Flavonoids: The Innocuous Agents Offering Protection against Alzheimer's Disease Through Modulation of Proinflammatory and Apoptotic Pathways.

BACKGROUND: Beginning from mild cognitive impairment in patients suffering from Alzheimer's disease (AD), dementia sets in with the progress of the disease. The pathological changes in the brain begin fifteen to twenty years before AD related dementia develops. Presence of senile plaques and neurofibrillary tangles are considered the hallmarks of AD brain. Chronic inflammation resulting from the disruption of the equilibrium between anti-inflammatory and pro-inflammatory signalling emerges as another important feature of AD and also other neurodegenerative diseases. Substantial studies demonstrate that this sustained immune response in the brain is associated with neuronal loss, along with facilitation and aggravation of Aß and NFT pathologies. Although it is well accepted that neuroinflammation and oxidative stress have both detrimental and beneficial influences on the brain tissues, the involvement of microglia and astrocytes in the onset and progress of the neurodegenerative process in AD is becoming increasingly recognized. Although the cause of neuronal loss is known to be apoptosis, the mechanism of promotion of neuronal death remains undisclosed. OBJECTIVE: Controlling the activation of the resident immune cells and/or the excessive production of pro-inflammatory and pro-oxidant factors could be effective as therapeutics. Among the phytonutrients, the neuroprotective role of flavonoids is beyond doubt. This review is an exploration of the literature on the role of flavonoids in these aspects. CONCLUSION: Flavonoids are not only effective in ameliorating the adverse consequences of oxidative stress but also impede the development of late onset Alzheimer's disease by modulating affected signalling pathways and boosting signalling crosstalk.

Impact of Advocacy, Communication, Social Mobilization and Active Case Finding on TB Notification in Jharkhand, India.

Community-level benefits of screening for active tuberculosis (TB) disease remain uncertain. Project Axshya (meaning free of TB) conducted advocacy, communication, social mobilization, and active case finding among vulnerable/marginalized populations of India. Among 15 districts of Jharkhand state, the project was initiated in 36 subdistrict level administrative units - tuberculosis units (TUs) in a staggered manner between April 2013 and September 2014, and continued till the end of 2015. Seven TUs did not implement the project. We assessed the relative change in the quarterly TB case finding indicators (n = 4) after inclusion of a TU within the project. By fitting four multilevel models (mixed-effects maximum likelihood regression using random intercept), we adjusted for secular (over previous five quarters) and seasonal trends, baseline differences within Axshya and non-Axshya TUs, and population size and clustering within districts and within TUs. After inclusion of a TU within the project, we found a significant increase [95% confidence interval (CI)] in TU-level presumptive TB sputum examination rate, new sputum-positive TB Case Notification Rate (CNR), sputum-positive TB CNR, and all forms TB CNR by 12 (5.5, 18.5), 1.1 (0.5, 1.7), 1.3 (0.6, 2.0), and 1.2 (0.1, 2.2) per 100,000 population per quarter, respectively. Overall, the project resulted in an increase (95% CI) in sputum examination and detection of new sputum-positive TB, sputum-positive TB and all forms of TB patients by 22,410 (10,203, 34,077), 2066 (923, 3210), 2380 (1162, 3616), and 2122 (203, 4059), respectively. This provides evidence for implementing project Axshya over and above the existing passive case finding.

Phytochemical composition, ß-glucuronidase inhibition, and antioxidant properties of two fractions of Piper betle leaf aqueous extract.

RATIONALE: Piper betle leaf, used as masticatory in South Asia, is also medicinally important. OBJECTIVE: This work was done to analyze phytochemical composition of two solvent fractions (chloroform and ethyl acetate) of the aqueous extracts obtained from eight varieties of P. betle leaves and to identify the active components against ß-glucuronidase by chemometric analysis. RESULTS: Twenty-four phenolic compounds, in addition to different organic acids, fatty acids, amino acids, sugars, and polyols, were identified from the solvent fractions. The extracts inhibited the enzyme ß-glucuronidase. Piceatannol was the most active constituent against the enzyme (activity 12 times higher than that of silymarin), Chlorogenic acid also inhibited ß-glucuronidase (activity 4.4 times higher when compared to silymarin). 2,2'-Diphenyl-1-picrylhydrazyl and superoxide free radical scavenging activities of both the fractions of eight varieties of P. betle leaf extracts showed very strong antioxidant potentiality. CONCLUSION: The findings validated some medicinal properties of the said leaves. PRACTICAL APPLICATIONS: Edible leaves of Piper betle are medicinally and economically important. Leaves of different local varieties are reported to be used for the treatment of different diseases. The leaves have many biological properties, hepatoprotection being one of them. A large number of rural population is economically dependent on the cultivation of betel vine. But with a rapid change in lifestyle, the chewing habit of P. betle is decreasing ultimately affecting the livelihood of farmers dependent on betel cultivation. Knowledge on ß-glucuronidase inhibitory activity and the mechanism for hepatoprotection of different P. betle varieties may validate the medicinal properties of betel, which would increase consumption of these leaves.

Active versus passive case finding for tuberculosis in marginalised and vulnerable populations in India: comparison of treatment outcomes.

Background: Community-based active case finding (ACF) for tuberculosis (TB) implemented among marginalised and vulnerable populations in 285 districts of India resulted in reduction of diagnosis delay and prevalence of catastrophic costs due to TB diagnosis. We were interested to know whether this translated into improved treatment outcomes. Globally, there is limited published literature from marginalised and vulnerable populations on the independent effect of community-based ACF on treatment outcomes when compared to passive case finding (PCF). Objectives: To determine the relative differences in unfavourable treatment outcomes (death, loss-to-follow-up, failure, not evaluated) of ACF and PCF-diagnosed people. Methods: Cohort study involving record reviews and interviews in 18 randomly selected districts. We enrolled all ACF-diagnosed people with new smear-positive pulmonary TB, registered under the national TB programme between March 2016 and February 2017, and an equal number of randomly selected PCF-diagnosed people in the same settings. We used log binomial models to adjust for confounders. Results: Of 572 enrolled, 275 belonged to the ACF and 297 to the PCF group. The proportion of unfavourable outcomes were 10.2% (95% CI: 7.1%, 14.3%) in the ACF and 12.5% (95% CI: 9.2%, 16.7%) in the PCF group (p = 0.468). The association between ACF and unfavourable outcomes remained non-significant after adjusting for confounders available from records [aRR: 0.83 (95% CI: 0.56, 1.21)]. Due to patient non-availability at their residence, interviews were conducted for 465 (81.3%). In the 465 cohort too, there was no association after adjusting for confounders from records and interviews [aRR: 1.05 (95% CI: 0.62, 1.77)]. Conclusion: We did not find significant differences in the treatment outcomes. Due to the wide CIs, studies with larger sample sizes are urgently required. Studies are required to understand how to translate the benefits of ACF to improved treatment outcomes.

Are we missing 'previously treated' smear-positive pulmonary tuberculosis under programme settings in India? A cross-sectional study.

Background: In 2007, a field observation from India reported 11% misclassification among 'new' patients registered under the revised national tuberculosis (TB) control programme. Ten years down the line, it is important to know what proportion of newly registered patients has a past history of TB treatment for at least one month (henceforth called 'misclassification'). Methods: A study was conducted among new smear-positive pulmonary TB patients registered between March 2016 and February 2017 in 18 randomly selected districts to determine the effectiveness of an active case-finding strategy in marginalised and vulnerable populations. We included all patients detected through active case-finding. An equal number of randomly selected patients registered through passive case-finding from marginalised and vulnerable populations in the same districts were included. Before enrolment, we enquired about any history of previous TB treatment through interviews. Results: Of 629 patients, we interviewed 521, of whom, 11% (n=56) had past history of TB treatment (public or private) for at least a month: 13% (34/268) among the active case-finding group and 9% (22/253) among the passive case-finding group (p=0.18). No factors were found to be significantly associated with misclassification. Conclusion: Around one in every ten patients registered as 'new' had previous history of TB treatment. Corrective measures need to be implemented, followed by monitoring of any change in the proportion of 'previously treated' patients among all registered patients treated under the programme at national level.

Patient characteristics, health seeking and delays among new sputum smear positive TB patients identified through active case finding when compared to passive case finding in India.

BACKGROUND: Axshya SAMVAD is an active tuberculosis (TB) case finding (ACF) strategy under project Axshya (Axshya meaning 'free of TB' and SAMVAD meaning 'conversation') among marginalized and vulnerable populations in 285 districts of India. OBJECTIVES: To compare patient characteristics, health seeking, delays in diagnosis and treatment initiation among new sputum smear positive TB patients detected through ACF and passive case finding (PCF) under the national TB programme in marginalized and vulnerable populations between March 2016 and February 2017. METHODS: This observational analytic study was conducted in 18 randomly sampled Axshya districts. We enrolled all TB patients detected through ACF and an equal number of randomly selected patients detected through PCF in the same settings. Data on patient characteristics, health seeking and delays were collected through record review and patient interviews (at their residence). Delays included patient level delay (from eligibility for sputum examination to first contact with any health care provider (HCP)), health system level diagnosis delay (from contact with first HCP to TB diagnosis) and treatment initiation delays (from diagnosis to treatment initiation). Total delay was the sum of patient level, health system level diagnosis delay and treatment initiation delays. RESULTS: We included 234 ACF-diagnosed and 231 PCF-diagnosed patients. When compared to PCF, ACF patients were relatively older (≥65 years, 14% versus 8%, p = 0.041), had no formal education (57% versus 36%, p<0.001), had lower monthly income per capita (median 13.1 versus 15.7 USD, p = 0.014), were more likely from rural areas (92% versus 81%, p<0.002) and residing far away from the sputum microscopy centres (more than 15 km, 24% versus 18%, p = 0.126). Fewer patients had history of significant loss of weight (68% versus 78%, p = 0.011) and sputum grade of 3+ (15% versus 21%, p = 0.060). Compared to PCF, HCP visits among ACF patients was significantly lower (median one versus two HCPs, p<0.001). ACF patients had significantly lower health system level diagnosis delay (median five versus 19 days, p = 0.008) and the association remained significant after adjusting for potential confounders. Patient level and total delays were not significantly different. CONCLUSION: Axshya SAMVAD linked the most impoverished communities to TB care and resulted in reduction of health system level diagnosis delay.

Active case finding among marginalised and vulnerable populations reduces catastrophic costs due to tuberculosis diagnosis.

BACKGROUND: There is limited evidence on whether active case finding (ACF) among marginalised and vulnerable populations mitigates the financial burden during tuberculosis (TB) diagnosis. OBJECTIVES: To determine the effect of ACF among marginalised and vulnerable populations on prevalence and inequity of catastrophic costs due to TB diagnosis among TB-affected households when compared with passive case finding (PCF). METHODS: In 18 randomly sampled ACF districts in India, during March 2016 to February 2017, we enrolled all new sputum-smear-positive TB patients detected through ACF and an equal number of randomly selected patients detected through PCF. Direct (medical and non-medical) and indirect costs due to TB diagnosis were collected through patient interviews at their residence. We defined costs due to TB diagnosis as 'catastrophic' if the total costs (direct and indirect) due to TB diagnosis exceeded 20% of annual pre-TB household income. We used concentration curves and indices to assess the extent of inequity. RESULTS: When compared with patients detected through PCF (n = 231), ACF patients (n = 234) incurred lower median total costs (US$ 4.6 and 20.4, p < 0.001). The prevalence of catastrophic costs in ACF and PCF was 10.3 and 11.5% respectively. Adjusted analysis showed that patients detected through ACF had a 32% lower prevalence of catastrophic costs relative to PCF [adjusted prevalence ratio (95% CI): 0.68 (0.69, 0.97)]. The concentration indices (95% CI) for total costs in both ACF [-0.15 (-0.32, 0.11)] and PCF [-0.06 (-0.20, 0.08)] were not significantly different from the line of equality and each other. The concentration indices (95% CI) for catastrophic costs in both ACF [-0.60 (-0.81, -0.39)] and PCF [-0.58 (-0.78, -0.38)] were not significantly different from each other: however, both the curves had a significant distribution among the poorest quintiles. CONCLUSION: ACF among marginalised and vulnerable populations reduced total costs and prevalence of catastrophic costs due to TB diagnosis, but could not address inequity.

Van Wyk-Grumbach syndrome with hemangioma in an infant.

Background Van Wyk-Grumbach syndrome (VWGS) is characterized by juvenile primary hypothyroidism, delayed bone age and isosexual incomplete precocious puberty with reversal to the prepubertal state following thyroid hormone replacement. Case presentation In this case, an 18-month-old girl presented with premature menarche since 9 months of age, delayed bone age and enlarged bilateral multicystic ovaries along with a superficial infantile hemangioma over the upper anterior chest. VWGS was diagnosed based on the clinical features. High serum thyroid stimulating hormone and low free thyroxine with the absence of any carpal bones in the wrist X-ray were suggestive of congenital hypothyroidism. Interestingly, the coexisting hemangioma could also play a role in the etiology of the hypothyroidism through "consumptive hypothyroidism". Thyroid hormone replacement resulted in the complete resolution of signs and symptoms. Conclusions Untreated congenital hypothyroidism of short duration, onset of symptoms in infancy and association of an infantile hemangioma in VWGS were the unique features in our case.

Gene-specific methylation control of H3K9 and H3K36 on neurotrophic BDNF versus astroglial GFAP genes by KDM4A/C regulates neural stem cell differentiation.

Neural stem cell (NSC) state and fate depend on spatially and temporally synchronized transcriptional and epigenetic regulation of the expression of extrinsic signaling factors and intrinsic cell-specific genes, but the functional roles for chromatin-modifying enzymes in neural differentiation remain poorly understood. Here we show that the histone demethylases KDM4A (JMJD2A) and KDM4C (JMJD2C) are essential for proper differentiation of NSCs in vitro and in vivo. KDM4A/C were required for neuronal differentiation, survival and expression of the neurotrophic signaling factor BDNF in association with promoter H3K9 demethylation and RNA polymerase II recruitment. Unexpectedly, KDM4A/C were essential for selective H3K36 demethylation and loss of RNA polymerase II recruitment in transcribed regions of the astrocyte-characteristic gene GFAP, thereby in parallel repressing astrocytic differentiation by control of elongation. We propose that gene- and lysine-specific KDM4A/C-mediated control of histone methylation and thereby regulation of intrinsic factors and signaling factors such as BDNF provide a novel control mechanism of lineage decision.

Expression of aromatase, androgen and estrogen receptors in peripheral target tissues in diabetes.

Our previous studies have shown that diabetes in the male streptozotocin (STZ)-induced diabetic rat is characterized by a decrease in circulating testosterone and concomitant increase in estradiol levels. Interestingly, this increase in estradiol levels persists even after castration, suggesting extra-testicular origins of estradiol in diabetes. The aim of the present study was to examine whether other target organs of diabetes may be sources of estradiol. The study was performed in male Sprague-Dawley non-diabetic (ND), STZ-induced diabetic (D) and STZ-induced diabetic castrated (Dcas) rats (n=8-9/group). 14 weeks of diabetes was associated with decreased testicular (ND, 26.3+/-4.19; D, 18.4+/-1.54; P<0.05), but increased renal (ND, 1.83+/-0.92; D, 7.85+/-1.38; P<0.05) and ocular (D, 23.4+/-3.66; D, 87.1+/-28.1; P<0.05) aromatase activity. This increase in renal (Dcas, 6.30+/-1.25) and ocular (Dcas, 62.7+/-11.9) aromatase activity persisted after castration. The diabetic kidney also had increased levels of tissue estrogen (ND, 0.31+/-0.01; D, 0.51+/-0.11; Dcas, 0.45+/-0.08) as well as estrogen receptor alpha protein expression (ND, 0.63+/-0.09; D, 1.62+/-0.28; Dcas, 1.38+/-0.20). These data suggest that in male STZ-induced diabetic rats, tissues other than the testis may become sources of estradiol. In particular, the diabetic kidney appears to produce estradiol following castration, a state that is associated with a high degree or renal injury. Overall, our data provides evidence for the extra-testicular source of estradiol that in males, through an intracrine mechanism, may contribute to the development and/or progression of end-organ damage associated with diabetes.

Limiting the extent of the RDN1 heterochromatin domain by a silencing barrier and Sir2 protein levels in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, transcriptional silencing occurs at the cryptic mating-type loci (HML and HMR), telomeres, and ribosomal DNA (rDNA; RDN1). Silencing in the rDNA is unusual in that polymerase II (Pol II) promoters within RDN1 are repressed by Sir2 but not Sir3 or Sir4. rDNA silencing unidirectionally spreads leftward, but the mechanism of limiting its spreading is unclear. We searched for silencing barriers flanking the left end of RDN1 by using an established assay for detecting barriers to HMR silencing. Unexpectedly, the unique sequence immediately adjacent to RDN1, which overlaps a prominent cohesin binding site (CARL2), did not have appreciable barrier activity. Instead, a fragment located 2.4 kb to the left, containing a tRNA(Gln) gene and the Ty1 long terminal repeat, had robust barrier activity. The barrier activity was dependent on Pol III transcription of tRNA(Gln), the cohesin protein Smc1, and the SAS1 and Gcn5 histone acetyltransferases. The location of the barrier correlates with the detectable limit of rDNA silencing when SIR2 is overexpressed, where it blocks the spreading of rDNA heterochromatin. We propose a model in which normal Sir2 activity results in termination of silencing near the physical rDNA boundary, while tRNA(Gln) blocks silencing from spreading too far when nucleolar Sir2 pools become elevated.

Intracranial aneurysms in Finnish families: confirmation of linkage and refinement of the interval to chromosome 19q13.3.

We recently reported a two-stage genomewide screen of 48 sib pairs affected with intracranial aneurysms (IAs) that revealed suggestive linkage to chromosome 19q13, with a LOD score of 2.58. The region supporting linkage spanned approximately 22 cM. Here, we report a follow-up study of the locus at 19q13, with a sample size expanded to 139 affected sib pairs, along with 83 other affected relative pairs (222 affected relative pairs in total). Suggestive linkage was observed in both independent sample sets, and linkage was significant in the combined set at 70 cM (LOD score 3.50; P=.00006) and at 80 cM (LOD score 3.93; P=.00002). Linkage was highly significant at 70 cM (LOD score 5.70; P=.000001) and at 80 cM (LOD score 3.99; P=.00005) when a covariate measuring the number of affected individuals in the nuclear family was included. To evaluate further the contribution to the linkage signal from families with more than two affected relatives, we performed model-based linkage analysis with a recessive model and a range of penetrances, and we obtained maximum linkage at 70 cM (LOD score 3.16; P=.00007) with a penetrance of 0.3. We then estimated location by using GENEFINDER. The most likely location for a gene predisposing to IAs in the Finnish population is in a region with a 95% confidence interval of 11.6 cM (P=.00007) centered 2.0 cM proximal to D19S246.