010) was carried out (n=171; males=86; mean age±SD 48±20 years) and data were extracted from emergency department and specialist allergy clinic records. RESULTS: 34 patients (20%) had a grade 1 reaction, 61 (36%) grade 2, 46 (27%) grade 3 and 6 patients (4%) grade 4 (24 patients (13%) could not be graded due to lack of adequate clinical details) and 6% developed a biphasic response. Serial tryptase measurements were not available in 117 (69%) of the cohort. 97 (57%) patients were referred for specialist assessment, and 72 (74%) attended. 50% of cases were diagnosed with idiopathic systemic reactions/anaphylaxis and 28%, 14% and 8% triggered by drugs, foods and other allergies including disorders of mast cell overload, respectively. A weak positive correlation was detected between acute serum tryptase and severity. CONCLUSIONS: The correlation between acute serum tryptase and severity of anaphylaxis/systemic reactions is weak. A significant proportion of patients with raised acute serum tryptase had mild reactions which did not meet WAO criteria for anaphylaxis and this may reduce the specificity of the test. The commonest aetiology in this cohort was idiopathic followed by drug and food allergies. NICE guidelines relating to serial tryptase measurements and specialist referral were not followed, and there is an urgent need to raise the awareness among clinicians involved in the management of anaphylaxis.

Functional assessment of adipose stem cells for xenotransplantation using myocardial infarction immunocompetent models: comparison with bone marrow stem cells.

Recently, preclinical studies have shown that allogeneic adipose-derived stem cells (ASCs), like bone marrow-derived mesenchymal stem cell (BMSCs) have significant clinical benefits in treating cardiovascular diseases, such as ischemic/infarcted heart. In this study, we tested whether ASCs are also immune tolerant, such that they can be used as universal donor cells for myocardial regenerative therapy. The study also focuses on investigating the potential therapeutic effects of human ASCs (hASCs) for myocardial infarction in xenotransplant model, and compares its effects with that of hBMSCs. The in vitro study confirms the superior proliferation potential and viability of hASCs under normoxic and stressed hypoxic conditions compared with hBMSCs. hASCs also show higher potential in adopting cardiomyocyte phenotype. The major findings of the in vivo study are that (1) both hASCs and hBMSCs implanted into immunocompetent rat hearts with acute myocardial infarction survived the extreme environment of xenogeneic mismatch for 6 weeks; (2) both hASCs and hBMSCs showed significant improvement in myocardial pro/anti-inflammatory cytokine levels with no detectable inflammatory reaction, despite the lack of any immunosuppressive therapy; and (3) hASCs contributed to the remarkable improvement in cardiac function and reduced infarction which was significantly better than that of hBMSC and untreated control groups. Thus, our findings suggest the feasibility of using ASCs, instead of BMSCs, as universal donor cells for xenogeneic or allogeneic cell therapy.

Bromelain induces cardioprotection against ischemia-reperfusion injury through Akt/FOXO pathway in rat myocardium.

Bromelain (Br), a proteolytic enzyme extracted from the stem of the pineapple, is known to possess anti-inflammatory activity and has been shown to reduce blood viscosity, prevent the aggregation of blood platelets, and improve ischemia-reperfusion (I/R) injury in a skeletal muscle model. We investigated the capacity of Br to limit myocardial injury in a global I/R model. Adult male Sprague-Dawley rats were divided into two groups: control (PBS) and Br at 10 mg/kg in PBS administered via intraperitoneal injection (twice/day) for 15 consecutive days. On day 16, the hearts were excised and subjected to 30 min of global ischemia followed by 2 h of reperfusion. Br treatment showed higher left ventricular functional recovery throughout reperfusion compared with the controls [maximum rate of rise in intraventricular pressure (dP/dt max), 2,225 vs. 1,578 mmHg/s at 2 h reperfusion]. Aortic flow was also found to be increased in Br treatment when compared with that in untreated rats (11 vs. 1 ml). Furthermore, Br treatment reduced both the infarct size (34% vs. 43%) and the degree of apoptosis (28% vs. 37%) compared with the control animals. Western blot analysis showed an increased phosphorylation of both Akt and FOXO3A in the treatment group compared with the control. These results demonstrated for the first time that Br triggers an Akt-dependent survival pathway in the heart, revealing a novel mechanism of cardioprotective action and a potential therapeutic target against I/R injury.

Diet, nutritional status and food related traditions of Oraon tribes of New Mal (West Bengal), India.

INTRODUCTION: According to the 2001 census conducted by the Government of India, India has more than 84 million tribals who constitute 8.2% of India's population. The Oraons are an agricultural tribe found mainly in Orissa, Bihar, Jharkhand and West Bengal. The present study was undertaken on a group of Oraon tribals working in a tea gardens of New Mal in Jalpaiguri district of West Bengal. The children attended the local primary school. The Oraons are covered by the Integrated Child Development Scheme (ICDS) of the Government of India, which is concerned with the health, nutrition and development of children and their mothers. To evaluate the effect of ICDS, the practices of adults towards hygiene, medication, addictive substances and diet were also recorded. METHODS: 500 Oraon tribals, including 200 men and 150 women aged 20-45 years, and 150 children aged 6-12 years, were surveyed for their dietary intake by 24-hour recall and semi-quantitative food frequency questionnaire methodology and anthropometry, and a description of food-related traditions. RESULTS: The diet of all Oraon groups was deficient in all food groups. Cereal intake was least deficient, while the intake of milk and fruit was almost negligible. Their diet was supplemented by a locally grown green leafy vegetable dheki saag, and fermented leftover rice. The energy available from the diet for all age groups was only 52-53% of the recommended dietary allowances of the Indian Council of Medical Research. Children were enrolled in a midday meal program at the local primary school; however, their energy intake was severely deficient, and of the same order as their parents. The mean basal mass index (BMI) of adult Oraons was not low, but children were severely undernourished. Men were less undernourished than were women. Some potentially useful traditions practiced included wiping washed utensils with leaves of a local plant mirchaiya, preparing herbal tablets called ranoodava to make an alcoholic and a medicinal drink called hadiya. The Oraons' knowledge of contraception, vaccinations, proper diet and supplements needed for successful pregnancy was severely deficient. CONCLUSIONS: A remarkable finding of this study on the Oraon tribals is that the BMI of children was substantially below that of adult men and women. This deficiency cannot be attributed to energy intake because energy intake of children, as percentage of recommended dietary allowance, was about the same as adults. The study shows that the midday meal program provided only approximately 25% of the energy requirements of the children; moreover, it was qualitatively deficient. It also seems that the midday meal replaced rather than supplemented home meals. Despite ICDS coverage, knowledge with regard to contraception, vaccinations, proper diet and supplements needed for successful pregnancy was very low. Interesting traditional practices concerned with methods of preparing food and use of local plants as medicines were observed and documented. Rural health professionals should ensure adequate quantity and quality of food supplementation. They should strive to disseminate health related knowledge. Traditional tribal practices should be studied for their nutritional and medicinal value. They could be responsible for the adequate BMI of adult Oraon, despite severe deficiency in energy intake.

Membrane localization of membrane type 5 matrix metalloproteinase by AMPA receptor binding protein and cleavage of cadherins.

Matrix metalloproteinases (MMPs) have been proposed to remodel the extracellular environment of neurons. Here, we report that the metalloproteinase membrane-type 5 MMP (MT5-MMP) binds to AMPA receptor binding protein (ABP) and GRIP (glutamate receptor interaction protein), two related postsynaptic density (PSD) PDZ (postsynaptic density-95/Discs large/zona occludens-1) domain proteins that target AMPA receptors to synapses. The MT5-MMP C terminus binds ABP PDZ5 and the two proteins coimmunoprecipitated and colocalized in heterologous cells and neurons. MT5-MMP localized in filopodia at the tips of growth cones in young [2-5 d in vitro (DIV)] cultured embryonic hippocampal neurons, and at synapses in mature (21 DIV) neurons. Its enrichment in synaptosomes also indicated a synaptic localization in the mature brain. Deletion of the PDZ binding site impaired membrane trafficking of MT5-MMP, whereas exogenous ABP splice forms that are associated either with the plasma membrane or with the cytosol, respectively, colocalized with MT5-MMP in synaptic spines or recruited MT5-MMP to intracellular compartments. We show that endogenous MT5-MMP is found in cultured neurons and brain lysates in a proenzyme form that is activated by furin and degraded by auto-proteolysis. We also identify cadherins as MT5-MMP substrates. These results suggest that ABP directs MT5-MMP proteolytic activity to growth cones and synaptic sites in neurons, where it may regulate axon pathfinding or synapse remodeling through proteolysis of cadherins or other ECM or cell adhesion molecules.