A systematic review of current knowledge of HIV epidemiology and of sexual behaviour in Nepal

OBJECTIVE: To systematically review information on HIV epidemiology and on sexual behaviour in Nepal with a view to identifying gaps in current knowledge. METHODS: Systematic review covering electronic databases, web-based information, personal contact with experts and hand searching of key journals. RESULTS: HIV-1 seroprevalence has been rising rapidly in association with high-risk behaviours, with current levels of 40% amongst the nation's injecting drug users and approaching 20% amongst Kathmandu's female commercial sex workers (FCSWs). HIV seroprevalence remains low in the general population (0.29% of 15–49 year olds). There are significant methodological limitations in many of the seroprevalence studies identified, and these estimates need to be treated with caution. There are extensive migration patterns both within the country and internationally which provide the potential for considerable sexual networking. However, studies of sexual behaviour have focused on FCSWs and the extent of sexual networks within the general population is largely unknown. CONCLUSIONS: Whilst some of the ingredients are present for an explosive HIV epidemic in Nepal, crucial knowledge on sexual behaviour in the general population is missing. Research on sexual networking is urgently required to guide HIV control in Nepal. There is also a need for further good-quality epidemiological studies of HIV seroprevalence

Age-related shift in LTD is dependent on neuronal adenosine A(2A) receptors interplay with mGluR5 and NMDA receptors

Synaptic dysfunction plays a central role in Alzheimer's disease (AD), since it drives the cognitive decline. An association between a polymorphism of the adenosine A2A receptor (A2AR) encoding gene-ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of A2AR in age-related conditions. We report, for the first time, a significant overexpression of A2AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of A2AR overexpression in rats was sufficient to drive age-like memory impairments in young animals and to uncover a hippocampal LTD-to-LTP shift. This was accompanied by increased NMDA receptor gating, dependent on mGluR5 and linked to enhanced Ca(2+) influx. We confirmed the same plasticity shift in memory-impaired aged rats and APP/PS1 mice modeling AD, which was rescued upon A2AR blockade. This A2AR/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity

HIV-1 subtype A infection in a community of intravenous drug users in Pakistan

BACKGROUND: Data on the subtypes of HIV in a population help in predicting the potential foci of epidemic, tracking the routes of infection and following the patterns of the virus' genetic divergence. Globally, the most prevalent HIV infection is the HIV-1 subtype C. In Asia, predominant subtypes of HIV-1 are B, C, and CRF-01AE. During the last few years, HIV prevalence in Pakistan has taken the form of a concentrated epidemic in at least two high risk groups, namely, Intravenous Drug Users (IDUs) and Male Sex Workers (MSWs). Factors that have facilitated the proliferation of HIV infection include transmission through a large number of repatriates and needle-sharing intravenous drug users, unscreened blood transfusions, and sexual illiteracy. The HIV subtypes infecting Pakistani populations have not been explored to date. In this study, we analyzed HIV-1 subtypes from in a high-risk community of IDUs in Karachi, the largest city of Pakistan. METHODS: Samples were collected from 34 IDUs after their informed consent. In addition, the study subjects were administered a questionnaire regarding their sexual behavior and travel history. For HIV analysis, DNA was extracted from the samples and analyzed for HIV types and subtypes using subtype-specific primers in a nested polymerase chain reaction (PCR). The results from this PCR were further confirmed using the Heteroduplex Mobility Assay (HMA). RESULTS: We found HIV-1 subtype A in all the 34 samples analyzed. A few of the study subjects were found to have a history of travel and stay in the United Arab Emirates. The same subjects also admitted to having contact with commercial sex workers during their stay abroad. CONCLUSION: Our study therefore shows clade A HIV-1 to be prevalent among the IDUs in Karachi. As the prevalence of HIV in Pakistan continues to rise, more work needs to be done to track the infection, and to analyze the strains of HIV spreading through the country

Structure-activity relationships of anthraquinone derivatives derived from bromaminic acid as inhibitors of ectonucleoside triphosphate diphosphohydrolases (E-NTPDases)

Reactive blue 2 (RB-2) had been characterized as a relatively potent ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) inhibitor with some selectivity for NTPDase3. In search for the pharmacophore and to analyze structure-activity relationships we synthesized a series of truncated derivatives and analogs of RB-2, including 1-amino-2-sulfo-4-ar(alk)ylaminoanthraquinones, 1-amino-2-methyl-4-arylaminoanthraquinones, 1-amino-4-bromoanthraquinone 2-sulfonic acid esters and sulfonamides, and bis-(1-amino-4-bromoanthraquinone) sulfonamides, and investigated them in preparations of rat NTPDase1, 2, and 3 using a capillary electrophoresis assay. Several 1-amino-2-sulfo-4-ar(alk)ylaminoanthraquinone derivatives inhibited E-NTPDases in a concentration-dependent manner. The 2-sulfonate group was found to be required for inhibitory activity, since 2-methyl-substituted derivatives were inactive. 1-Amino-2-sulfo-4-p-chloroanilinoanthraquinone (18) was identified as a nonselective competitive blocker of NTPDases1, 2, and 3 (Ki 16–18 μM), while 1-amino-2-sulfo-4-(2-naphthylamino)anthraquinone (21) was a potent inhibitor with preference for NTPDase1 (Ki 0.328 μM) and NTPDase3 (Ki 2.22 μM). Its isomer, 1-amino-2-sulfo-4-(1-naphthylamino)anthraquinone (20), was a potent and selective inhibitor of rat NTPDase3 (Ki 1.5 μM)

Structural Insights into the Inhibition of Cytosolic 5′-Nucleotidase II (cN-II) by Ribonucleoside 5′-Monophosphate Analogues

Cytosolic 5′-nucleotidase II (cN-II) regulates the intracellular nucleotide pools within the cell by catalyzing the dephosphorylation of 6-hydroxypurine nucleoside 5′-monophosphates. Beside this physiological function, high level of cN-II expression is correlated with abnormal patient outcome when treated with cytotoxic nucleoside analogues. To identify its specific role in the resistance phenomenon observed during cancer therapy, we screened a particular class of chemical compounds, namely ribonucleoside phosphonates to predict them as potential cN-II inhibitors. These compounds incorporate a chemically and enzymatically stable phosphorus-carbon linkage instead of a regular phosphoester bond. Amongst them, six compounds were predicted as better ligands than the natural substrate of cN-II, inosine 5′-monophosphate (IMP). The study of purine and pyrimidine containing analogues and the introduction of chemical modifications within the phosphonate chain has allowed us to define general rules governing the theoretical affinity of such ligands. The binding strength of these compounds was scrutinized in silico and explained by an impressive number of van der Waals contacts, highlighting the decisive role of three cN-II residues that are Phe 157, His 209 and Tyr 210. Docking predictions were confirmed by experimental measurements of the nucleotidase activity in the presence of the three best available phosphonate analogues. These compounds were shown to induce a total inhibition of the cN-II activity at 2 mM. Altogether, this study emphasizes the importance of the non-hydrolysable phosphonate bond in the design of new competitive cN-II inhibitors and the crucial hydrophobic stacking promoted by three protein residues

Disease recurrence in paediatric renal transplantation

Renal transplantation (Tx) is the treatment of choice for end-stage renal disease. The incidence of acute rejection after renal Tx has decreased because of improving early immunosuppression, but the risk of disease recurrence (DR) is becoming relatively high, with a greater prevalence in children than in adults, thereby increasing patient morbidity, graft loss (GL) and, sometimes, mortality rate. The current overall graft loss to DR is 7–8%, mainly due to primary glomerulonephritis (70–80%) and inherited metabolic diseases. The more typical presentation is a recurrence of the full disease, either with a high risk of GL (focal and segmental glomerulosclerosis 14–50% DR, 40–60% GL; atypical haemolytic uraemic syndrome 20–80% DR, 10–83% GL; membranoproliferative glomerulonephritis 30–100% DR, 17–61% GL; membranous nephropathy ∼30% DR, ∼50% GL; lipoprotein glomerulopathy ∼100% DR and GL; primary hyperoxaluria type 1 80–100% DR and GL) or with a low risk of GL [immunoglobulin (Ig)A nephropathy 36–60% DR, 7–10% GL; systemic lupus erythematosus 0–30% DR, 0–5% GL; anti-neutrophilic cytoplasmic antibody (ANCA)-associated glomerulonephritis]. Recurrence may also occur with a delayed risk of GL, such as insulin-dependent diabetes mellitus, sickle cell disease, endemic nephropathy, and sarcoidosis. In other primary diseases, the post-Tx course may be complicated by specific events that are different from overt recurrence: proteinuria or cancer in some genetic forms of nephrotic syndrome, anti-glomerular basement membrane antibodies-associated glomerulonephritis (Alport syndrome, Goodpasture syndrome), and graft involvement as a consequence of lower urinary tract abnormality or human immunodeficiency virus (HIV) nephropathy. Some other post-Tx conditions may mimic recurrence, such as de novo membranous glomerulonephritis, IgA nephropathy, microangiopathy, or isolated specific deposits (cystinosis, Fabry disease). Adequate strategies should therefore be added to kidney Tx, such as donor selection, associated liver Tx, plasmatherapy, specific immunosuppression protocols. In such conditions, very few patients may be excluded from kidney Tx only because of a major risk of DR and repeated GL. In the near future the issue of DR after kidney Tx may benefit from alternatives to organ Tx, such as recombinant proteins, specific monoclonal antibodies, cell/gene therapy, and chaperone molecules

Lupus nephritis in Chinese children--a territory-wide cohort study in Hong Kong

We report a multicenter study of Chinese children in Hong Kong with systemic lupus erythematosus (SLE) nephritis. Children were included if: they fulfilled the ACR criteria, had significant proteinuria or casturia, were Chinese and younger than 19 years and had been diagnosed with SLE between January 1990 and December 2003. Investigators in each center retrieved data on clinical features, biopsy reports, treatment and outcome of these patients. There were 128 patients (eight boys, 120 girls; mean age: 11.9+/-2.8 years). About 50% presented with multisystem illness and 40% with nephritic/nephrotic symptoms. Negative anti-dsDNA antibodies were found in 6% of the patients. Renal biopsy revealed WHO Class II, III, IV and V nephritis in 13 (10%), 22 (17%), 69 (54%) and 13 (10%) patients, respectively. The clinical severity of the nephritis did not accurately predict renal biopsy findings. The follow-up period ranged from 1 to 16.5 years (mean+/-SD: 5.76+/-3.61 years). During the study five patients died (two from lupus flare, one from cardiomyopathy, two from infections). Four patients had endstage renal failure (ESRF) (one died during a lupus flare). All deaths and end-stage renal failure occurred in the Class IV nephritis group. Chronic organ damage was infrequent in the survivors. The actuarial patient survival rates at 5, 10 and 15 years of age were 95.3, 91.8, and 91.8%, respectively. For Class IV nephritis patients, the survival rates without ESRF at 5, 10, and 15 years were 91.5, 82.3 and 76%, respectively. The survival and chronic morbidity rates of the Chinese SLE children in the present study are comparable to those of other published studies.postprin

Influence of Ecto-Nucleoside Triphosphate Diphosphohydrolase Activity on Trypanosoma cruzi Infectivity and Virulence

The protozoan Trypanosoma cruzi is the causative agent of Chagas disease, an endemic zoonosis present in some countries of South and Central Americas. The World Health Organization estimates that 100 million people are at risk of acquiring this disease. The infection affects mainly muscle tissues in the heart and digestive tract. There are no vaccines or effective treatment, especially in the chronic phase when most patients are diagnosed, which makes a strong case for the development of new drugs to treat the disease. In this work we evaluate a family of proteins called Ecto-Nucleoside-Triphosphate-Diphosphohydrolase (Ecto-NTPDase) as new chemotherapy target to block T. cruzi infection in mammalian cells and in mice. We have used inhibitors and antibodies against this protein and demonstrated that T. cruzi Ecto-NTPDases act as facilitators of infection in mammalian cells and virulence factors in mice model. Two of the drugs used in this study (Suramin and Gadolinium) are currently used for other diseases in humans, supporting the possibility of their use in the treatment of Chagas disease