Inhibition of Alzheimer’s type toxic aggregates of tau with fungal secondary metabolites

Tau is a microtubule-associated protein that is typically found in the axons of neurons. The aggregation of the tau is a significant event in many neurodegenerative diseases including Alzheimer's disease. In these disease tau dissociates from microtubules and begins to form toxic insoluble intracellular tau aggregates. The process of conversion of soluble monomeric tau to insoluble aggregates in not well understood. Differential conformational changes in pathological forms of the protein may affect its propensity for aggregation and function. Post translational modifications such as hyperphosphorylation or truncation may induce these conformational changes and alter aggregation and function. The studies described here used in vitro assays to determine how truncation affects tau conformation and how they can alter aggregation and function. This information helps to describe how intrinsic differences due to modifications of tau can manifest themselves in the varying pathologies of tauopathies. Tau aggregation in a common mode of pathogenesis in tauopathies, including Alzheimer's disease. Tau aggregation correlates with dementia and neurodegeneration and is viewed as a potential therapeutic target for AD. Fungi have historically been a good source of medicinally important compounds. We identified secondary metabolites obtained from Aspergillus nidulans as tau aggregation inhibitors. We identified a novel class of tau aggregation inhibitors, azaphilones. Four of the azaphilones inhibited tau aggregation and disassembled pre-formed tau aggregates without inhibiting tau’s ability to polymerize microtubules. Preliminary NMR studies showed that our most potent azaphilone, aza-9 interacts with specific residues of tau protein in a dose dependent fashion. Aza-9 also disassembled tau aggregates formed by aggregation enhancing truncation mutant 1-391 in a dose dependent fashion. Azaphilones are therefore very promising lead compounds for tau aggregation inhibitors, provide a novel scaffold for the same and represent a new class of compounds with tau aggregation inhibitor activity

Anti-filarial IgG antibodies in patients with Bancroftian filariasis and tropical pulmonary eosinophilia

Anti-filarial (anti- B. malayi adult as well as anti- B. malayi microfilarial) IgG antibody levels were measured by enzyme linked immunosorbent assay (ELISA) in asymptomatic microfilaria carriers, acute, chronic and tropical pulmonary eosinophilia (TPE) patients, endemic and non-endemic controls. Controls from endemic areas had higher antibody titres compared with controls from non-endemic areas. The antibody response in different groups of filariasis patients was not stage specific. There were no association between clinical disease and antibody levels except in TPE. Though TPE patients had very high antibody levels, a proportion of them had low levels suggesting heterogeneity in TPE population

Comparison of capillary based microflurometric assay for CD4+ T cell count estimation with dual platform Flow cytometry

The CD4+ T cell count estimation is an important monitoring tool for HIV disease progression and efficacy of anti-retroviral treatment (ART). Due to availability of ART at low cost in developing countries, quest for reliable cost effective alternative methods for CD4+ T cell count estimation has gained importance. A simple capillary-based microflurometric assay (EasyCD4 System, Guava Technology) was compared with the conventional flow cytometric assay for estimation of CD4+ T cell counts in 79 HIV infected individuals. CD4+ T cell count estimation by both the assays showed strong correlation (r = 0.938, p < 0.001, 95% CI 0.90 to 0.96). The Bland Altman plot analysis showed that the limits of variation were within agreeable limits of ± 2SD (-161 to 129 cells/mm(3)). The Easy CD4 assay showed 100% sensitivity for estimating the CD4+ T cell counts < 200 cells/mm(3 )and < 350 cells/mm(3 )and 97% sensitivity to estimate CD4+ T cell count < 500 cells/mm(3). The specificity ranged from 82 to 100%. The Kappa factor ranged from 0.735 for the CD4+ T cell counts < 350 cells/mm(3 )to 0.771 for < 500 cells/mm(3 )CD4+ T cell counts. The system works with a simple protocol, is easy to maintain and has low running cost. The system is compact and generates minimum amount of waste. Hence the EasyCD4 System could be applied for estimation of CD4+ T cell counts in resource poor settings

HIV and cancer registry linkage identifies a substantial burden of cancers in persons with HIV in India.

We utilized computerized record-linkage methods to link HIV and cancer databases with limited unique identifiers in Pune, India, to determine feasibility of linkage and obtain preliminary estimates of cancer risk in persons living with HIV (PLHIV) as compared with the general population.Records of 32,575 PLHIV were linked to 31,754 Pune Cancer Registry records (1996-2008) using a probabilistic-matching algorithm. Cancer risk was estimated by calculating standardized incidence ratios (SIRs) in the early (4-27 months after HIV registration), late (28-60 months), and overall (4-60 months) incidence periods. Cancers diagnosed prior to or within 3 months of HIV registration were considered prevalent.Of 613 linked cancers to PLHIV, 188 were prevalent, 106 early incident, and 319 late incident. Incident cancers comprised 11.5% AIDS-defining cancers (ADCs), including cervical cancer and non-Hodgkin lymphoma (NHL), but not Kaposi sarcoma (KS), and 88.5% non-AIDS-defining cancers (NADCs). Risk for any incident cancer diagnosis in early, late, and combined periods was significantly elevated among PLHIV (SIRs: 5.6 [95% CI 4.6-6.8], 17.7 [95% CI 15.8-19.8], and 11.5 [95% CI 10-12.6], respectively). Cervical cancer risk was elevated in both incidence periods (SIRs: 9.6 [95% CI 4.8-17.2] and 22.6 [95% CI 14.3-33.9], respectively), while NHL risk was elevated only in the late incidence period (SIR: 18.0 [95% CI 9.8-30.20]). Risks for NADCs were dramatically elevated (SIR &gt; 100) for eye-orbit, substantially (SIR &gt; 20) for all-mouth, esophagus, breast, unspecified-leukemia, colon-rectum-anus, and other/unspecified cancers; moderately elevated (SIR &gt; 10) for salivary gland, penis, nasopharynx, and brain-nervous system, and mildly elevated (SIR &gt; 5) for stomach. Risks for 6 NADCs (small intestine, testis, lymphocytic leukemia, prostate, ovary, and melanoma) were not elevated and 5 cancers, including multiple myeloma not seen.Our study demonstrates the feasibility of using probabilistic record-linkage to study cancer/other comorbidities among PLHIV in India and provides preliminary population-based estimates of cancer risks in PLHIV in India. Our results, suggesting a potentially substantial burden and slightly different spectrum of cancers among PLHIV in India, support efforts to conduct multicenter linkage studies to obtain precise estimates and to monitor cancer risk in PLHIV in India

Condom use and prevalence of syphilis and HIV among female sex workers in Andhra Pradesh, India – following a large-scale HIV prevention intervention

<p>Abstract</p> <p>Background</p> <p>Avahan, the India AIDS initiative began HIV prevention interventions in 2003 in Andhra Pradesh (AP) among high-risk groups including female sex workers (FSWs), to help contain the HIV epidemic. This manuscript describes an assessment of this intervention using the published Avahan evaluation framework and assesses the coverage, outcomes and changes in STI and HIV prevalence among FSWs.</p> <p>Methodology</p> <p>Multiple data sources were utilized including Avahan routine program monitoring data, two rounds of cross-sectional survey data (in 2006 and 2009) and STI clinical quality monitoring assessments. Bi-variate and multivariate analyses, Wald Chi-square tests and multivariate logistic regressions were used to measure changes in behavioural and biological outcomes over time and their association.</p> <p>Results</p> <p>Avahan scaled up in conjunction with the Government program to operate in all districts in AP by March 2009. By March 2009, 80% of the FSWs were being contacted monthly and 21% were coming to STI services monthly. Survey data confirmed an increase in peer educator contacts with the mean number increasing from 2.9 in 2006 to 5.3 in 2009. By 2008 free and Avahan-supported socially marketed condoms were adequate to cover the estimated number of commercial sex acts, at 45 condoms/FSW/month. Consistent condom use was reported to increase with regular (63.6% to 83.4%; AOR=2.98; p<0.001) and occasional clients (70.8% to 83.7%; AOR=2.20; p<0.001). The prevalence of lifetime syphilis decreased (10.8% to 6.1%; AOR=0.39; p<0.001) and HIV prevalence decreased in all districts combined (17.7% to 13.2%; AOR 0.68; p<0.01). Prevalence of HIV among younger FSWs (aged 18 to 20 years) decreased (17.7% to 8.2%, p=0.008). A significant increase in condom use at last sex with occasional and regular clients and consistent condom use with occasional clients was observed among FSWs exposed to the Avahan program. There was no association between exposure and HIV or STIs, although numbers were small.</p> <p>Conclusions</p> <p>The absence of control groups is a limitation of this study and does not allow attribution of changes in outcomes and declines in HIV and STI to the Avahan program. However, the large scale implementation, high coverage, intermediate outcomes and association of these outcomes to the Avahan program provide plausible evidence that the declines were likely associated with Avahan. Declining HIV prevalence among the general population in Andhra Pradesh points towards a combined impact of Avahan and government interventions.</p

Inhibition of Tau Aggregation by Three Aspergillus nidulans Secondary Metabolites: 2,ω-Dihydroxyemodin, Asperthecin, and Asperbenzaldehyde

This is the published version. Copyright 2014 George Theime Verlag. All rights reserved.The aggregation of the microtubule-associated protein tau is a significant event in many neurodegenerative diseases including Alzheimerʼs disease. The inhibition or reversal of tau aggregation is therefore a potential therapeutic strategy for these diseases. Fungal natural products have proven to be a rich source of useful compounds having wide varieties of biological activity. We have screened Aspergillus nidulans secondary metabolites containing aromatic ring structures for their ability to inhibit tau aggregation in vitro using an arachidonic acid polymerization protocol and the previously identified aggregation inhibitor emodin as a positive control. While several compounds showed some activity, 2,ω-dihydroxyemodin, asperthecin, and asperbenzaldehyde were potent aggregation inhibitors as determined by both a filter trap assay and electron microscopy. In this study, these three compounds were stronger inhibitors than emodin, which has been shown in a prior study to inhibit the heparin induction of tau aggregation with an IC50 of 1–5 µM. Additionally, 2,ω-dihydroxyemodin, asperthecin, and asperbenzaldehyde reduced, but did not block, tau stabilization of microtubules. 2,ω-Dihydroxyemodin and asperthecin have similar structures to previously identified tau aggregation inhibitors, while asperbenzaldehyde represents a new class of compounds with tau aggregation inhibitor activity. Asperbenzaldehyde can be readily modified into compounds with strong lipoxygenase inhibitor activity, suggesting that compounds derived from asperbenzaldehyde could have dual activity. Together, our data demonstrates the potential of 2,ω-dihydroxyemodin, asperthecin, and asperbenzaldehyde as lead compounds for further development as therapeutics to inhibit tau aggregation in Alzheimerʼs disease and neurodegenerative tauopathies

Heading towards the Safer Highways: an assessment of the Avahan prevention programme among long distance truck drivers in India

<p>Abstract</p> <p>Background</p> <p>Using data from two rounds of a cross-sectional, national-level survey of long-distance truck drivers, this paper examines the extent and trend of sexual risk behavior, prevalence of STI/HIV, and the linkage between exposure to HIV prevention programs and safe sex behavior.</p> <p>Methods</p> <p>Following the time location cluster sampling approach, major transshipment locations covering the bulk of India’s transport volume along four routes, North-East (NE), North-South (NS), North-West (NW) and South-East (SE) were surveyed. First round of the survey was conducted in 2007 (sample size 2066) whereas the second round was undertaken in 2009-2010 (sample size 2085). Long distance truck drivers were interviewed about their sexual behaviors, condom use practices, exposure to different HIV prevention interventions, and tested for HIV, reactive syphilis serology, <it>Neiserria gonorrhoeae</it> and <it>Chlamydia trachomatis.</it> The key variable of this evaluation study - exposure to HIV prevention interventions was divided into three categories - no exposure, less intensive exposure and intensive exposure. Data were analyzed using multiple logistic regression methods to understand the relationship between risk behavior and exposure to intervention and between program exposure and condom use.</p> <p>Results</p> <p>The proportion of truckers exposed to HIV prevention interventions has increased over time with much significant increase in the intensive exposure across all the four routes (NE: from 14.9% to 28%, P < 0.01; NS: from 20.9% to 38.1%; NW: 11.5% to 39.5%, P < 0.01; SE: 4.7% to 9.7%, P <0.05). Overall, the consistent condom use in sex with non-regular female partners too has increased over the time (paid female partners: from 67.1% to 73.2%, P <0.05; non-paid female partners: from 17.9% to 37.1%, P <0.05). At the aggregate level, the proportion tested HIV positive has declined from 3.2% to 2.5% in (p<0.10) and proportion tested positive for Syphilis too has reduced from 3.2% to 1.7% (p<0.05). Truckers who had sex with paid female partners (men at risk) were significantly more likely to get exposed to intensive program (aOR: 2.6, 95%CI 1.9-3.4) as compared to those who did not have sex with paid partners. Truckers who had sex with paid partners and exposed to intervention program were more likely to use condoms consistently (aOR: 2.1, 95% CI 1.2-3.7). The consistent condom use among respondents who travel through states with targeted interventions towards female sex workers was higher than those who travel through states with less intensive program among FSWs.</p> <p>Conclusions</p> <p>These evaluation study results highlight the ability of intensive program to reach truckers who have sex outside marriage with HIV prevention interventions and promote safe sex behaviors among them. Truckers who practice safe sex behaviors with an exposure to intensive program are less likely to suffer from STIs and HIV, which has implications for HIV prevention program with truckers’ population in India and elsewhere. The simultaneous targeted interventions among female sex workers appeared to have contributed to safe sexual practices among truckers.</p

Assessment of the population-level eff ectiveness of the Avahan HIV-prevention programme in South India: a preplanned, causal-pathway-based modelling analysis

Background Avahan, the India AIDS initiative of the Bill & Melinda Gates Foundation, was a large-scale, targeted HIV prevention intervention. We aimed to assess its overall eff ectiveness by estimating the number and proportion of HIV infections averted across Avahan districts, following the causal pathway of the intervention. Methods We created a mathematical model of HIV transmission in high-risk groups and the general population using data from serial cross-sectional surveys (integrated behavioural and biological assessments, IBBAs) within a Bayesian framework, which we used to reproduce HIV prevalence trends in female sex workers and their clients, men who have sex with men, and the general population in 24 South Indian districts over the fi rst 4 years (2004–07 or 2005–08 dependent on the district) and the full 10 years (2004–13) of the Avahan programme. We tested whether these prevalence trends were more consistent with self-reported increases in consistent condom use after the implementation of Avahan or with a counterfactual (assuming consistent condom use increased at slower, pre-Avahan rates) using a Bayes factor, which gave a measure of the strength of evidence for the eff ectiveness estimates. Using regression analysis, we extrapolated the prevention eff ect in the districts covered by IBBAs to all 69 Avahan districts. Findings In 13 of 24 IBBA districts, modelling suggested medium to strong evidence for the large self-reported increase in consistent condom use since Avahan implementation. In the remaining 11 IBBA districts, the evidence was weaker, with consistent condom use generally already high before Avahan began. Roughly 32 700 HIV infections (95% credibility interval 17 900–61 600) were averted over the fi rst 4 years of the programme in the IBBA districts with moderate to strong evidence. Addition of the districts with weaker evidence increased this total to 62 800 (32 000–118 000) averted infections, and extrapolation suggested that 202 000 (98 300–407 000) infections were averted across all 69 Avahan districts in South India, increasing to 606 000 (290 000–1 193 000) over 10 years. Over the fi rst 4 years of the programme 42% of HIV infections were averted, and over 10 years 57% were averted. Interpretation This is the fi rst assessment of Avahan to account for the causal pathway of the intervention, that of changing risk behaviours in female sex workers and high-risk men who have sex with men to avert HIV infections in these groups and the general population. The fi ndings suggest that substantial preventive eff ects can be achieved by targeted behavioural HIV prevention initiatives