Targeted therapy of cognitive deficits in fragile X syndrome.

Breaking an impasse in finding mechanism-based therapies of neuropsychiatric disorders requires a strategic shift towards alleviating individual symptoms. Here we present a symptom and circuit-specific approach to rescue deficits of reward learning in Fmr1 knockout mice, a model of Fragile X syndrome (FXS), the most common monogenetic cause of inherited mental disability and autism. We use high-throughput, ecologically-relevant automated tests of cognition and social behavior to assess effectiveness of the circuit-targeted injections of designer nanoparticles, loaded with TIMP metalloproteinase inhibitor 1 protein (TIMP-1). Further, to investigate the impact of our therapeutic strategy on neuronal plasticity we perform long-term potentiation recordings and high-resolution electron microscopy. We show that central amygdala-targeted delivery of TIMP-1 designer nanoparticles reverses impaired cognition in Fmr1 knockouts, while having no impact on deficits of social behavior, hence corroborating symptom-specificity of the proposed approach. Moreover, we elucidate the neural correlates of the highly specific behavioral rescue by showing that the applied therapeutic intervention restores functional synaptic plasticity and ultrastructure of neurons in the central amygdala. Thus, we present a targeted, symptom-specific and mechanism-based strategy to remedy cognitive deficits in Fragile X syndrome.

Epidemiology of cancers among older adults in India: findings from the National Cancer Registry Programme.

OBJECTIVE: This study describes the epidemiology, clinical extent of disease at diagnosis and treatment modalities of cancer among older adults (aged 60 years and older) in India. STUDY DESIGN: Secondary data analysis of the National Cancer Registry Programme, which includes 28 Population-Based Cancer Registries (PBCRs) and 96 Hospital-Based Cancer Registries (HBCRs). METHODS: PBCR data were used to estimate the incidence in terms of crude rate (CR), age-adjusted incidence rate (AAR), age-specific rate (ASpR) and cumulative risk. Trends in the AAR were calculated with the Annual Percentage Change (APC) using join-point regression. HBCR data were used to describe the clinical extent of the disease at diagnosis and the treatment modalities. RESULTS: There is a wide heterogeneity across the country for the incidence of cancer and for the leading cancer sites among older adults. Males had a higher incidence rate compared to females in the majority of the registries. Aizawl had the highest AARs among both genders (males: 1388.8; females: 1033.0). Females had the highest ASpR at 65-69 years (482.8), whereas for males it was above 75 years (710.4). Cervical, stomach and oesophageal cancers were on the decline. The incidence of cancer among older adults was estimated to increase by 13.5% in 2025 as compared to 2020. CONCLUSION: The increasing cancer incidence among older adults in India poses a huge burden on the health system. There is a need to increase their participation in clinical trials, advocating comprehensive geriatric assessment and strengthening geriatric oncology within programs addressing older adult's care to deal with the rising cancer burden on the health system borne by them.

A comparative study of the informed consent process with or without audiovisual recording.

BACKGROUND.: The Central Standard Drugs Control Organization (CDSCO) issued an administrative order in November 201 3 mandating audiovisual (AV) recording of the informed consent process for all regulatory studies. At this point, a phase 2/3 trial ongoing at our centre had recruited 45 participants using the written, informed consent process. Another 40 participants were recruited after the order and underwent AV recording of the consent process. We assessed the difference in participants' understanding between the two consenting processes as the trial fortuitously had both forms of consent. METHODS.: A 16-item questionnaire with six domains (purpose, study procedures, risks, benefits, payment for participation, and rights and confidentiality) was designed and validated. It was administered to the participants after approval of the institutional ethics committee and written informed consent. Answers given were matched with a template of model answers. The responses were scored as fully correct (3), partially correct (2), 'don't remember' (1 ), and incorrect (0) with a total possible score of 48. Between-group analysis was done for total scores and domain-specific scores. Domain-wise analysis was done for the proportion of all categories of responses. The impact of potential confounders on participants' understanding was also factored in. RESULTS.: A total of 38 respondents-21 in the AV consent group and 1 7 in the written consent group-agreed to participate. The total mean (SD) score of the AV consent group was significantly higher (40.3 [5.9]) compared to that of the written consent group (34.8 [7.94]; p = 0.01). Between the groups the score was significant in the domains of rights and confidentiality (p = 0.01). The proportion of participants who gave fully correct answers was statistically significant in the domain of purpose (p = 0.04). The time elapsed between the original consent and this study showed a weak inverse correlation (ρ = -0.3, p = 0.01). CONCLUSION.: AV recording of the informed consent process in a clinical trial appears to improve the understanding of participants relative to the written informed consent alone.

Sternocleidomastoid Abscess Mimicking a Thyroid Swelling in a Young Female.

Primary pyomyositis is a bacterial infection of skeletal muscle with acute or subacute clinical course. This usually present with localized abscess.We report a case of an 18 years old female presenting with swelling in midline of neck moving with deglutition mimicking a thyroid swelling. On further investigation patient was confirmed to have sternocleidomastoid myositis. Previous case reports have showed various etiologies for development of abscess. After thorough examination and investigations, patient was found to have an idiopathic sternocleidomastoid abscess which responded well to empirical antibiotic therapy.This is a very uncommon condition and very sparsely reported and so far, to the best of our knowledge there is no case report from India.

Kyrle's Disease: A Rare Skin Manifestation of Diabetes Mellitus.

Kyrle's disease is a rare skin disorder which is characterized by hyperkeratotic papules and nodules with a central keratotic plug mostly located in lower limbs. Exact etiology of Kyrle's disease is unknown, but its association has been reported sparsely with renal disorders, uremic patients on dialysis, diabetes mellitus, liver disease and paraneoplastic syndromes, tuberculosis and some fungal diseases. We report Kyrle's disease in a middle aged female suffering from diabetes mellitus with diabetic nephropathy on hemodialysis.

Ebstein's Anomaly with Various Unexplained Arrhythmias in a 57-Year Old Man.

There are very few congenital cardiac disease which may remain asymptomatic up to adulthood, Ebstein's anomaly is one of them. With rapid advancement in the field of echocardiography many new cases identified in day-to-day practice. Timely surgical intervention in these cases may distinct survival advantage. We present a case of Ebstein's anomaly of adult age group which is seen with typical manifestation and seen in less than 5% cases.

Impact assessment of on-site sanitation system on groundwater quality in alluvial settings: A case study from Lucknow city in North India.

The present case study has been undertaken to investigate the impact of on-site sanitation on groundwater quality in alluvial settings in Lucknow City in India. The groundwater samples have been collected in the areas of Lucknow City where the on-site sanitation systems have been implemented. The groundwater samples have been analyzed for the major physicochemical parameters and fecal coliform. The results of analysis reveal that none of the groundwater samples exceeded the Bureau of Indian Standards (BIS) limits for all the parameters. Fecal coliform was not found in majority of the samples including those samples which were very close to the septic tank. The study area has a thick alluvium cover as a top layer which acts as a natural barrier for groundwater contamination from the on-site sanitation system. The t test has been performed to assess the seasonal effect on groundwater quality. The statistical t test implies that there is a significant effect of season on groundwater quality in the study area.

Risk factors for chronic hepatitis B virus infection among blood donors in Bangalore, India.

OBJECTIVES AND AIM: We performed a study of hepatitis B virus (HBV) risk factors among blood donors in Bangalore, India. BACKGROUND: HBV infection is prevalent in India and poses a potential risk of transmission by blood transfusion, but studies of risk factors for hepatitis B surface antigen (HBsAg) carriage among Indian blood donors are lacking. METHODS/MATERIALS: Using a case-cohort design, we enrolled 71 cases with repeatedly reactive HBsAg results and a cohort of 212 contemporaneous blood donors with unknown HBsAg status. Questionnaire data were analysed using multivariable logistic regression. RESULTS: In our multivariate analysis controlling for age, HBsAg positivity was associated with repeat donor status (OR = 0·34, 95% CI 0·17-0·71 vs first-time donor status), residence outside Bangalore and Hosur (rural areas) (OR = 15·66, 95% CI 3·60-68·07vs Bangalore residence), having been a customer at a local barber shop (OR = 4·07, 95% CI 2·06-8·03), close contact with a person who had jaundice (OR = 13·64, 95% CI 3·71-50·24) and cigarette smoking (OR = 3·25, 95% CI 1·39-7·60). CONCLUSION: In addition to recognised demographic risk factors, associations with patronage of local barbers and contact with jaundiced individuals suggest behavioural risk factors that could be adopted as exclusionary criteria for blood donation in India.

Assessing the water quality index of water treatment plant and bore wells, in Delhi, India.

Water quality monitoring exercise was carried out with water quality index (WQI) method by using water characteristics data for bore wells and a water treatment plant in Delhi city from December 2006 to August 2007. The water treatment plant received surface water as raw water, and product water is supplied after treatment. The WQI is used to classify water quality as excellent, good, medium, bad, and very bad. The National Sanitation Foundation WQI procedure was used to calculate the WQI. The index ranges from 0 to 100, where 100 represents an excellent water quality condition. Water samples were collected monthly from a bore well in Nehru Camp (site 1), a bore well in Sanjay Gandhi pumping station (site 2), and water treatment plant in Haiderpur (site 3). Five parameters were analyzed, namely, nitrate, pH, total dissolved solids, turbidity, and temperature. We found that the WQI was around 73-80 in site 3, which corresponds to "good," and it decreased to 54.32-60.19 and 59.93-70.63 in site 1 and site 2, respectively, indicating that these bore wells were classified as "medium" quality.

Evidence that TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates constitutive NF-kappaB activation and proliferation in human head and neck squamous cell carcinoma.

Constitutively activated nuclear factor-kappaB (NF-kappaB) has been associated with a variety of aggressive tumor types, including head and neck squamous cell carcinoma (HNSCC); however, the mechanism of its activation is not fully understood. Therefore, we investigated the molecular pathway that mediates constitutive activation of NF-kappaB in a series of HNSCC cell lines. We confirmed that NF-kappaB was constitutively active in all HNSCC cell lines (FaDu, LICR-LON-HN5 and SCC4) examined as indicated by DNA binding, immunocytochemical localization of p65, by NF-kappaB-dependent reporter gene expression and its inhibition by dominant-negative (DN)-inhibitory subunit of NF-kappaB (IkappaBalpha), the natural inhibitor of NF-kappaB. Constitutive NF-kappaB activation in HNSCC was found to be due to constitutive activation of IkappaBalpha kinase (IKK); and this correlated with constitutive expression of phosphorylated forms of IkappaBalpha and p65 proteins. All HNSCC showed the expression of p50, p52, p100 and receptor-interacting protein; all linked with NF-kappaB activation. The expression of constitutively active NF-kappaB in HNSCC is mediated through the tumor necrosis factor (TNF) signaling pathway, as NF-kappaB reporter activity was inhibited by DN-TNF receptor-associated death domain (TRADD), DN-TNF receptor-associated factor (TRAF)2, DN-receptor-interacting protein (RIP), DN-transforming growth factor-beta-activated kinase 1 (TAK1), DN-kappa-Ras, DN-AKT and DN-IKK but not by DN-TRAF5 or DN-TRAF6. Constitutive NF-kappaB activation was also associated with the autocrine expression of TNF, TNF receptors and receptor-activator of NF-kappaB and its ligand in HNSCC cells but not interleukin (IL)-1beta. All HNSCC cell lines expressed IL-6, a NF-kappaB-regulated gene product. Furthermore, treatment of HNSCC cells with anti-TNF antibody downregulated constitutively active NF-kappaB, and this was associated with inhibition of IL-6 expression and cell proliferation. Our results clearly demonstrate that constitutive activation of NF-kappaB is mediated through the TRADD-TRAF2-RIP-TAK1-IKK pathway, making TNF a novel target in the treatment of head and neck cancer.

Rapid assessment of immunization practices in Agra district.

A cross sectional study was conducted utilizing rapid assessment procedures, covering 516 children of 12-23 months in 80 clusters of both urban and rural areas of district Agra. The results revealed that 41.5% had immunization cards; only 37.2% children were fully immunized and 37.6% children were unimmunized. 43.6% had received measles vaccine. The most common reason for non immunization was obstacles (46%), followed by lack of motivation (22.6%), lack of information (19.4%). 13.8% had received vitamin-A oil along with measles vaccine while only 5.3% had received vitamin A upto three years.

A study on clinico-social factors for sexually transmitted diseases among urban males.

This health center based study was conducted to find out the proportion and distribution of clinico-social factors for sexually transmitted diseases among male OPD attanders of urban health centre, Subharti Medical College, Meerut. Out of the total 150 male cases of genital diseases from January to June 2005, 42 were found to be symptomatic for STDs according to syndromic approach. The most common symptom was urethral discharge (35.7%). Illiteracy, trucker's occupation, multiple sex partners, extra marital relationship and non-usage of condom were found to be important socio-clinical factors for STDs.

Anethole blocks both early and late cellular responses transduced by tumor necrosis factor: effect on NF-kappaB, AP-1, JNK, MAPKK and apoptosis.

Anethole, a chief constituent of anise, camphor, and fennel, has been shown to block both inflammation and carcinogenesis, but just how these effects are mediated is not known. One possibility is TNF-mediated signaling, which has also been associated with both inflammation and carcinogenesis. In the present report we show that anethole is a potent inhibitor of TNF-induced NF-kappaB activation (an early response) as monitored by electrophoretic mobility shift assay, IkappaBalpha phosphorylation and degradation, and NF-kappaB reporter gene expression. Suppression of IkappaBalpha phosphorylation and NF-kappaB reporter gene expression induced by TRAF2 and NIK, suggests that anethole acts on IkappaBalpha kinase. Anethole also blocked the NF-kappaB activation induced by a variety of other inflammatory agents. Besides NF-kappaB, anethole also suppressed TNF-induced activation of the transcription factor AP-1, c-jun N-terminal kinase and MAPK-kinase. In addition, anethole abrogated TNF-induced apoptosis as measured by both caspase activation and cell viability. The anethole analogues eugenol and isoeugenol also blocked TNF signaling. Anethole suppressed TNF-induced both lipid peroxidation and ROI generation. Overall, our results demonstrate that anethole inhibits TNF-induced cellular responses, which may explain its role in suppression of inflammation and carcinogenesis. Oncogene (2000).

Evidence for a synergistic role of two types of human tumor necrosis factor receptors for the ligand-dependent activation of the nuclear transcription factor NF-kappaB.

Tumor necrosis factor (TNF) is a multipotential cytokine that interacts with a wide variety of cells through two distinct receptors, referred to as the p60 and p80 receptors. Why there are two distinct receptors for the same ligand and whether these receptors mediate their signal independently or synergistically is not known. We examined the role of these two receptors in the ligand-dependent activation of a transcriptional factor, NF-kappaB, an early response (5-15 min) to TNF in human myeloid ML-1a cells. By using receptor type-specific antibodies, these cells were found to express almost equal amounts of both receptors. TNF-dependent activation of NF-kappaB could be blocked partially by both anti-p60 and anti-p80, suggesting that TNF mediates its effect independently through the p60 and p80 receptors. In comparison, the activation of NF-kappaB by lymphotoxin (LT), which shares receptors with TNF, was completely blocked by anti-p60, whereas anti-p80 had no effect. Anti-p60 but not anti-p80 by itself was found to activate NF-kappaB in a dose-dependent manner, but on a molar basis anti-p60 was found to be 100 times less potent than TNF. Interestingly, even though anti-p80 by itself was inactive, it potentiated the effect of anti-p60 synergistically, suggesting an interaction between the two types of TNF receptor. Thus, overall these results demonstrate that the two forms of TNF receptors could mediate their signal in both an independent and synergistic manner and that TNF mediates its signal through both forms of receptors, whereas LT mediates its signal through the p60 receptor.

Antifertility effect of chronically administered Martynia annua root extract on male rats.

The effects of 50% ethanol extract of Martynia annua L. root on reproduction was studied on male rats. The study was divided into four groups of five animals each. The first group (I) received vehicle alone to serve as control. The second, third and fourth groups (II, III and IV) of animals were administered the root extract daily at 50 mg/kg body weight, po, 100 mg/kg body weight, po, and 200 mg/kg body weight, po, respectively, for a period of 60 days. Significant decreases in the weights of testes, epididymides, seminal vesicle and ventral prostate were observed. A dose related reduction in the testicular sperm count, epididymal sperm count and motility, number of fertile males, ratio between delivered and inseminated females and number of pups were observed. The testis showed a clear correlation between the dose and severity of lesions of seminiferous epithelium. In general, the seminiferous tubules appear reduced in size with a frequently filled eosinophilic material. Spermatogenesis arrested at the secondary spermatocyte stage. Pachytene spermatocytes were undergoing degeneration. Disorganisation and sloughing of immature germ cells were visible. Leydig cells were atrophied. No morphological changes were observed in Sertoli cells. Significant reduction in serum concentration of luteinising hormone and testosterone were observed. No distinct change in serum FSII concentration was recorded. The final body weights of all groups were elevated markedly. No alterations were recorded in any hematological parameters. It is concluded that the 50% ethanol extract of M. annua root produced dose related effects on male reproduction without altering general body metabolism.

Treatment of threshold retinopathy of prematurity.

This report deals with our experience in the management of threshold retinopathy of prematurity (ROP). A total of 45 eyes of 23 infants were subjected to treatment of threshold ROP. 26.1% of these infants had a birth weight of > 1,500 gm. The preferred modality of treatment was laser indirect photocoagulation, which was facilitated by scleral depression. Cryopexy was done in cases with nondilating pupils or medial haze and was always under general anaesthesia. Retreatment with either modality was needed in 42.2% eyes; in this the skip areas were covered. Total regression of diseases was achieved in 91.1% eyes with no sequelae. All the 4 eyes that progressed to stage 5 despite treatment had zone 1 disease. Major treatment-induced complications did not occur in this series. This study underscores the importance of routine screening of infants upto 2,000 gm birth weight for ROP and the excellent response that is achieved with laser photocoagulation in inducing regression of threshold ROP. Laser is the preferred method of treatment in view of the absence of treatment-related morbidity to the premature infants.

Mega dose intravenous methylprednisolone in bilateral simultaneous optic neuritis.

OBJECTIVES: The study was carried out to assess the efficacy of megadose intravenous methylprednisolone in patients of bilateral simultaneous optic neuropathy (BSON) of unknown etiology. METHODS: Fifteen consecutive patients admitted in neurology unit were included in the study. These patients were subjected to various investigations including MRI and CSF exam to exclude all known causes of optic neuropathy including multiple sclerosis. All patients were put on single dose intravenous methylprednisolone, 1 gm/day in adults and 500 mg/day in children for three days. Pre and post-treatment visual parameters including visual evoked potentials (VEP) were carried out. RESULTS: There was a female preponderance and the average age was 28 years. The visual acuity and P100 latences of visual evoked potentials (VEP) improved in all cases. The improvement was statistically significant (P < 0.001). CONCLUSION: Use of intravenous methylprednisolone is a preferred drug in bilateral simultaneous optic neuropathy (BSON) as compared to oral or retrobulbar steroids.