The antimalarial activity of Ru–chloroquine complexes against resistant Plasmodium falciparum is related to lipophilicity, basicity, and heme aggregation inhibition ability near water/n-octanol interfaces

We have measured water/n-octanol partition coefficients, pK _a values, heme binding constants, and heme aggregation inhibition activity of a series of ruthenium–π-arene–chloroquine (CQ) complexes recently reported to be active against CQ-resistant strains of Plasmodium falciparum. Measurements of heme aggregation inhibition activity of the metal complexes near water/n-octanol interfaces qualitatively predict their superior antiplasmodial action against resistant parasites, in relation to CQ; we conclude that this modified method may be a better predictor of antimalarial potency than standard tests in aqueous acidic buffer. Some interesting tendencies emerge from our data, indicating that the antiplasmodial activity is related to a balance of effects associated with the lipophilicity, basicity, and structural details of the compounds studied. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Hyperglycaemia, stress oxidant, liver dysfunction and histological changes in diabetic male rat pancreas and liver: protective effect of 17 beta-estradiol

Oxidative stress is thought to play a crucial role in the pathogenesis of chronic diabetic complications. We investigated the protective effects of 17 beta-estradiol (E2) on alloxan-induced stress oxidant, hepatic dysfunction and histological changes in male rats liver and pancreas. Our results showed that 17 beta-estradiol could attenuate the increase of blood glucose in plasma and normalise the hepatic glycogen level. In addition, E2 enhanced superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) (by 207, 52 and 72%, respectively, as compared to diabetic rats), reduced lipid peroxidation in the hepatic tissue (by 54%) and improved the liver dysfunction parameters by the significant decrease of gamma-glytamyl transferase (GGT), phosphatases alkalines (PAL), lactate deshydrogenase (LDH) and aspartate and lactate transaminases (AST and ALT) activities which increased in diabetic rats. Moreover, 17 beta-estradiol treatment in diabetic rats protects against alloxan-induced pancreatic beta-cells and hepatic cells damages.     

Sequence diversity in the amino-terminal region of the malaria-vaccine candidate serine repeat antigen in natural Plasmodium falciparum populations

The amino-terminal region of the serine repeat antigen (SERA) of Plasmodium falciparum is a major malaria-vaccine candidate. Variation in this molecule is essentially dimorphic and alleles may be grouped into the types FCR3, K1 and Honduras1. The Honduras1-type is thought to be the product of homologous recombination between FCR3 and K1 alleles. Here we have examined patterns of sequence diversity in exon II of SERA gene, which encodes most of the amino-terminal region of the antigen, in wild P. falciparum isolates from Indonesia (n=60), Myanmar (n=10) and Thailand (n=14). Among the Indonesian isolates the FCR-3 type predominated (56/60), twenty of which we characterized as novel alleles. A new K1-type allele was also found. In Myanmar, however, all isolates displayed K1-type SERA sequences, which included one new allele. The Honduras1-type was not detected in both countries. In contrast, the 14 isolates from Thailand displayed all three allelic types, with one new Honduras1-type and three new K1-type alleles. On examining the global distribution of SERA alleles by combining previously published sequence data with our results, the FCR3-type alleles predominated in Indonesia, Brazil, and Solomon Islands, but were not found in wild isolates from Myanmar and Africa. Brazil was the only area where K1-type alleles were not found. The distribution of Honduras1-type alleles seems to be mostly restricted to parasite populations from Vietnam, Thailand and Africa. In the allelic families FCR3 and K1, most diversity resulted from variation in sequence and number of octamer repeat units and of allotypes encoding the stretch of serine residues. Sequence analysis indicated that both insertions and deletions of repetitive motifs (creating variation within dimorphic allelic families) and homologous recombination between alleles belonging to different allelic families (creating Honduras1-type alleles) play a role in generating new SERA alleles. Since repeat motifs in the amino-terminal region of SERA contain epitopes recognized by parasite-inhibitory antibodies, sequence variation in exon II may represent one of the parasite's immune-evasion strategies.     

Ethnic differences in the frequency of prostate cancer susceptibility alleles at SRD5A2 and CYP3A4

OBJECTIVES: Ethnic differences in prostate cancer incidence are well documented, with African-Americans having among the highest rates in the world. Ethnic differences in genotypes for genes associated with androgen metabolism including SRD5A2 and CYP3A4 also may exist. The aim of this study was to evaluate differences in these genotypes by ethnicity. METHODS: We studied cancer-free controls representative of four groups: 147 African Americans, 410 Caucasian-Americans, 129 Ghanaians, and 178 Senegalese. PCR-based genotype analysis was undertaken to identify two alleles (V89L, A49T) at SRD5A2 and *1B allele at CYP3A4. RESULTS: Differences were observed for V89L (variant frequency of 30% in Caucasians, 27% in African Americans, 19% in Ghanaians, and 18% in Senegalese, p = 0.002) and were observed for CYP3A4*1B (variant frequencies of 8% in Caucasians, 59% in African Americans, 81% in Ghanaians, and 78% in Senegalese, p = 0.0001). Pooled data combining the present data and previously published data from from Asian, Hispanic, and Arab cancer-free controls showed significant ethnic differences for SRD5A2 and CYP3A4 polymorphisms. Overall, Asians were least likely to have alleles associated with increased prostate cancer risk, while Africans were most likely to have those alleles. CONCLUSIONS: These results suggest that ethnicity-specific differences in genotype frequencies exist for SRD5A2 and CYP3A4. Africans and African-Americans have the highest frequency of those alleles that have previously been associated with increased prostate cancer risk. Future studies should address whether allele frequency differences in part explain differences in prostate cancer incidence in these populations.     

QKI-mediated alternative splicing of the histone variant MacroH2A1 regulates cancer cell proliferation

The histone variant macroH2A1 contains a carboxyl-terminal ～30-kDa domain called a macro domain. MacroH2A1 is produced as one of two alternatively spliced forms, macroH2A1.1 and macroH2A1.2. While the macro domain of macroH2A1.1 can interact with NAD(+)-derived small molecules, such as poly(ADP-ribose), macroH2A1.2's macro domain cannot. Here, we show that changes in the alternative splicing of macroH2A1 pre-mRNA, which lead to a decrease in macroH2A1.1 expression, occur in a variety of cancers, including testicular, lung, bladder, cervical, breast, colon, ovarian, and endometrial. Furthermore, reintroduction of macroH2A1.1 suppresses the proliferation of lung and cervical cancer cells in a manner that requires the ability of macroH2A1.1 to bind NAD(+)-derived metabolites. MacroH2A1.1-mediated suppression of proliferation occurs, at least in part, through the reduction of poly(ADP-ribose) polymerase 1 (PARP-1) protein levels. By analyzing publically available expression and splicing microarray data, we identified splicing factors that correlate with alterations in macroH2A1 splicing. Using RNA interference, we demonstrate that one of these factors, QKI, regulates the alternative splicing of macroH2A1 pre-mRNA, resulting in increased levels of macroH2A1.1. Finally, we demonstrate that QKI expression is significantly reduced in many of the same cancer types that demonstrate a reduction in macroH2A1.1 splicing.     

Dominant Sequences of Human Major Histocompatibility Complex Conserved Extended Haplotypes from HLA-DQA2 to DAXX

We resequenced and phased 27 kb of DNA within 580 kb of the MHC class II region in 158 population chromosomes, most of which were conserved extended haplotypes (CEHs) of European descent or contained their centromeric fragments. We determined the single nucleotide polymorphism and deletion-insertion polymorphism alleles of the dominant sequences from HLA-DQA2 to DAXX for these CEHs. Nine of 13 CEHs remained sufficiently intact to possess a dominant sequence extending at least to DAXX, 230 kb centromeric to HLA-DPB1. We identified the regions centromeric to HLA-DQB1 within which single instances of eight “common” European MHC haplotypes previously sequenced by the MHC Haplotype Project (MHP) were representative of those dominant CEH sequences. Only two MHP haplotypes had a dominant CEH sequence throughout the centromeric and extended class II region and one MHP haplotype did not represent a known European CEH anywhere in the region. We identified the centromeric recombination transition points of other MHP sequences from CEH representation to non-representation. Several CEH pairs or groups shared sequence identity in small blocks but had significantly different (although still conserved for each separate CEH) sequences in surrounding regions. These patterns partly explain strong calculated linkage disequilibrium over only short (tens to hundreds of kilobases) distances in the context of a finite number of observed megabase-length CEHs comprising half a population''s haplotypes. Our results provide a clearer picture of European CEH class II allelic structure and population haplotype architecture, improved regional CEH markers, and raise questions concerning regional recombination hotspots.     

Polymorphism at the Apical Membrane Antigen 1 Gene (AMA1) of the Malaria Parasite Plasmodium falciparum in a Vietnamese Population

The patterns of molecular evolution of the most diverse region of the apical membrane antigen 1 (AMA1) gene in Plasmodium falciparum from a Vietnamese subpopulation (Bao Loc) were investigated. Within the Bao Loc population, the sequenced gene region showed relatively high allelic and nucleotide diversity (0.985 and 0.02694, respectively). Further, the level of population recombination was substantial, resulting in a significant decay of linkage disequilibrium along the gene region. The results suggest that AMA1 is a useful genetic marker for studying the relationships between adaptation of parasite populations (to the human host immune system) and malaria epidemiology.     

Protection influence on grassland structure in Widou Thiengoly's grazing areas at Ferlo

This work consisted of analysing the impact of protection on the Widou Thiengoly's grasslands structure. Data were collected from three selected sites by the quadrat point methodology, consisting of reading the herbaceous on a 10 m line. These sites were the 2013 defended plot (site A), the 2009 semi‐protected plot (site B) and the unprotected grazing areas or off plot (site C). The results revealed a floristic composition of 45 species, belonging to 34 genera and 17 botanical families. The number of species identified was 28 in site A, 31 in site B and 29 in site C. Despite a certain similarity noted in the number of species, the herbaceous vegetation was more balanced in 2013 plot than in 2009 plot and in off plot where it tended to be homogeneous. The herbaceous cover in October 2015 was 99.8% in the 2013 plot; 98.8% in the 2009 plot; and 96.8% in the unprotected sites. The vertical stratification of herbaceous cover showed a better development at the intermediate strata (between 20 cm and 50 cm) in all the sites except in off plot where small grasses dominated. In this study, protection improved the specific balance, while semi‐protection had a positive effect on the specific richness and growth of the grasses.     

Use of a Computerized C-Reactive Protein (CRP) Based Sepsis Evaluation in Very Low Birth Weight (VLBW) Infants: A Five-Year Experience

Background

Serial C-reactive protein (CRP) values may be useful for decision-making regarding duration of antibiotics in neonates. However, established standard of practice for its use in preterm very low birth weight (<1500 g, VLBW) infants are lacking.

Objective

Evaluate compliance with a CRP-guided computerized decision support (CDS) algorithm and compare characteristics and outcomes of compliant versus non-compliant cases. Measure correlation between CRPs and white blood count (WBC) indices.

Methods

We examined 3 populations: 1) all preterm VLBW infants born at Vanderbilt 2006–2011 – we assessed provider compliance with CDS algorithm and measured relevant outcomes; 2) all patients with positive blood culture results admitted to the Vanderbilt NICU 2006–2012 – we tested the correlation between CRP and WBC results within 7 days of blood culture phlebotomy; 3) 1,000 randomly selected patients out of the 7,062 patients admitted to the NICU 2006–2012 – we correlated time-associated CRP values and absolute neutrophil counts.

Results

Of 636 VLBW infants in cohort 1), 569 (89%) received empiric antibiotics for suspected early-onset sepsis. In 409 infants (72%) the CDS algorithm was followed; antibiotics were discontinued ≤48 hours in 311 (55%) with normal serial CRPs and continued in 98 (17%) with positive CRPs, resulting in significant reduction in antibiotic exposure (p<0.001) without increase in complications or subsequent infections. One hundred sixty (28%) were considered non-compliant because antibiotics were continued beyond 48 hours despite negative serial CRPs and blood cultures. Serial CRPs remained negative in 38 (12%) of 308 blood culture-positive infants from cohort 2, but only 4 patients had clinically probable sepsis with single organisms and no immunodeficiency besides extreme prematurity. Leukopenia of any cell type was not linked with CRPs in cohorts 2 and 3.

Conclusions

CDS/CRP-guided antibiotic use is safe and effective in culture-negative VLBW infants. CRP results are not affected by low WBC indices.