Phosphate Tether-Mediated Approach to the Formal Total Synthesis of (-)-Salicylihalamides A and B

A concise formal synthesis of the cytotoxic macrolides (-)-salicylihalamides A and B is reported. Key features of the synthetic strategy include a chemoselective hydroboration, highly regio- and diastereoselective methyl cuprate addition, Pd-catalyzed formate reduction, and an E-selective ring-closing metathesis to construct the 12-membered macrocycle subunit. Overall, two routes have been developed from a readily prepared bicyclic phosphate (4-steps), a 13-step route and a more efficient 9-step sequence relying on regioselective esterification of a key diol

A Kallikrein 15 (KLK15) single nucleotide polymorphism located close to a novel exon shows evidence of association with poor ovarian cancer survival.

BACKGROUND: KLK15 over-expression is reported to be a significant predictor of reduced progression-free survival and overall survival in ovarian cancer. Our aim was to analyse the KLK15 gene for putative functional single nucleotide polymorphisms (SNPs) and assess the association of these and KLK15 HapMap tag SNPs with ovarian cancer survival. RESULTS: In silico analysis was performed to identify KLK15 regulatory elements and to classify potentially functional SNPs in these regions. After SNP validation and identification by DNA sequencing of ovarian cancer cell lines and aggressive ovarian cancer patients, 9 SNPs were shortlisted and genotyped using the Sequenom iPLEX Mass Array platform in a cohort of Australian ovarian cancer patients (N = 319). In the Australian dataset we observed significantly worse survival for the KLK15 rs266851 SNP in a dominant model (Hazard Ratio (HR) 1.42, 95% CI 1.02-1.96). This association was observed in the same direction in two independent datasets, with a combined HR for the three studies of 1.16 (1.00-1.34). This SNP lies 15 bp downstream of a novel exon and is predicted to be involved in mRNA splicing. The mutant allele is also predicted to abrogate an HSF-2 binding site. CONCLUSIONS: We provide evidence of association for the SNP rs266851 with ovarian cancer survival. Our results provide the impetus for downstream functional assays and additional independent validation studies to assess the role of KLK15 regulatory SNPs and KLK15 isoforms with alternative intracellular functional roles in ovarian cancer survival.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Public perceptions and attitudes toward thalassaemia: Influencing factors in a multi-racial population

<p>Abstract</p> <p>Background</p> <p>Thalassaemia is a common public health problem in Malaysia and about 4.5 to 6% of the Malays and Chinese are carriers of this genetic disorder. The major forms of thalassaemia result in death <it>in utero </it>of affected foetuses (α-thalassaemia) or life-long blood transfusions for survival in β-thalassaemia. This study, the first nationwide population based survey of thalassaemia in Malaysia, aimed to determine differences in public awareness, perceptions and attitudes toward thalassaemia in the multi-racial population in Malaysia.</p> <p>Methods</p> <p>A cross-sectional computer-assisted telephone interview survey of a representative sample of multi-racial Malaysians aged 18 years and above was conducted between July and December 2009.</p> <p>Results</p> <p>Of a total of 3723 responding households, 2846 (76.4%) have heard of thalassaemia. Mean knowledge score was 11.85 (SD ± 4.03), out of a maximum of 21, with higher scores indicating better knowledge. Statistically significant differences (<it>P </it>< 0.05) in total knowledge score by age groups, education attainment, employment status, and average household income were observed. Although the majority expressed very positive attitudes toward screening for thalassaemia, only 13.6% of married participants interviewed have been screened for thalassaemia. The majority (63.4%) were unsupportive of selective termination of foetuses diagnosed with thalassaemia major.</p> <p>Conclusion</p> <p>Study shows that carrier and premarital screening programs for thalassaemia may be more effective and culturally acceptable in the reduction of pregnancies with thalassaemia major. The findings provide insights into culturally congruent educational interventions to reach out diverse socio-demographic and ethnic communities to increase knowledge and cultivate positive attitudes toward prevention of thalassaemia.</p

Cerebral edema in intracerebral hemorrhage : pathogenesis, natural history and potential treatments from translation to clinical trials

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.Peer reviewedPublisher PD

Performance of a Novel Low-Cost, Instrument-Free Plasma Separation Device for HIV Viral Load Quantification and Determination of Treatment Failure in People Living with HIV in Malaysia: a Diagnostic Accuracy Study

HIV viral load (VL) testing is the recommended method for monitoring the response of people living with HIV and receiving antiretroviral therapy (ART). The availability of standard plasma VL testing in low- and middle-income countries (LMICs), and access to this testing, are limited by the need to use fresh plasma. Good specimen collection methods for HIV VL testing that are applicable to resource-constrained settings are needed. We assessed the diagnostic performance of the filtered dried plasma spot (FDPS), created using the newly developed, instrument-free VLPlasma device, in identifying treatment failure at a VL threshold of 1,000 copies/ml in fresh plasma. Performance was compared with that of the conventional dried blood spot (DBS). Venous blood samples from 201 people living with HIV and attending an infectious disease clinic in Malaysia were collected, and HIV VL was quantified using fresh plasma (the reference standard), FDPS, and DBS specimens. VL testing was done using the Roche Cobas AmpliPrep/Cobas TaqMan v2.0 assay. At a threshold of 1,000 copies/ml, the diagnostic performance of the FDPS was superior (sensitivity, 100% [95% confidence interval {CI}, 89.1 to 100%]; specificity, 100% [95% CI, 97.8 to 100%]) to that of the DBS (sensitivity, 100% [95% CI, 89.4 to 100%]; specificity, 36.8% [95% CI, 29.4 to 44.7%]) (P 0.001). A stronger correlation was observed between the FDPS VL and the plasma VL (r 0.94; P 0.001) than between the DBS VL and the plasma VL (r 0.85; P 0.001). The mean difference in VL measures between the FDPS and plasma (plasma VL minus FDPS VL) was 0.127 log10 copies/ml (standard deviation [SD], 0.32), in contrast to – 0.95 log10 copies/ml (SD, 0.84) between the DBS and plasma. HIV VL measurement using the FDPS outperformed that with the DBS in identifying treatment failure at a threshold of 1,000 copies/ml and compared well with the quantification of VL in plasma. The FDPS can be an attractive alternative to fresh plasma for improving access to HIV VL monitoring among people living with HIV on ART in LMICs

Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist

Norwalk Virus–specific Binding to Oyster Digestive Tissues

Specific binding of virus to oysters can selectively concentrate a human pathogen

Dichotomy in the Impact of Elevated Maternal Glucose Levels on Neonatal Epigenome

Context Antenatal hyperglycemia is associated with increased risk of future adverse health outcomes in both mother and child. Variations in offspring's epigenome can reflect the impact and response to in utero glycemic exposure, and may have different consequences for the child. Objective We examined possible differences in associations of basal glucose status and glucose handling during pregnancy with both clinical covariates and offspring cord tissue DNA methylation. Research Design and Methods This study included 830 mother-offspring dyads from the Growing Up in Singapore Towards Healthy Outcomes cohort. The fetal epigenome of umbilical cord tissue was profiled using Illumina HumanMethylation450 arrays. Associations of maternal mid-pregnancy fasting (fasting plasma glucose [FPG]) and 2-hour plasma glucose (2hPG) after a 75-g oral glucose challenge with both maternal clinical phenotypes and offspring epigenome at delivery were investigated separately. Results Maternal age, prepregnancy body mass index, and blood pressure measures were associated with both FPG and 2hPG, whereas Chinese ethnicity (P = 1.9 x 10(-4)), maternal height (P = 1.1 x 10(-4)), pregnancy weight gain (P = 2.2 x 10(-3)), prepregnancy alcohol consumption (P = 4.6 x 10(-4)), and tobacco exposure (P = 1.9 x 10(-3)) showed significantly opposite associations between the 2 glucose measures. Most importantly, we observed a dichotomy in the effects of these glycemic indices on the offspring epigenome. Offspring born to mothers with elevated 2hPG showed global hypomethylation. CpGs most associated with the 2 measures also reflected differences in gene ontologies and had different associations with offspring birthweight. Conclusions Our findings suggest that 2 traditionally used glycemic indices for diagnosing gestational diabetes may reflect distinctive pathophysiologies in pregnancy, and have differential impacts on the offspring's DNA methylome.Peer reviewe

Dichotomy in the Impact of Elevated Maternal Glucose Levels on Neonatal Epigenome

Context Antenatal hyperglycemia is associated with increased risk of future adverse health outcomes in both mother and child. Variations in offspring's epigenome can reflect the impact and response to in utero glycemic exposure, and may have different consequences for the child. Objective We examined possible differences in associations of basal glucose status and glucose handling during pregnancy with both clinical covariates and offspring cord tissue DNA methylation. Research Design and Methods This study included 830 mother-offspring dyads from the Growing Up in Singapore Towards Healthy Outcomes cohort. The fetal epigenome of umbilical cord tissue was profiled using Illumina HumanMethylation450 arrays. Associations of maternal mid-pregnancy fasting (fasting plasma glucose [FPG]) and 2-hour plasma glucose (2hPG) after a 75-g oral glucose challenge with both maternal clinical phenotypes and offspring epigenome at delivery were investigated separately. Results Maternal age, prepregnancy body mass index, and blood pressure measures were associated with both FPG and 2hPG, whereas Chinese ethnicity (P = 1.9 x 10(-4)), maternal height (P = 1.1 x 10(-4)), pregnancy weight gain (P = 2.2 x 10(-3)), prepregnancy alcohol consumption (P = 4.6 x 10(-4)), and tobacco exposure (P = 1.9 x 10(-3)) showed significantly opposite associations between the 2 glucose measures. Most importantly, we observed a dichotomy in the effects of these glycemic indices on the offspring epigenome. Offspring born to mothers with elevated 2hPG showed global hypomethylation. CpGs most associated with the 2 measures also reflected differences in gene ontologies and had different associations with offspring birthweight. Conclusions Our findings suggest that 2 traditionally used glycemic indices for diagnosing gestational diabetes may reflect distinctive pathophysiologies in pregnancy, and have differential impacts on the offspring's DNA methylome.Peer reviewe

Hemorrhage-Adjusted Iron Requirements, Hematinics and Hepcidin Define Hereditary Hemorrhagic Telangiectasia as a Model of Hemorrhagic Iron Deficiency

BACKGROUND: Iron deficiency anemia remains a major global health problem. Higher iron demands provide the potential for a targeted preventative approach before anemia develops. The primary study objective was to develop and validate a metric that stratifies recommended dietary iron intake to compensate for patient-specific non-menstrual hemorrhagic losses. The secondary objective was to examine whether iron deficiency can be attributed to under-replacement of epistaxis (nosebleed) hemorrhagic iron losses in hereditary hemorrhagic telangiectasia (HHT). METHODOLOGY/PRINCIPAL FINDINGS: The hemorrhage adjusted iron requirement (HAIR) sums the recommended dietary allowance, and iron required to replace additional quantified hemorrhagic losses, based on the pre-menopausal increment to compensate for menstrual losses (formula provided). In a study population of 50 HHT patients completing concurrent dietary and nosebleed questionnaires, 43/50 (86%) met their recommended dietary allowance, but only 10/50 (20%) met their HAIR. Higher HAIR was a powerful predictor of lower hemoglobin (p = 0.009), lower mean corpuscular hemoglobin content (p<0.001), lower log-transformed serum iron (p = 0.009), and higher log-transformed red cell distribution width (p<0.001). There was no evidence of generalised abnormalities in iron handling Ferritin and ferritin(2) explained 60% of the hepcidin variance (p<0.001), and the mean hepcidinferritin ratio was similar to reported controls. Iron supplement use increased the proportion of individuals meeting their HAIR, and blunted associations between HAIR and hematinic indices. Once adjusted for supplement use however, reciprocal relationships between HAIR and hemoglobin/serum iron persisted. Of 568 individuals using iron tablets, most reported problems completing the course. For patients with hereditary hemorrhagic telangiectasia, persistent anemia was reported three-times more frequently if iron tablets caused diarrhea or needed to be stopped. CONCLUSIONS/SIGNIFICANCE: HAIR values, providing an indication of individuals' iron requirements, may be a useful tool in prevention, assessment and management of iron deficiency. Iron deficiency in HHT can be explained by under-replacement of nosebleed hemorrhagic iron losses