Single Nucleotide Polymorphism in Gene Encoding Transcription Factor Prep1 Is Associated with HIV-1-Associated Dementia

BACKGROUND: Infection with HIV-1 may result in severe cognitive and motor impairment, referred to as HIV-1-associated dementia (HAD). While its prevalence has dropped significantly in the era of combination antiretroviral therapy, milder neurocognitive disorders persist with a high prevalence. To identify additional therapeutic targets for treating HIV-associated neurocognitive disorders, several candidate gene polymorphisms have been evaluated, but few have been replicated across multiple studies. METHODS: We here tested 7 candidate gene polymorphisms for association with HAD in a case-control study consisting of 86 HAD cases and 246 non-HAD AIDS patients as controls. Since infected monocytes and macrophages are thought to play an important role in the infection of the brain, 5 recently identified single nucleotide polymorphisms (SNPs) affecting HIV-1 replication in macrophages in vitro were also tested. RESULTS: The CCR5 wt/Δ32 genotype was only associated with HAD in individuals who developed AIDS prior to 1991, in agreement with the observed fading effect of this genotype on viral load set point. A significant difference in genotype distribution among all cases and controls irrespective of year of AIDS diagnosis was found only for a SNP in candidate gene PREP1 (p = 1.2 × 10(-5)). Prep1 has recently been identified as a transcription factor preferentially binding the -2,518 G allele in the promoter of the gene encoding MCP-1, a protein with a well established role in the etiology of HAD. CONCLUSION: These results support previous findings suggesting an important role for MCP-1 in the onset of HIV-1-associated neurocognitive disorders

Artesunate potentiates antibiotics by inactivating heme-harbouring bacterial nitric oxide synthase and catalase

<p>Abstract</p> <p>Background</p> <p>A current challenge of coping with bacterial infection is that bacterial pathogens are becoming less susceptible to or more tolerant of commonly used antibiotics. It is urgent to work out a practical solution to combat the multidrug resistant bacterial pathogens.</p> <p>Findings</p> <p>Oxidative stress-acclimatized bacteria thrive in rifampicin by generating antibiotic-detoxifying nitric oxide (NO), which can be repressed by artesunate or an inhibitor of nitric oxide synthase (NOS). Suppressed bacterial proliferation correlates with mitigated NO production upon the combined treatment of bacteria by artesunate with antibiotics. Detection of the heme-artesunate conjugate and accordingly declined activities of heme-harbouring bacterial NOS and catalase indicates that artesunate renders bacteria susceptible to antibiotics by alkylating the prosthetic heme group of hemo-enzymes.</p> <p>Conclusions</p> <p>By compromising NO-mediated protection from antibiotics and triggering harmful hydrogen peroxide burst, artesunate may serve as a promising antibiotic synergist for killing the multidrug resistant pathogenic bacteria.</p

Decrease in thyroid adenoma associated (THADA) expression is a marker of dedifferentiation of thyroid tissue

<p>Abstract</p> <p>Background</p> <p><it>Thyroid adenoma associated (THADA) </it>has been identified as the target gene affected by chromosome 2p21 translocations in thyroid adenomas, but the role of THADA in the thyroid is still elusive. The aim of this study was to quantify <it>THADA </it>gene expression in normal tissues and in thyroid hyper- and neoplasias, using real-time PCR.</p> <p>Methods</p> <p>For the analysis <it>THADA </it>and 18S rRNA gene expression assays were performed on 34 normal tissue samples, including thyroid, salivary gland, heart, endometrium, myometrium, lung, blood, and adipose tissue as well as on 85 thyroid hyper- and neoplasias, including three adenomas with a 2p21 translocation. In addition, <it>NIS </it>(<it>sodium-iodide symporter</it>) gene expression was measured on 34 of the pathological thyroid samples.</p> <p>Results</p> <p>Results illustrated that <it>THADA </it>expression in normal thyroid tissue was significantly higher (<it>p </it>< 0.0001, exact Wilcoxon test) than in the other tissues. Significant differences were also found between non-malignant pathological thyroid samples (goiters and adenomas) and malignant tumors (<it>p </it>< 0.001, Wilcoxon test, t approximation), anaplastic carcinomas (ATCs) and all other samples and also between ATCs and all other malignant tumors (<it>p </it>< 0.05, Wilcoxon test, t approximation). Furthermore, in thyroid tumors <it>THADA </it>mRNA expression was found to be inversely correlated with <it>HMGA2 </it>mRNA. <it>HMGA2 </it>expression was recently identified as a marker revealing malignant transformation of thyroid follicular tumors. A correlation between <it>THADA </it>and <it>NIS </it>has also been found in thyroid normal tissue and malignant tumors.</p> <p>Conclusions</p> <p>The results suggest <it>THADA </it>being a marker of dedifferentiation of thyroid tissue.</p

Catch-up growth following intra-uterine growth-restriction programmes an insulin-resistant phenotype in adipose tissue.

BACKGROUND: It is now widely accepted that the early-life nutritional environment is important in determining susceptibility to metabolic diseases. In particular, intra-uterine growth restriction followed by accelerated postnatal growth is associated with an increased risk of obesity, type-2 diabetes and other features of the metabolic syndrome. The mechanisms underlying these observations are not fully understood. AIM: Using a well-established maternal protein-restriction rodent model, our aim was to determine if exposure to mismatched nutrition in early-life programmes adipose tissue structure and function, and expression of key components of the insulin-signalling pathway. METHODS: Offspring of dams fed a low-protein (8%) diet during pregnancy were suckled by control (20%)-fed dams to drive catch-up growth. This 'recuperated' group was compared with offspring of dams fed a 20% protein diet during pregnancy and lactation (control group). Epididymal adipose tissue from 22-day and 3-month-old control and recuperated male rats was studied using histological analysis. Expression and phosphorylation of insulin-signalling proteins and gene expression were assessed by western blotting and reverse-transcriptase PCR, respectively. RESULTS: Recuperated offspring at both ages had larger adipocytes (P<0.001). Fasting serum glucose, insulin and leptin levels were comparable between groups but increased with age. Recuperated offspring had reduced expression of IRS-1 (P<0.01) and PI3K p110β (P<0.001) in adipose tissue. In adult recuperated rats, Akt phosphorylation (P<0.01) and protein levels of Akt-2 (P<0.01) were also reduced. Messenger RNA expression levels of these proteins were not different, indicating a post-transcriptional effect. CONCLUSION: Early-life nutrition programmes alterations in adipocyte cell size and impairs the protein expression of several insulin-signalling proteins through post-transcriptional mechanisms. These indices may represent early markers of insulin resistance and metabolic disease risk

Beyond crime statistics: the construction and application of a criminogenity monitor in Amsterdam

Criminologists have devoted a great deal of attention to risk factors - also called criminogenic factors - leading to criminal offending. This paper presents a criminogenity monitor which includes 19 risk factors that underlie crime. These factors do not themselves cause criminal behaviour; rather, they must be seen as signals that crimes may be committed. After discussing how the criminogenity monitor was constructed, we apply the risk factors we examined to the situation in Amsterdam, capital city of the Netherlands. The monitor is intended to function particularly as an instrument to rationalise policy-makers' work in targeting and preventing symptoms of crime at three geographical levels: the entire city, its boroughs and its neighbourhoods. © 2012 The Author(s)

Genome-Wide Association Study Identifies Single Nucleotide Polymorphism in DYRK1A Associated with Replication of HIV-1 in Monocyte-Derived Macrophages

Background: HIV-1 infected macrophages play an important role in rendering resting T cells permissive for infection, in spreading HIV-1 to T cells, and in the pathogenesis of AIDS dementia. During highly active anti-retroviral treatment (HAART), macrophages keep producing virus because tissue penetration of antiretrovirals is suboptimal and the efficacy of some is reduced. Thus, to cure HIV-1 infection with antiretrovirals we will also need to efficiently inhibit viral replication in macrophages. The majority of the current drugs block the action of viral enzymes, whereas there is an abundance of yet unidentified host factors that could be targeted. We here present results from a genome-wide association study identifying novel genetic polymorphisms that affect in vitro HIV-1 replication in macrophages. Methodology/Principal Findings: Monocyte-derived macrophages from 393 blood donors were infected with HIV-1 and viral replication was determined using Gag p24 antigen levels. Genomic DNA from individuals with macrophages that had relatively low (n = 96) or high (n = 96) p24 production was used for SNP genotyping with the Illumina 610 Quad beadchip. A total of 494,656 SNPs that passed quality control were tested for association with HIV-1 replication in macrophages, using linear regression. We found a strong association between in vitro HIV-1 replication in monocyte-derived macrophages and SNP rs12483205 in DYRK1A (p = 2.16×10-5). While the association was not genome-wide significant (p<1×10-7), we could replicate this association using monocyte-derived macrophages from an independent group of 31 individuals (p = 0.0034). Combined analysis of the initial and replication cohort increased the strength of the association (p = 4.84×10-6). In addition, we found this SNP to be associated with HIV-1 disease progression in vivo in two independent cohort studies (p = 0.035 and p = 0.0048). Conclusions/Significance: These findings suggest that the kinase DYRK1A is involved in the replication of HIV-1, in vitro in macrophages as well as in vivo. © 2011 Bol et al

Phosphorus dynamics in a tropical forest soil restored after strip mining

Background and aims We hypothesized that successful early ecosystem and soil development in these P-deficient soil materials will initially depend on effective re-establishment of P storage and cycling through organic matter. This hypothesis was tested in a 26-year chronosequence of seven lightly fertilized, oxidic soil materials restored to eucalypt forest communities after bauxite mining. Methods Total P (Pt) status, Hedley P fractions and partial chemical speciation (NaOH-EDTA extraction and analysed using solution 31P NMR spectroscopy) were determined in the restored soils. Results Concentrations of Pt and most Hedley fractions changed with restoration period, declined with depth and were strongly positively correlated with C and N concentrations. Biological P dominated the Labile and Intermediate P fractions while Long-term P was dominantly inorganic. Organic P concentrations in NaOH-EDTA extracts and their chemical natures were similar in restored and unburned native forest sites. Phosphomonoesters were the dominant class of organic P. Conclusions Surprisingly rapid P accretion and fractional changes occurred over 26 years, largely in the surface soils and closely associated with organic matter status. Alkaline hydrolysis products of phosphodiesters and pyrophosphate indicated the importance of microbial P cycling. The important consequences for long-term ecosystem development and biological diversity require further study

Lymphatic filariasis in the Democratic Republic of Congo; micro-stratification overlap mapping (MOM) as a prerequisite for control and surveillance

<p>Abstract</p> <p>Background</p> <p>The Democratic Republic of Congo (DRC) has a significant burden of lymphatic filariasis (LF) caused by the parasite <it>Wuchereria bancrofti</it>. A major impediment to the expansion of the LF elimination programme is the risk of serious adverse events (SAEs) associated with the use of ivermectin in areas co-endemic for onchocerciasis and loiasis. It is important to analyse these and other factors, such as soil transmitted helminths (STH) and malaria co-endemicity, which will impact on LF elimination.</p> <p>Results</p> <p>We analysed maps of onchocerciasis community-directed treatment with ivermectin (CDTi) from the African Programme for Onchocerciasis Control (APOC); maps of predicted prevalence of <it>Loa loa</it>; planned STH control maps of albendazole (and mebendazole) from the Global Atlas of Helminth Infections (GAHI); and bed nets and insecticide treated nets (ITNs) distribution from Demographic and Health Surveys (DHS) as well as published historic data which were incorporated into overlay maps. We developed an approach we designate as micro-stratification overlap mapping (MOM) to identify areas that will assist the implementation of LF elimination in the DRC. The historic data on LF was found through an extensive review of the literature as no recently published information was available.</p> <p>Conclusions</p> <p>This paper identifies an approach that takes account of the various factors that will influence not only country strategies, but suggests that country plans will require a finer resolution mapping than usual, before implementation of LF activities can be efficiently deployed. This is because 1) distribution of ivermectin through APOC projects will already have had an impact of LF intensity and prevalence 2) DRC has been up scaling bed net distribution which will impact over time on transmission of <it>W. bancrofti </it>and 3) recently available predictive maps of <it>L. loa </it>allow higher risk areas to be identified, which allow LF implementation to be initiated with reduced risk where <it>L. loa </it>is considered non-endemic. We believe that using the proposed MOM approach is essential for planning the expanded distribution of drugs for LF programmes in countries co-endemic for filarial infections.</p