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Justification: Neurodevelopmental disorders, as per DSM-V, are described as a group of conditions with onset in the development period of childhood. There is a need to distinguish the process of habilitation and rehabilitation, especially in a developing country like India, and define the roles of all stakeholders to reduce the burden of neurodevelopmental disorders., Process: Subject experts and members of Indian Academy of Pediatrics (IAP) Chapter of Neurodevelopmental Pediatrics, who reviewed the literature on the topic, developed key questions and prepared the first draft on guidelines. The guidelines were then discussed by the whole group through online meetings, and the contentious issues were discussed until a general consensus was arrived at. Following this, the final guidelines were drafted by the writing group and approved by all contributors., Objectives: These guidelines aim to provide practical clinical guidelines for pediatricians on the prevention, early diagnosis and management of neurodevelopmental disorders (NDDs) in the Indian settings. It also defines the roles of developmental pediatricians and development nurse counselor., Statement: There is a need for nationwide studies with representative sampling on epidemiology of babies with early NDD in the first 1000 days in India. Specific learning disability (SLD) has been documented as the most common NDD after 6 years in India, and special efforts should be made to establish the epidemiology of infants and toddlers at risk for SLD, where ever measures are available. Preconception counseling as part of focusing on first 1000 days; Promoting efforts to organize systematic training programs in Newborn Resuscitation Program (NRP); Lactation management; Developmental follow-up and Early stimulation for SNCU/ NICU graduates; Risk stratification of NICU graduates, Newborn Screening; Counseling parents; Screening for developmental delay by trained professionals using simple validated Indian screening tools at 4, 8, 12, 18 and 24 months; Holistic assessment of 10 NDDs at child developmental clinics (CDCs) / district early intervention centre (DEICs) by multidisciplinary team members; Confirmation of diagnosis by developmental pediatrician/developmental neurologist/child psychiatrist using clinical/diagnostic tools; Providing parent guided low intensity multimodal therapies before 3 years age as a center-based or home-based or community-based rehabilitation; Developmental pediatrician to seek guidance of pediatric neurologist, geneticist, child psychiatrist, physiatrist, and other specialists, when necessary; and Need to promote ongoing academic programs in clinical child development for capacity building of community based therapies, are the chief recommendations.

Competing Interests: Declaration of interests KB, SH, SC, PM, RP, RC-R, KM, JF, TR, HSW, and YS report support from the Wellcome Trust and the Oak Foundation for the Pathfinder Initiative. KB also reports support from the National Institute for Health and Care Research (NIHR) Centre on Non-communicable Diseases and Environmental Change (NIHR203247). RH reports a move of institution to the Wellcome Trust; however, their contribution to the Commission report was completed during their time at C40. SW, RG, and BA report support from the Wellcome Trust and the Oak Foundation for the Pathfinder Initiative and receiving other grants or contracts from the UK Energy Research Centre. RCH reports receiving support from the Wellcome Trust and the Oak Foundation for the Pathfinder Initiative and other grants or contracts from Fondation Botnar and Bernard van Leer Foundation; and reports receiving payment for consulting work from The Clean Air Fund and The Children's Investment Fund Foundation and payment as support for travel from Capita.org. AH reports support from the Wellcome Trust and the Oak Foundation for the Pathfinder Initiative; grants or contracts from the Wellcome Trust for other projects (Sustainable Healthy Food Systems and Complex Urban Systems for Sustainability and Health); payment from Cambridge University Press for the coauthored book Planetary Health; other financial or non-financial interests with the Wellcome Trust (Senior Advisor on Climate Change and Health); support for attending meetings and travel from WHO and Human Frontiers Science Program; and leadership or a fiduciary role in other board, society, committee, or advocacy groups (paid or unpaid) for the Cool Roofs trial steering committee, Burkina Faso/University of Heidelberg, the NIHR Clean-Air (Africa) Global Health Research Unit, the Collaboration for the Establishment of an African Population Cohort Consortium, the InterAcademy Partnership, Climate Change and Health working group, and the Academy of Medical Sciences/Royal Society working group on A healthy future—tackling climate change mitigation and human health together. All other authors declare no competing interests.

Background: High parenting stress (PS) in members of the general population during the COVID-19 pandemic was exacerbated by work-, family-, and child-related factors. However, the negative effects of PS on the mental health and work participation of healthcare workers (HCWs) have received limited attention. This study aimed to examine the proportion of severe PS among HCWs and identify its contributory factors., Methods: This cross-sectional survey was conducted in two COVID-19-care hospitals attached to medical colleges in India between November 1 and December 24, 2021, following the delta variant-driven second wave of COVID-19. The study recruited 662 HCW parent and child dyads (aged 1.5-18 years) and assessed workplace, family, and child-related characteristics. The Parenting Stress Scale (PSS) and Child Behavior Checklist (CBCL) were used to identify severe PS and child behavioral issues, respectively. Univariable and multivariable logistic regression analyzes were used to identify the significant and independent risk factors associated with severe PS, respectively., Results: Equal proportions of medical and paramedical HCWs completed the survey [mean age: 36.96 ± 5.89; female: 466 (70%)]. The median PSS score of HCWs was 33 [interquartile range (IQR): 28-39], and 23% (155/662) of the HCW parents experienced severe PS. The independent predictors of severe PS included the female sex [adjusted odds ratio (aOR): 3.31; 95% confidence interval (CI): 1.74-6.29], HCWs with >15-day postings in COVID-19 care (aOR: 3.74; 95% CI: 1.53-9.16), having children with behavioral issues (aOR: 3.49; 95% CI: 1.29-9.48), HCWs at the Dehradun center (aOR: 2.25; 95% CI: 1.24-4.10), having an HCW spouse simultaneously working in COVID-19 care (aOR: 1.88; 95% CI: 1.01-3.49), and HCWs with joint families (aOR: 1.93; 95% CI: 1.17-3.18)., Conclusion: Overall, 23% of the cohort of HCWs continued to experience severe PS after the second COVID-19 wave driven by the delta variant in India. Routine screening of HCWs for PS using the PSS or similar measures, anticipatory guidance for parenting, and targeting at-risk HCWs with appropriate supportive measures may help reduce the incidence of severe PS and optimize the participation of HCWs in the fight against current and future pandemic-like situations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kalrao, Srivastava and Kumar.)

Purpose: Parenting a child with special health care needs (SHCN) is often stressful. This study aimed to measure and compare stress among mothers of children with (a) Autism Spectrum Disorder (ASD) - ASD group, (b) Developmental delay without ASD group, (c) SHCN without developmental delay group, and (d) Typically developing group. To assess factors associated with maternal stress in children with developmental disorders., Methods: A cross-sectional analytical study was performed with children aged 2-12 years and their mothers. The study population was classified into four groups as defined above help of detailed history, developmental & behavioral assessments, psychological assessments, and Child Special Health Care Needs Screener (CSHCN). Parental Stress Scale (PSS) Questionnaire was administered. The main outcome measurement was the PSS and various factors affecting it., Results: The mothers of the ASD group reported a high stress score (50.4±11.4) compared to SHCN without developmental delay group (38.2±8.8) and the Typically developing group (22.3±3.3) (p < 0.05) and higher but not significant stress than Developmental delay without ASD group (45.3±9.6, p > 0.05). Maladaptive behavioral issues and irregular interventions were the factors contributing to higher parental stress in the ASD group (p < 0.05). A moderate positive correlation was observed in rewarding and challenging scores of PSS among mothers of the ASD group, Developmental delay without ASD group, and SHCN without developmental delay group., Conclusion: Mothers of the ASD group perceived higher stress as compared to SHCN without developmental delay group and Typically developing group. Evaluation of stress and stressors is crucial for holistic management of ASD.

Justification: Global developmental delay (GDD) is a relatively common neurodevelopmental disorder; however, paucity of published literature and absence of uniform guidelines increases the complexity of clinical management of this condition. Hence, there is a need of practical guidelines for the pediatrician on the diagnosis and management of GDD, summarizing the available evidence, and filling in the gaps in existing knowledge and practices., Process: Seven subcommittees of subject experts comprising of writing and expert group from among members of Indian Academy of Pediatrics (IAP) and its chapters of Neurology, Neurodevelopment Pediatrics and Growth Development and Behavioral Pediatrics were constituted, who reviewed literature, developed key questions and prepared the first draft on guidelines after multiple rounds of discussion. The guidelines were then discussed by the whole group in an online meeting. The points of contention were discussed and a general consensus was arrived at, after which final guidelines were drafted by the writing group and approved by all contributors. The guidelines were then approved by the Executive Board of IAP., Guidelines: GDD is defined as significant delay (at least 2 standard deviations below the mean with standardized developmental tests) in at least two developmental domains in children under 5 years of age; however, children whose delay can be explained primarily by motor issues or severe uncorrected visual/hearing impairment are excluded. Severity of GDD can be classified as mild, moderate, severe and profound on adaptive functioning. For all children, in addition to routine surveillance, developmental screening using standardized tools should be done at 9-12 months,18-24 months, and at school entry; whereas, for high risk infants, it should be done 6-monthly till 24 months and yearly till 5 years of age; in addition to once at school entry. All children, especially those diagnosed with GDD, should be screened for ASD at 18-24 months, and if screen negative, again at 3 years of age. It is recommended that investigations should always follow a careful history and examination to plan targeted testing and, vision and hearing screening should be done in all cases prior to standardized tests of development. Neuro-imaging, preferably magnetic resonance imaging of the brain, should be obtained when specific clinical indicators are present. Biochemical and metabolic investigations should be targeted towards identifying treatable conditions and genetic tests are recommended in presence of clinical suspicion of a genetic syndrome and/or in the absence of a clear etiology. Multidisciplinary intervention should be initiated soon after the delay is recognized even before a formal diagnosis is made, and early intervention for high risk infants should start in the nursery with developmentally supportive care. Detailed structured counselling of family regarding the diagnosis, etiology, comorbidities, investigations, management, prognosis and follow-up is recommended. Regular targeted follow-up should be done, preferably in consultation with a team of experts led by a developmental pediatrician/ pediatric neurologist.

Studies from high-income countries report associations of preeclampsia (PE) with reduced cognitive function and adverse behavioural outcomes in children. We examined these associations in Indian children aged 5-7 years. Children of mothers with PE (n=74) and without PE (non-PE; n=234) were recruited at delivery at Bharati Hospital, Pune, India. The cognitive performance was assessed using 3 core tests from the Kaufman Assessment Battery and additional tests including Verbal fluency, Kohs block design, and Coding A (from Wechsler Intelligence Scale for Children). The parent-reported Strengths and Difficulties Questionnaire (SDQ) was used to assess children's behavioral characteristics. Scores were compared between children from PE and non-PE groups, and associations analyzed further using regression models, adjusted for potential confounders. After adjusting for age, sex, socio-economic status and maternal education, children of PE mothers had lower Kohs block design scores (adjusted odds ratio per score category 0.57, [95% CI 0.34-0.96] p=0.034; 0.62 [95%CI (0.36, 1.07), p=0.09 on further adjustment for birth weight and gestation) compared to children of mothers without PE. In the SDQ, there was a lower prevalence of abnormal 'conduct problem' scores in PE group than non-PE group (OR=0.33, 95% CI 0.13-0.83, p=0.018, in the fully adjusted model); there were no differences for other behavioral domains. This preliminary study in Indian children suggests that fetal exposure to maternal PE may have an adverse impact on visuo-spatial performance but does not adversely affect behavior. Further studies with larger sample sizes are essential to understand effects of maternal PE on cognitive/behavioral outcomes in children.

Context: The pandemic has substantially increased the workload of hospital palliative care providers, requiring them to be responsive and innovative despite limited information on the specific end of life care needs of patients with COVID-19. Multi-site data detailing clinical characteristics of patient deaths from large populations, managed by specialist and generalist palliative care providers are lacking., Objectives: To conduct a large multicenter study examining characteristics of COVID-19 hospital deaths and implications for care., Methods: A multi-center retrospective evaluation examined 434 COVID-19 deaths in 5 hospital trusts over the period March 23, 2020 to May 10, 2020., Results: Eighty three percent of patients were over 70%-32% were admitted from care homes. Diagnostic timing indicated over 90% of those who died contracted the virus in the community. Dying was recognized in over 90% of patients, with the possibility of dying being identified less than 48 hours from admission for a third. In over a quarter, death occurred less than 24 hours later. Patients who were recognized to be dying more than 72 hours prior to death are most likely to have access to medication for symptom control., Conclusion: This large multicenter study comprehensively describes COVID-19 deaths throughout the hospital setting. Clinicians are alert to and diagnose dying appropriately in most patients. Outcomes could be improved by advance care planning to establish preferences, including whether hospital admission is desirable, and alongside this, support the prompt use of anticipatory subcutaneous medications and syringe drivers if needed. Finally, rapid discharges and direct hospice admissions could better utilize hospice beds and improve care., (Copyright © 2021 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Justification: Early Childhood Development (ECD) has lifelong impact on learning, education, productivity, socio-emotional functioning, health and disease. A Consensus Statement for promoting ECD is needed to improve patient care and promote research., Process: Indian Academy of Pediatrics convened a National Consultative Meeting on 20 September, 2019 at Surat to discuss the way forward for pediatricians in ECD and form a consensus advisory statement. Experts from Chapters of Infant and Young Child Feeding, Neurodevelopmental Pediatrics, Neonatology, Growth Development and Behavior, Adolescent Health Academy, Parenting for Peace and UNICEF participated., Objectives: To formulate, endorse and disseminate a consensus advisory statement of working at current levels of resources and to build future framework for ECD from Indian perspective., Conclusions: Interventions for ECD should begin from conception to adolescence, prioritized in first 3 years, inclusive and equitable for all, especially for high risk, vulnerable and marginalized families. Pediatric clinics can play a pivotal role as cost effective delivery points for guidance and interventions. Age appropriate approaches, active care giver's involvement, advocacy and integration with different sectors, community and policy makers should be done to enable supportive environment. Research should be promoted into finding cost effective novel scalable interventions.

Complement system proteins, their regulators and endpoint effector complex significantly promote tumor growth by upregulation of oncogenic growth factors, activation of mitogenic signalling pathways and breakage of normal cell cycle. Contrastingly, complement cascades, initiated by anti-tumor therapeutic antibodies, also play a pivotal role in therapy response. This contradictory role of complement system possibly be a very crucial factor for the outcomes of antibody mediated immunotherapies. Herein, we reviewed the twin role of the complement system in cancer and also the genetic variations in complement system genes. Future studies should be focused on the biomarker discovery for the personalised cancer immunotherapies., (Copyright © 2020 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Lead exposure is increasingly becoming an important risk factor for osteoporosis. In adults, approximately 80-90 % of absorbed lead is stored in the bones. These bone lead deposits are released into the blood during periods of enhanced bone resorption like menopause, forming a potential endogenous source of lead exposure. Postmenopausal women are at a higher risk for bone lead release because of hormonal and age related changes in bone metabolism. Estrogen deficiency is associated with increase in osteoclasts number and activity leading to both the early and late form of osteoporosis. Hence, high blood lead level coupled with concomitant environmental exposure exposes women in this age group to lead related adverse outcomes like hypertension, reduced kidney and neurocognitive functions as well as increased risk of atherosclerosis and cardiovascular mortality. A few studies have also identified coexisting variates like ethnicity, occupation, residence, education, smoking, alcohol medications, water etc. as significant determinants of bone and blood lead in women, thus increasing the magnitude of postmenopausal bone changes. Hence, interventions focused on reducing the intensity of bone resorption during menopause will help decrease exposure to endogenous lead. This would play a significant role in decreasing the morbidity and mortality associated with menopause. Also, identification of modifiable factors that prevent bone lead release will reduce the risk of chronic lead exposure and improve the health outcomes of post-menopausal women.

In this study, the quick, easy, cheap, effective, rugged, and safe (QuEChERS) method was applied for the analysis of the multiclass pesticide residues of 12 organochlorines (OCs), 9 organophosphates (OPs), 11 synthetic pyrethroids (SPs), 4 herbicides, 6 phthalates in raw tea (loose tea, branded tea and herbal tea), and tea infusion in 4 different containers (glass cup, earthen cup, plastic bag and disposal cup). In loose tea and branded tea residues, malathion (0.257 and 0.118 mg kg -1 ), cypermethrin (0.065 and 0.030 mg kg -1 ), and fenvalerate (0.032 and 0.030 mg kg -1 ) were detected, respectively. In herbal tea, residues of only cypermethrin (0.053 mg kg -1 ) and fenvalerate (0.045 mg kg -1 ) were detected. Tea infusion samples contained in a plastic bag were found to be contaminated with only dibutyl phthalate (DBP) (0.038 mg kg -1 ). Disposable cup was found to be contaminated with DBP (0.026 mg kg -1 ) and diethyl phthalate (DEP) (0.004 mg kg -1 ). Further, to know the processing behavior of pesticides, the spiked raw tea was subjected to tea infusion at different brewing times (2, 5, 10 min). The analysis demonstrated that dimethoate, dichlorvos, and malathion had shown more than 10 % of translocation at 5 min of brewing time. Further brewing for 10 min revealed the reduction in concentration of pesticides. Leaching of phthalate residues from different plastic containers was also studied at 10, 30, and 60 min. DBP, benzyl butyl phthalate (BzBP), and di-2-(ethylhexyl) phthalate (DEHP) were leached in the tea infusion samples packed in plastic bags. On the other hand, in disposable cups, leaching of DBP, DEP, and dimethyl phthalate were found. The concentration of phthalate residues increased with retention time. Pesticide and phthalate contaminants were recorded at low quantities in few samples only.

High-fat diet (HFD) induced obesity is associated not only with metabolic dysregulation, e.g., impaired glucose homeostasis and insulin sensitivity, but also with neurological dysfunction manifested with aberrant behavior and/or neurotransmitter imbalance. Most studies have examined HFD's effects predominantly in male subjects, either in the periphery or on the brain, in isolation and after a finite feeding period. In this study, we evaluated the time-course of selected metabolic, behavioral, and neurochemical effects of HFD intake in parallel and at multiple time points in female (C57BL/6) mice. Peripheral effects were evaluated at three feeding intervals (short: 5-6 weeks, long: 20-22 weeks, and prolonged: 33-36 weeks). Central effects were evaluated only after long and prolonged feeding durations; we have previously reported those effects after the short (5-6 weeks) feeding duration. Ongoing HFD feeding resulted in an obese phenotype characterized by increased visceral adiposity and, after prolonged HFD intake, an increase in liver and kidney weights. Peripherally, 5 weeks of HFD intake was sufficient to impair glucose tolerance significantly, with the deleterious effects of HFD being greater with prolonged intake. Similarly, 5 weeks of HFD consumption was sufficient to impair insulin sensitivity. However, sensitivity to insulin after prolonged HFD intake was not different between control, low-fat diet (LFD) and HFD-fed mice, most likely due to age-dependent decrease in insulin sensitivity in the LFD-fed mice. HFD intake also induced bi-phasic hepatic inflammation and it increased gut permeability. Behaviorally, prolonged intake of HFD caused mice to be hypoactive and bury fewer marbles in a marble burying task; the latter was associated with significantly impaired hippocampal serotonin homeostasis. Cognitive (short-term recognition memory) function of mice was unaffected by chronic HFD feeding. Considering our prior findings of short-term (5-6 weeks) HFD-induced central (hyperactivity/anxiety and altered ventral hippocampal neurochemistry) effects and our current results, it seems that in female mice some metabolic/inflammatory dysregulations caused by HFD, such as gut permeability, appear early and persist, whereas others, such as glucose intolerance, are exaggerated with continuous HFD feeding; behaviorally, prolonged HFD consumption mainly affects locomotor activity and anxiety-like responses, likely due to the advanced obesity phenotype; neurochemically, the serotonergic system appears to be most sensitive to continued HFD feeding., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Hyperhomocysteinemia (HHCY) has been demonstrated to affect cochlear microvasculature as well as cochlear epithelial cells directly, with a resultant alteration of the expression of matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). Hence, ascertaining the optimum concentration of MMPs and TIMPs in the cochlea could help to inhibit hearing loss due to HHCY by the administration of appropriate MMP inhibitors, Since infections/inflammations as well as ototoxic antibiotics have a similar mechanism of otic pathology, the cochlear damage they cause could also be similarly prevented.

The current epidemic affecting Indians is coronary artery disease (CAD), and is currently one of the most common causes of mortality and morbidity in developed and developing countries. The higher rate of CAD in Indians, as compared to people of other ethnic origin, may indicate a possible genetic susceptibility. Hence, Lp(a), an independent genetic risk marker for atherosclerosis and cardiovascular disease assumes great importance. Lp(a), an atherogenic lipoprotein, contains a cholesterol rich LDL particle, one molecule of apolipoprotein B-100 and a unique protein, apolipoprotein (a) which distinguishes it from LDL. Apo(a) is highly polymorphic and an inverse relationship between Lp(a) concentration and apo(a) isoform size has been observed. This is genetically controlled suggesting a functional diversity among the apo(a) isoforms. The LPA gene codes for apo(a) whose genetic heterogeneity is due to variations in its number of kringles. The exact pathogenic mechanism of Lp(a) is still not completely elucidated, but the structural homology of Lp(a) with LDL and plasmin is possibly responsible for its acting as a link between atherosclerosis and thrombosis. Upper limits of normal Lp(a) levels have not been defined for the Indian population. A cut off limit of 20 mg/dL has been suggested while for the Caucasian population it is 30 mg/dL. Though a variety of assays are available for its measurement, standardization of the analytical method is highly complicated as a majority of the methods are affected by the heterogeneity in apo(a) size. No therapeutic drug selectively targets Lp(a) but recently, new modifiers of apo(a) synthesis are being considered.

Background: In utero latent iron deficiency has been associated with abnormal neurodevelopmental outcomes during childhood. Its concomitant effect on auditory neural maturation has not been well studied in late preterm and term infants., Objective: The objective was to determine whether in utero iron status is associated with auditory neural maturation in late preterm and term infants., Design: This prospective cohort study was performed at Sir Ganga Ram Hospital, New Delhi, India. Infants with a gestational age ≥34 wk were eligible unless they met the exclusion criteria: craniofacial anomalies, chromosomal disorders, hemolytic disease, multiple gestation, third-trimester maternal infection, chorioamnionitis, toxoplasmosis, other infections, rubella, cytomegalovirus infection, and herpes simplex virus infections (TORCH), Apgar score <5 at 5 min, sepsis, cord blood not collected, or auditory evaluation unable to be performed. Sixty consecutive infants with risk factors for iron deficiency, such as small for gestational age and maternal diabetes, and 30 without risk factors for iron deficiency were enrolled. Absolute wave latencies and interpeak latencies, evaluated by auditory brainstem response within 48 h after birth, were measured and compared between infants with latent iron deficiency (serum ferritin ≤75 ng/mL) and infants with normal iron status (serum ferritin >75 ng/mL) at birth., Results: Twenty-three infants had latent iron deficiency. Infants with latent iron deficiency had significantly prolonged wave V latencies (7.10 ± 0.68 compared with 6.60 ± 0.66), III-V interpeak latencies (2.37 ± 0.64 compared with 2.07 ± 0.33), and I-V interpeak latencies (5.10 ± 0.57 compared with 4.72 ± 0.56) compared with infants with normal iron status (P < 0.05). This difference remained significant on regression analyses after control for confounders. No difference was noted between latencies I and III and interpeak latencies I-III., Conclusion: Latent iron deficiency is associated with abnormal auditory neural maturation in infants at ≥34 wk gestational age. This trial was registered at clinicaltrials.gov as NCT02503397., (© 2015 American Society for Nutrition.)

The milk pentasaccharide LNFPIII has therapeutic action for metabolic and autoimmune diseases and prolongs transplant survival in mice when presented as a neoglycoconjugate. Within LNFPIII is the Lewisx trisaccharide, expressed by many helminth parasites. In humans, LNFPIII is found in human milk and also known as stage-specific embryonic antigen-1. LNFPIII-NGC drives alternative activation of macrophages and dendritic cells via NFκB activation in a TLR4 dependent mechanism. However, the connection between LNFPIII-NGC activation of APCs, TLR4 signaling and subsequent MAP kinase signaling leading to anti-inflammatory activation of APCs remains unknown. In this study we determined that the innate receptor CD14 was essential for LNFPIII-NGC induction of both ERK and NFkB activation in APCs. Induction of ERK activation by LNFPIII-NGC was completely dependent on CD14/TLR4-Ras-Raf1/TPL2-MEK axis in bone marrow derived dendritic cells (BMDCs). In addition, LNFPIII-NGC preferentially induced the production of Th2 "favoring" chemokines CCL22 and matrix metalloprotease protein-9 in a CD14 dependent manner in BMDCs. In contrast, LNFPIII-NGC induces significantly lower levels of Th1 "favoring" chemokines, MIP1α, MIP1β and MIP-2 compared to levels in LPS stimulated cells. Interestingly, NGC of the identical human milk sugar LNnT, minus the alpha 1-3 linked fucose, failed to activate APCs via TLR4/MD2/CD14 receptor complex, suggesting that the alpha 1-3 linked fucose in LNFPIII and not on LNnT, is required for this process. Using specific chemical inhibitors of the MAPK pathway, we found that LNFPIII-NGC induction of CCL22, MMP9 and IL-10 production was dependent on ERK activation. Over all, this study suggests that LNFPIII-NGC utilizes CD14/TLR4-MAPK (ERK) axis in modulating APC activation to produce anti-inflammatory chemokines and cytokines in a manner distinct from that seen for the pro-inflammatory PAMP LPS. These pathways may explain the in vivo therapeutic effect of LNFPIII-NGC treatment for inflammation based diseases.

Antigen-presenting cell (APC) plasticity is critical for controlling inflammation in metabolic diseases and infections. The roles that pattern recognition receptors (PRRs) play in regulating APC phenotypes are just now being defined. We evaluated the expression of PRRs on APCs in mice infected with the helminth parasite Schistosoma mansoni and observed an upregulation of CD14 expression on macrophages. Schistosome-infected Cd14(-/-) mice showed significantly increased alternative activation of (M2) macrophages in the livers compared to infected wild-type (wt) mice. In addition, splenocytes from infected Cd14(-/-) mice exhibited increased production of CD4(+)-specific interleukin-4 (IL-4), IL-5, and IL-13 and CD4(+)Foxp3(+)IL-10(+) regulatory T cells compared to cells from infected wt mice. S. mansoni-infected Cd14(-/-) mice also presented with smaller liver egg granulomas associated with increased collagen deposition compared to granulomas in infected wt mice. The highest expression of CD14 was found on liver macrophages in infected mice. To determine if the Cd14(-/-) phenotype was in part due to increased M2 macrophages, we adoptively transferred wt macrophages into Cd14(-/-) mice and normalized the M2 and CD4(+) Th cell balance close to that observed in infected wt mice. Finally, we demonstrated that CD14 regulates STAT6 activation, as Cd14(-/-) mice had increased STAT6 activation in vivo, suggesting that lack of CD14 impacts the IL-4Rα-STAT6 pathway, altering macrophage polarization during parasite infection. Collectively, these data identify a previously unrecognized role for CD14 in regulating macrophage plasticity and CD4(+) T cell biasing during helminth infection., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Single dose of imidacloprid (IMI-20mg/kg bodyweight) was orally administered in female rats. Its disposition along with two metabolites 6-chloro nicotinic acid (6-CNA) and 6-hydroxy nicotinic acid (6-HNA) was monitored in organs (brain, liver, kidney, and ovary) and bodily fluids (blood, urine) at 6, 12, 24 and 48h and faeces at 24 and 48h. Maximum concentration (Cmax) of IMI and metabolites in each organ and bodily fluid occurred after 12h. Area under curve (AUC) of IMI ranged from 35 to 358μg/ml/h; 6-CNA: 27.12-1006.42μg/ml/h and 6-HNA: 14.98-302.74μg/ml/h in different organs and bodily fluids. Clearance rate of IMI was maximum in ovary followed by kidney, liver, brain, faeces, blood and urine. Percent inhibition of acetyl-cholinesterase (AChE) was comparable in brain and Red Blood Cells (RBC) at 6-48h which suggests the RBC-AChE as valid biomarker for assessing IMI exposure. It is evident that IMI was absorbed, metabolized, and excreted showing increased level of serum enzymes like Glutamic oxaloacetic transaminase (GOT), Glutamic pyruvic transaminase (GPT) and biochemical constituents like billirubin and Blood Urea Nitrogen (BUN) at 48h. These data suggest that IMI is widely distributed, metabolized and induced toxicology effects at 20mg/kg bodyweight to female rats., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A total of 162 samples of different varieties of mango: Deshehari, Langra, Safeda in three growing stages (Pre-mature, Unripe and Ripe) were collected from Lucknow, India, and analyzed for the presence of seventeen organophosphate pesticide residues. The QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) method of extraction coupled with gas chromatography was validated for pesticides and qualitatively confirmed by gas chromatography-mass spectrometry. The method was validated with different concentrations of mixture of seventeen organophosphate pesticides (0.05, 0.10, 0.50 mg kg(-1)) in mango. The average recovery varied from 70.20% to 95.25% with less than 10% relative standard deviation. The limit of quantification of different pesticides ranged from 0.007 to 0.033 mg kg(-1). Out of seventeen organophosphate pesticides only malathion and chlorpyriphos were detected. Approximately 20% of the mango samples have shown the presence of these two pesticides. The malathion residues ranged from ND-1.407 mg kg(-1) and chlorpyriphos ND-0.313 mg kg(-1) which is well below the maximum residues limit (PFA-1954). In three varieties of mango at different stages from unpeeled to peeled sample reduction of malathion and chlorpyriphos ranged from 35.48%-100% and 46.66%-100% respectively. The estimated daily intake of malathion ranged from 0.032 to 0.121 µg kg(-1) and chlorpyriphos ranged from zero to 0.022 µg kg(-1) body weight from three different stages of mango. The hazard indices ranged from 0.0015 to 0.0060 for malathion and zero to 0.0022 for chlorpyriphos. It is therefore indicated that seasonal consumption of these three varieties of mango may not pose any health hazards for the population of Lucknow, city, India because the hazard indices for malathion and chlorpyriphos residues were below to one.

The mechanism of alternative activation of antigen-presenting cells (APCs) is largely unknown. Lacto-N-fucopentaose III (LNFPIII) is a biologically conserved pentasaccharide that contains the Lewis(x) trisaccharide. LNFPIII conjugates and schistosome egg antigens, which contain the Lewis(x) trisaccharide, drive alternative activation of APCs and induce anti-inflammatory responses in vivo, preventing inflammation-based diseases, including psoriasis, transplant organ rejection, and metabolic disease. In this study, we show that LNFPIII conjugates and schistosome egg antigens interact with APCs via a receptor-mediated process, requiring internalization of these molecules through a clathrin/dynamin-dependent but caveolus-independent endocytic pathway. Using inhibitors/small interfering RNA (siRNA) against dynamin and clathrin, we show for the first time that endocytosis of Lewis(x)-containing glycans is required to drive alternative maturation of antigen-presenting cells and Th2 immune responses. We identified mouse SIGNR-1 as a cell surface receptor for LNFPIII conjugates. Elimination of SIGNR-1 showed no effect on uptake of LNFPIII conjugates, suggesting that other receptors bind to and facilitate uptake of LNFPIII conjugates. We demonstrate that disruption of actin filaments partially prevented the entry of LNFPIII conjugates into APCs and that LNFPIII colocalizes with both early and late endosomal markers and follows the classical endosomal pathway leading to lysosome maturation. The results of this study show that the ability of LNFPIII to induce alternative activation utilizes a receptor-mediated process that requires a dynamin-dependent endocytosis. Thus, key steps have been defined in the previously unknown mechanism of alternative activation that ultimately leads to induction of anti-inflammatory responses.

Coronary artery disease (CAD) affects Indians 5-6 years earlier than in the west, is diffuse and malignant, and poses a heavy burden on India's developing economy. Traditional risk factors have failed to explain this high incidence of premature CAD and hence this study investigated the association of two novel risk biomarkers, cystatin C and small dense LDL (sdLDL) with the presence and severity of CAD. Cystatin C and sdLDL were estimated in 204 CAD patients ≤45 years of age and compared with 161 age-matched healthy controls. The traditional lipid profile parameters, i.e., cholesterol, LDL, HDL, triglycerides, apolipoproteins A1 and B, and Lp(a) were also measured in both groups. Cystatin C was significantly raised and mean LDL particle size significantly reduced in CAD patients as compared to controls. 62.7 % of CAD patients showed pattern B while 37.3 % patients showed pattern A. Of the traditional lipid tests, only HDL and apolipoprotein A1 showed a significant decrease in the CAD group. sdLDL was significantly associated with the severity of CAD, while cystatin C was not. Both cystatin C and sdLDL emerged as independent risk factors, however, of the two, sdLDL was a more sensitive predictor of CAD events. Cystatin C and mean LDL particle size are significantly and independently associated with the presence of CAD events in patients ≤45 years with normal kidney function. Hence, these novel risk biomarkers can be useful tools in reducing the morbidity and mortality associated with CAD in the productive Indian workforce.

A national survey has shown that approximately 75-80% use of fire wood and chips, 10% of dung cake rural women in Uttar Pradesh, India. Considering the respiratory health risk of biomass fuel exposure to women, a cross sectional study was conducted to elucidate the relationship between cooking smoke and lung function impairments. The present study showed significant decline in air flow limitation based on reduced PEFR (3.69 | sec(-1)) and FEV1 (1.34 | sec(-1)) in women cooking with biomass fuels compared to PEFR (4.26 | sec(-1)) and FEV1 (1.73 | sec(-1)) in women cooking with cleaner fuels. The noxious gases and particles generated from biomass fuels during cooking reported in earlier studies may be the reason for the slight decline in airway status PEFR (3.69 | sec(-1)) and lung volumes FEV1 (1.34 | sec(-1)). The higher mean bio-fuels exposure index (52.5 hr-yrs) can attribute to reduced lung function in rural women.

A total of 250 samples-including fruits, fruit juices, and baby foods (50 samples each), vegetables (70 samples), and cereals (30 samples)-were collected from Lucknow, India, and analyzed for the presence of imidacloprid residues. The QuEChERS (quick, easy, cheap, effective, rugged, and safe) method of extraction coupled with high-performance liquid chromatographic analysis were carried out, and imidacloprid residues were qualitatively confirmed by liquid chromatography-mass spectrometry. Imidacloprid was not detected in samples of fruit juices and baby foods. It was, however, detected in 38 samples of fruits, vegetables, and cereals, which is about 15.20% of the total samples. Of samples of fruits, 22% showed the presence of imidacloprid, and 2% of samples showed residues above the maximal residue limit. Although imidacloprid was detected in 24% of vegetable samples, only 5.71% showed the presence of imidacloprid above the maximal residue limit. However, 33% of cereal samples showed the presence of imidacloprid, and about 3% of samples were above the maximal residue limit. The calculated estimated daily intake ranged between 0.004 and 0.131 µg/kg body weight, and the hazard indices ranged from 0.007 to 0.218 for these food commodities. It is therefore indicated that lifetime consumption of vegetables, fruits, fruit juices, baby foods, wheat, rice, and pulses may not pose a health hazard for the population of Lucknow because the hazard indices for imidacloprid residues were below one., (Copyright © 2012 SETAC.)

Previous work has indicated an association between seizures early in life and increased risk of psychiatric disorders, including schizophrenia. However, because early-life seizures are commonly treated with antiepileptic drugs (AEDs) such as phenobarbital, the possibility that drug treatment may affect later-life psychiatric outcomes needs to be evaluated. We therefore tested the hypothesis that phenobarbital exposure in the neonatal rat increases the risk of schizophrenia-like behavioral abnormalities in adulthood. Thus, in this study, we examined the effects of a single acute neonatal exposure to phenobarbital on adult behavioral outcomes in the rat neonatal ventral hippocampal (nVH) lesion model of schizophrenia. We compared these outcomes to those in rats a) without nVH lesions and b) with nVH lesions, without phenobarbital. The tasks used for behavioral evaluation were: amphetamine-induced locomotion, prepulse inhibition, elevated plus-maze, and novel object recognition task. We found that neonatal phenobarbital treatment (in the absence of nVH lesions) was sufficient to disrupt sensorimotor gating (as tested by prepulse inhibition) in adulthood to an extent equivalent to nVH lesions. Additionally, neonatal phenobarbital exposure enhanced the locomotor response to amphetamine in adult animals with and without nVH lesions. Our findings suggest that neonatal exposure to phenobarbital can predispose to schizophrenia-like behavioral abnormalities. Our findings underscore the importance of examining AED exposure early in life as a potential risk factor for later-life neuropsychiatric abnormalities in clinical populations., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Hyperhomocysteinemia is more commonly associated with vascular disease in Indians than in the western populations. It is caused by genetic polymorphisms or dietary deficiencies of the B vitamins. We attempted to identify the association of hyperhomocysteinemia with vitamin B(12) and folate in Indian patients of vascular disease. Homocysteine, vitamin B(12) and folate levels were estimated in 100 controls and 100 patients of vascular disease. Homocysteine estimation was repeated in 73 patients on different vitamin supplements for 6 months. Homocysteine exhibited a significant negative correlation with B(12) only in cerebrovascular disease and peripheral vascular diseasepatients, and with folate in coronary artery disease and cerebrovascular disease patients as well as controls. Single daily dose of folate was as effective as a combination of folate and cobalamin in reducing plasma homocysteine concentrations. Low levels of B(12) contribute to the higher incidence of cerebrovascular disease and peripheral vascular disease, and low folate levels account for higher prevalence of hyperhomocysteinemia in coronary artery disease and cerebrovascular disease. Moreover, irrespective of the cause of hyperhomocysteinemia, folate is known to ameliorate it. Hence, large-scale corrective measures like food fortification or dietary supplementation with folate might benefit the Indian population and reduce the incidence and morbidity of vascular disease.

Homocysteine is a sulfur-containing amino acid, which is derived from dietary methionine. Hyperhomocysteinemia has been implicated in vascular disease for over a decade now, and can be treated with B vitamins. Among its causes is polymorphism of the MTHFR gene, the most common being the cytidine to thymidine at position 677 (MTHFR C677T), which gives rise to three genotypes - normal homozygous CC, heterozygous CT and homozygous variant TT. An attempt was made to ascertain the prevalence of this MTHFR C677T in our population so that preventive measures may accordingly be instituted. Blood samples from 70 patients with vascular disease and 70 healthy controls were analyzed for plasma homocysteine levels (chemiluminescent immunoassay) and for the presence of MTHFR C677T (polymerase chain reaction analysis). Homocysteine was higher in the homozygous subjects (TT genotype) than in the heterozygous (CT genotype). In patients, the frequency of the C allele was significantly lower, and that of the T allele was significantly higher than the corresponding frequencies in controls. In conclusion, the North Indian urban population has higher homocysteine levels associated with the TT genotype. Hence, instituting measures towards reduction of homocysteine levels in the population would probably reduce the incidence and morbidity of vascular disease in our population.

Helminth parasites bias host CD4(+) T helper (Th) cells toward Th2 responses, drive alternative activation of macrophages, and expand T regulatory cells. Helminth-expressed carbohydrates play critical roles in driving much of this immune cell biasing. Studies on helminth glycans have focused on Lewis X, LDN, LDN-DF, other fucosylated structures, chitin, tyvelose, and trehalose, which interact with host antigen presenting cells (APCs) minimally via C-type lectins and/or Toll-like receptors (TLR). Here, we review recent findings on helminth glycan activation of APCs via C-type lectin/TLRs and introduce the concept that glycosylated helminth molecules require endocytosis to function as immune modulators. Second, we describe unpublished data showing that in vivo glycoconjugates comprising multiple copies of glycans on carriers are directly immune modulatory. Lastly, we discuss the observation that CD14 negatively regulates alternative activation of APCs during helminth infection. We close with a discussion on the use of immune modulatory glycans as vaccine adjuvants and as antiinflammatory therapeutics., (© 2012 New York Academy of Sciences.)

Technical imidacloprid was evaluated for its effect on ovarian morphology, hormones and antioxidant enzymes in female rats after 90 days oral exposure. Luteinizing hormone (LH), follicle stimulating hormone (FSH) and progesterone levels were estimated in serum of rats and activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and level of reduced glutathione (GSH) and lipid peroxidation (LPO) were estimated in ovary after oral administration of imidacloprid (5, 10, and 20mg/kg/day) for 90 days. Decreased ovarian weight together with significant patho-morphological changes in follicles, antral follicles and atretic follicles were observed at 20mg/kg/day. Imidacloprid at 5 and 10mg/kg/day has not produced any significant changes in ovarian morphology, hormones and antioxidant status of ovary. However 20mg/kg/day dose has produced significant alterations in the levels of LH, FSH and progesterone. Similarly significant changes in SOD, CAT, GPx, GSH, and LPO were observed at 20mg/kg/day dose level. Therefore, it is concluded that imidacloprid at 20mg/kg/day dose level has produced significant toxicological impact on ovary of female rats as evident by pathomorphological changes, hormonal imbalance and generating oxidative stress and can be considered primarily as Lowest Observed Effect Level (LOEL) for chronic study., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The use of pesticides on cash crops and exportable food commodities had always been a serious concern. Fruits form one of the important constituents of human diet, in that they give one third of the requirement of calories, vitamins, and minerals. This study has been carried out to determine the level of organochlorine pesticides namely HCH, DDT and Endosulfan in raw fruit nuts. Nuts have proteins and high level of fat content. These properties of nuts attract organochlorine pesticides to accumulate. The analysis of organochlorine pesticide residues in commonly used dry fruits like Cashewnut, Walnut, Coconut, Chilgoza, Chironji, Makhana, Resins, Apricot, Almonds, Date palm, Pistachio nut collected from local market of Lucknow India has indicated presence of very low level of HCH (0.007-1.328 mg kg(-1)), DDT(ND-0.140 mg kg(-1)) and Endosulfan (ND-0.091 mg kg(-1)). There are no MRL values established for nuts in the country. This finding is based on a smaller number of samples, which however suggest that the presence of low level of DDT, HCH and Endosulfan might be due to environmental rather than direct exposure.

Biogenesis of eukaryotic ribosomes requires a number of RNA helicases that drive molecular rearrangements at various points of the assembly pathway. While many ribosome synthesis factors are conserved among all eukaryotes, certain features of ribosome maturation, such as U8 snoRNA-assisted processing of the 5.8S and 28S rRNA precursors, are observed only in metazoan cells. Here, we identify the mammalian DEAD box helicase family member Ddx51 as a novel ribosome synthesis factor and an interacting partner of the nucleolar GTP-binding protein Nog1. Unlike any previously studied yeast helicases, Ddx51 is required for the formation of the 3' end of 28S rRNA. Ddx51 binds to pre-60S subunit complexes and promotes displacement of U8 snoRNA from pre-rRNA, which is necessary for the removal of the 3' external transcribed spacer from 28S rRNA and productive downstream processing. These data demonstrate the emergence of a novel factor that facilitates a pre-rRNA processing event specific for higher eukaryotes.

A 90 days oral toxicity study of imidacloprid was conducted in female rats with doses of 0, 5, 10, 20mg/kg/day. Decrease in the body weight gain was observed at 20mg/kg/day and at necropsy the relative body weights of liver, kidney and adrenal was also significantly increased at this dose level. No mortality occurred during treatment period while food intake was reduced at high dose level. In clinical chemistry parameters high dose of imidacloprid has caused significant elevation of serum GOT, GPT, glucose and BUN and decreased the activity of AChE in serum and brain. The spontaneous locomotor activity was also decreased at highest dose exposure where as there were no significant changes in hematological and urine parameters. The brain, liver and kidney of rats exposed with high dose of imidacloprid had showed mild pathological changes. Based on the morphological, biochemical, hematological and neuropathological studies it is evident that imidacloprid has not produced any significant effects at 5 and 10mg/kg/day doses but induced toxicological effects at 20mg/kg/day to female rats. Hence, 10mg/kg/day dose may be considered as no observed effect level (NOEL) for female rats., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Most transcripts in growing cells are ribosomal RNA precursors (pre-rRNA). Here, we show that in mammals, aberrant pre-rRNA transcripts generated by RNA polymerase I (Pol I) are polyadenylated and accumulate markedly after treatment with low concentrations of actinomycin D (ActD), which blocks the synthesis of full-length rRNA. The poly(A) polymerase-associated domain-containing protein 5 is required for polyadenylation, whereas the exosome is partly responsible for the degradation of the short aberrant transcripts. Thus, polyadenylation functions in the quality control of Pol I transcription in metazoan cells. The impact of excessive aberrant RNAs on the degradation machinery is an unrecognized mechanism that might contribute to biological properties of ActD.

Resurgence of multidrug resistant tuberculosis has lead to demand for rapid susceptibility testing. Conventional methods take > 3 weeks and are tedious. Automated methods have superseded them for first line drug susceptibility testing. An attempt was made to standardize first and second line susceptibility testing using the BacT Alert 3D system (Biomerieux). And compare results with Lowenstein Jensen's (LJ) method. 121 isolates of Mycobacterium tuberculosis, 67 pulmonary and 54 extra pulmonary were subjected to sensitivity to first and second line drugs. Multidrug resistance was detected equally by both methods at 15.7%. 100% agreement was observed between the two methods for aminoglycosides, rifampicin, ethionamide and ciprofloxacin. 91.5% agreement was observed for isoniazid, 85% for pyrazinamide and 72.4% for ethambutol. The time taken by LJ method was 18-32 days and BacT Alert 3D system took 4-12 days. In the lesser developed nations where tuberculosis is rampant a rapid effective method for confirming multidrug resistant tuberculosis is definitely desirable and the BacT Alert 3D system was found an effective method when compared to the 'gold standard' LJ proportion.

Rationale: Early environment can shape the development and function of the mesocorticolimbic dopamine (DA) system and represents a possible risk factor for adult pathologies. One critical variable in the early environment is nutrition, and exposure to high fat (HF) in adulthood is known to change this DA system., Objectives: We tested whether perinatal HF intake in rats could have long-term effects on DA function and behavior in adult offspring., Materials and Methods: Rat dams were fed either a control (5% fat, CD) or high fat (30% fat, HF) diet during the last week of gestation and lactation, and adult offspring were tested (PND 56-90) after weaning on CD. Locomotor responses to acute and repeated doses of D: -amphetamine (AMP, 0.75 mg/kg bw) were determined as were indices of DA function in the ventral tegmental area (VTA), nucleus accumbens (NAc), and the prefrontal cortex (PFC)., Results: Adult HF offspring displayed increased tyrosine hydroxylase expression in the VTA and NAc and significant increases in DA and DOPAC content in the NAc, suggesting an elevated DA tone in this target field. In the NAc, there were no significant changes in D1, D2 receptors, or DA transporter (DAT) levels between diet groups. Perinatal HF feeding reduced AMP-induced locomotion and behavioral sensitization to AMP, suggesting that early diet might have caused long-lasting desensitization of postsynaptic receptor mechanisms in the NAc., Conclusions: Our results demonstrate that both synthetic activity in VTA neurons and the responsiveness of accumbens DA neurons is altered by maternal nutrition. These effects subside long after termination of exposure to the HF diet.

Extracellular human granulocyte-macrophage colony stimulating factor (hGM-CSF) expression was studied under the control of the GAP promoter in recombinant Pichia pastoris in a series of continuous culture runs (dilution rates from 0.025 to 0.2 h(-1)). The inlet feed concentration was also varied and the steady state biomass concentration increased proportionally demonstrating efficient substrate utilization and constancy of the biomass yield coefficient (Y(x/s)) for a given dilution rate. The specific product formation rate (q(P)) showed a strong correlation with dilution rates demonstrating growth associated product formation of hGM-CSF. The volumetric product concentration achieved at the highest feed concentration (4x) and a dilution rate of 0.2 h(-1) was 82 mg l(-1) which was 5-fold higher compared to the continuous culture run with 1x feed concentration at the lowest dilution rate thus translating to a 40 fold increase in the volumetric productivity. The specific product yield (Y(P/X)) increased slightly from 2 to 2.5 mg g(-1), with increasing dilution rates, while it remained fairly invariant, for all feed concentrations demonstrating negligible product degradation or feed back inhibition. The robust nature of this expression system would make it easily amenable to scale up for industrial production.

We investigated the cellular and subcellular distributions of neuregulin tyrosine kinase receptor ErbB4 in the postnatal rat frontal cortex and hippocampus by light-, confocal- and electron-microscopic immunocytochemistry. At birth, ErbB4-immunoreactivity (ErbB4-IR) was prominent in the apical cytoplasm and dendrites of cortical plate neurons and hippocampal pyramidal cells. Throughout postnatal development and in adulthood, ErbB4-IR in both regions remained confined to the somatodendritic compartment of neurons, which increased in number to reach the adult pattern by the end of the first postnatal month (P30). At all ages examined, double-labeling experiments revealed that ErbB4-IR always co-localized with the neuronal marker neuronal nuclei (NeuN) and never with glial markers Nestin or glial fibrillary acidic protein (GFAP). Immunoperoxidase labeling at the ultrastructural level confirmed the exclusive localization of ErbB4-IR in somatodendrites, and notably in dendritic spines. Immunogold labeling showed preponderant ErbB4-IR in the cytoplasm, where it was associated with microtubules. Furthermore, ErbB4-IR was abundant in the nucleus of adult cortical and hippocampal neurons, suggesting a role for ErbB4 nuclear signaling in the brain beyond embryonic development. Taken together, these results show that ErbB4 is expressed by neuronal somatodendrites in cerebral cortex and hippocampus from birth to adulthood, and support a role for neuregulins in dendritic growth and plasticity.

The notion that oxidation of lipids and propagation of free radicals may contribute to the pathogenesis of atherosclerosis is supported by a large body of evidence. To circumvent the damage caused by oxygen free radicals, antioxidants are needed which provide the much needed neutralization of free radical by allowing the pairing of electrons. In this study we have investigated the effect of ascorbic acid, a water soluble antioxidant on the development of hypercholesterolemia induced atherosclerosis in rabbits. Rabbits were made hypercholesterolemic and atherosclerotic by feeding 100 mg cholesterol/day. Different doses of ascorbic acid were administered to these rabbits. Low dose of ascorbic acid (0.5 mg/100 g body weight/day) did not have any significant effect on the percent of total area covered by atherosclerotic plaque. However, ascorbic acid when fed at a higher dose (15 mg/100 g body weight/day) was highly effective in reducing the atherogenecity. With this dose the percent of total surface area covered by atherosclerotic plaque was significantly less (p < 0.001). This suggests that use of ascorbic acid may have great promise in the prevention of hypercholesterolemia induced atherosclerosis.

The spectrum of candidiasis has changed with the emergence of non-albicans Candida spp. and acquired antifungal resistance, especially in immunocompromised hosts. This changing scenario has necessitated routine antifungal susceptibility testing. In the present work, 102 Candida spp. isolates gathered during 2003 - 2004 were characterized by standard procedures, and antifungal susceptibility testing to amphotericin B, fluconazole and itraconazole was performed by broth macrodilution (BMD)-minimum inhibitory concentration (MIC) and disk diffusion (DD) methods. Among all isolates, 77.4% were from an ICU and 10.8% were obtained from a nursery. The majority of the isolates were C. tropicalis (48%), followed by C. parapsilosis (27.4%) and C. albicans (22.5%). Overall 6.9, 4.9 and 3.9% of all isolates were resistant to amphotericin B, fluconazole and itraconazole, respectively. Out of the 5 (4.9%) isolates resistant to fluconazole, 4 (3.9%) were from patients with AIDS on fluconazole prophylaxis. A discrepancy was observed between the results of susceptibility testing by DD and those by BMD-MIC: 15 (14.7%) isolates were reported to be resistant by DD despite having low MICs. Based on these results, it was concluded that initial antifungal screening of clinical isolates by the DD method followed by confirmation of resistant strains by the broth dilution method is desirable to optimize patient management.

128 isolates of Acinetobacter species from admitted and outdoor patients were subjected to biotyping and resistotyping. Resistance phenotype analysis included nine antibiotics and two betalactam inhibitor combination drugs. In 100 strains of Acinetobacter spp. ciprofloxacin, amikacin, cefotaxime and cefepime minimum inhibitory concentration (MIC) was done by agar dilution using NCCLS 2002 criteria. In forty-nine isolates MIC level was determined by E-strip also. Extended spectrum beta lactamase (ESBL) production was detected by double disc synergy technique. Inducible beta lactamases (IBL's) were detected by disc approximation method. The relationship between biotypes and resistance phenotype was analyzed. Majority of isolates (93.75%) were from admitted patients. The biotyping revealed Acinetobacter calcoaceticus-Acinetobacter baumannii complex (87.2%) to be the predominant species and they were isolated from tracheal aspirates of patients with ventilator associated pneumonia. By Kirby Bauer disc diffusion antimicrobial sensitivity testing Acinetobacter spp. were most sensitive to the combination of drug cefoperazone-sulbactam (95.6%) followed by meropenem (94.6%), piperacillin-tazobactam (92.6%). On screening incidence of Imipenem Nonsensitive Acinetobacter spp. (INSA) was (5.4%). Acinetobacter spp. were typable by six resistance phenotypes and six biotypes. Most common (66.6%) resistant phenotype of A. calcoaceticus-A. baumannii complex was susceptible to cefoperazone-sulbactam and or meropenem and or piperacillin-tazobactam. ESBL production was seen in 6% and IBL (Inducible Beta Lactamase) production was seen in 7% of Acinetobacter spp. The MIC90 for ciprofloxacin was =256 microg/ml, cefotaxime 512 microg/ml, cefepime 512 microg/ml, and amikacin 32 microg/ml. Multidrug resistance was seen in more than 90% of A. calcoaceticus-A. baumannii complex and 20% of Acinetobacter lwoffii. Acinetobacter spp. has other emerging novel mechanism of resistance that requires continuous research. Simpler, reproducible and reliable methods of biotyping and their subsequent correlation with resistotyping are more cost effective than molecular methods, which are available only in reference laboratories.

Biotechnology in India has made great progress in the development of infrastructure, manpower, research and development and manufacturing of biological reagents, biodiagnostics, biotherapeutics, therapeutic and, prophylactic vaccines and biodevices. Many of these indigenous biological reagents, biodiagnostics, therapeutic and prophylactic vaccines and biodevices have been commercialized. Commercially when biotechnology revenue has reached $25 billions in the U.S. alone in 2000 excluding the revenues of biotech companies that were acquired by pharmaceutical companies, India has yet to register a measurable success. The conservative nature and craze of the Indian Industry for marketing imported biotechnology products, lack of Government support, almost non-existing national healthcare system and lack of trained managers for marketing biological and new products seem to be the important factors responsible for poor economic development of biotechnology in India. With the liberalization of Indian economy, more and more imported biotechnology products will enter into the Indian market. The conditions of internal development of biotechnology are not likely to improve in the near future and it is destined to grow only very slowly. Even today biotechnology in India may be called to be in its infancy.

Neonatal ventral hippocampal (nVH) lesions in rats result in adult onset of a number of behavioral and cognitive abnormalities analogous to those seen in schizophrenia, including hyperresponsiveness to stress and psychostimulants and deficits in working memory, sensorimotor gating and social interaction. Molecular and neurochemical alterations in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) of nVH-lesioned animals suggest developmental reorganization of these structures following neonatal lesions. To determine whether nVH lesions lead to neuronal morphological changes, we investigated the effect of nVH lesion on dendritic structure and spine density of pyramidal neurons of the PFC and medium spiny neurons of the NAcc. Bilateral ibotenic acid-induced lesion of the VH was made in Sprague-Dawley pups at postnatal day 7 (P7); and at P70, neuronal morphology was quantified by modified Golgi-Cox staining. The results show that length of basilar dendrites and branching and the density of dendritic spines on layer 3 pyramidal neurons were significantly decreased in rats with nVH lesions. Medium spiny neurons from the NAcc showed a decrease in the density of dendritic spines without significant changes in dendritic length or arborization. The data, comparable to those observed in the PFC of schizophrenic patients, suggest that developmental loss of excitatory projections from the VH may lead to altered neuronal plasticity in the PFC and the NAcc that may contribute to the behavioral changes in these animals.

Background & Objectives: Tuberculosis continues to be a major public health problem in India, especially with the emergence of drug resistance. A study was carried out to establish a rapid and accurate method of susceptibility testing for Mycobacterium tuberculosis using three methods viz., proportion method by agar dilution on Middlebrook 7H11 agar, proportion method using the conventional Lowenstein-Jensen (L-J) medium and E test strip method., Methods: A total of seventy five clinical isolates from pulmonary and extrapulmonary sites were characterised and speciated by biochemical tests, growth and other standard parameters, and eight random isolates, also by polymerase chain reaction (PCR). Antimicrobial susceptibility of M.tuberculosis was performed by proportion method on L-J medium and Middlebrook 7H11 agar medium for isoniazide (INH), rifampicin (RIF), ethambutol (EMB), streptomycin (STM) and ciprofloxacin (CIP) using recommended critical concentrations. The two methods were compared with the E test method., Results: The 75 M.tuberculosis strains were isolated from sputum (47), pus (23), aspirate fluid (2), skin tissue (2) and gastric aspirate (1). Of these 49 (65.3%) isolates were sensitive and one (1.3%) was resistant to all the five drugs tested and by all the three methods. Eleven (14.7%) isolates were resistant to INH alone by the three methods. The E test method detected one isolate resistant to INH and 2 to RIF which were missed by the other two methods. The results obtained by all the three methods compared well., Interpretation & Conclusion: The three methods viz., proportion methods with L-J, Middlebrook 7H11 agar and the E test concurred fully in 57 isolates (76%). Association between L-J and Middlebrook 7H11 agar methods was 59 per cent. E test and the L-J methods did not differ significantly for all the drugs. The finding show that the E test method is superior to the other two methods in terms of simplicity of performance and the rapidity of results. Another advantage is that the MIC values can also be obtained simultaneously by this method.

Various population studies have reported the association of rare S2 allele of apolipoprotein C3 (APOC3) SstI polymorphism with hypertriglyceridemia (HTG) and coronary artery disease (CAD). We were the first to report an association of S2 allele with high triglyceride (TG) levels in healthy volunteers from Northern India. Since HTG is suggested to be a predominant risk factor for CAD among Indians, we have elucidated the relationship of APOC3 SstI polymorphism with the lipid profile and CAD. A total of 158 patients with > or = 70% stenosis in one or more coronary artery (angiographically proven CAD patients), 35 subjects with < 70% stenosis (NCAD) and 151 normal controls (free of heart disease) from Northern plains of India were recruited in the study. DNA samples were analyzed by polymerase chain reaction (PCR) followed by SstI digestion. Lipid profile was estimated by enzymatic kit. We found a strong association of S2 allele with high TG levels, which was more significant in patients. Prevalence of S2 allele in normal controls and CAD patients were comparable, despite the fact that mean TG level was significantly higher in patients. A greater insight into this observation revealed that the prevalence of high TG, if not coupled with other risk factors (like high total cholesterol, low HDL), was comparable in patients and controls. Thus, our study reveals that rare S2 allele may be employed as a susceptibility marker for high TG. However, high TG or S2 allele alone may not contribute to the etiology of CAD.

The decline in the levels of erythrocyte complement receptor 1 (ECR1) in systemic lupus erythematosus (SLE) has been widely reported. The most probable cause for this decline is excessive proteolytic shedding of CR1 from the cell surface. Similarly a decline in glomerular CR1 (GCR1) has also been reported in SLE. Because CR1 is excreted in urine it is imperative to study the relationship of urinary CR1 (uCR1) with ECR1 and GCR1, and their overall correlation with disease activity. We have determined the levels of uCR1, ECR1 and GCR1 in SLE patients and compared them with normal controls and minimal change disease (MCD) patients. We found a significant decline in both uCR1 and GCR1 in SLE but not in MCD; levels of uCR1 in MCD were either comparable to those of controls or higher. Immunofluorescence for GCR1 was very high in MCD. We did not find any correlation between ECR1, uCR1 and kidney function tests on divariate scatter analyses. The correlation coefficient for uCR1 and GCR1 was highly significant and positive. Our findings thus suggest that uCR1 reflects the levels of GCR1 expression, which decline drastically in SLE. Therefore we envisage uCR1 as a potential marker for glomerular involvement in SLE.

Homocysteine (Hcy) is a non-protein forming amino-acid, whose metabolism is at the intersection of two metabolic pathways: remethylation and transsulfuration which are dependent on the vitamins folic acid, B(12) and B(6), and the enzymes methylenetetrahydrofolate reductase and cystathionine-β-synthetase. A deficiency of any of these vitamins or enzymes results in hyperhomocysteinemia. This causes oxidative and other damage to blood vessels, thus affecting various organ systems of the body. As part of our ongoing research on cardiovascular risk factors, we have studied the Hcy levels in the plasma of normal controls and those suffering from vascular diseases. It was observed that Hcy is significantly higher in patients of vascular diseases (21.59±1.28 μmol/L, mean±SEM), as compared to normal controls (11.33±0.18 μmol/L). This significance, was more pronounced in cases of venous thrombosis (26.77±2.43 μmol/L) as opposed to cases of arterial block (17.27±0.84 μmol/L). This signifies that Hcy estimation would be beneficial in obtaining a differential diagnosis in addition to being a modifiable vascular risk factor.

Several studies including a small case-control (hypertriglyceridemic/normotriglyceridemic individuals) study by us revealed close association between rare S2 allele ofAPOC3 Sstl polymorphism and hypertriglyceridemia. With the understanding that Asian Indians are highly vulnerable to the adverse effects of hypertriglyceridemia, we extended the investigation and studied the frequency distribution of this polymorphism in 216 healthy volunteers from Northern plains of India. We found that more than 50% of the study population had one or two S2 allele. This may suggest that a larger fraction of this population is genetically predisposed to hypertriglyceridemia.