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Lygodactylus is the most speciose gekkonid group in Africa, with several additional, candidate species already identified from previous studies. However, in mainland Africa, several groups remain only partially resolved, and there are several taxonomic inconsistencies. Lygodactylus gutturalis was described from Guinea-Bissau in the 1870s and since then, the species has been recorded from West to East Africa, and it is widely distributed through different biomes and ecoregions. However, this taxon has never been studied in detail. In this work, we use an integrative approach, including molecular phylogenetic analysis, morphometrics, skull osteology, and biogeography to provide the first systematic revision of the L. gutturalis species complex. The L. gutturalis complex is a subgroup within the L. picturatus group and includes nine well-differentiated species. We elevate Lygodactylus gutturalis dysmicus to full species status, recognize Lygodactylus depressus as the sister species to L. gutturalis , describe five new species (Lygodactylus kibera sp. nov. , Lygodactylus karamoja sp. nov. , Lygodactylus mirabundus sp. nov. , Lygodactylus leopardinus sp. nov. and Lygodactylus gamblei sp. nov.), and propose an additional candidate species that requires further research. Also, in order to shed light on some taxonomic inconsistencies between the L. gutturalis and Lygodactylus angularis groups, we revisit the L. angularis group, within which we elevate Lygodactylus angularis heeneni and Lygodactylus angularis paurospilus to full species status. The L. gutturalis subgroup diversified during the Late Miocene (between 5–15 Mya), probably as a consequence of multiple vicariant events driven by the expansion of the African savannahs and the establishment of climatic refugia. [ABSTRACT FROM AUTHOR]

Data resource basics Cancer is a rare disease in children and young people[8],[9] and is commonly defined such that it includes any malignant tumour or benign central nervous system (CNS) tumour. Innovative data linkages with routinely collected administrative data facilitate the Yorkshire Register's world-leading programme of research on childhood and young-adult cancer outcomes, extending into ground-breaking areas of social and psychosocial morbidity. Key Features The Yorkshire Register is an established population-based research database of tumours diagnosed in the childhood, adolescent and young-adult age ranges.[1] Set up in 1984 to describe medium- and long-term outcomes for cancer survivors, it remains one of only three specialist databases in the UK covering the paediatric age range and the only one of its kind covering individuals diagnosed aged 25-29 years. 5 SMNs are defined as a malignant neoplasm of any site with a different morphology from that of the primary tumour regardless of time since diagnosis according to the recommended coding of multiple primary cancers.[21],[22] 6 ICCC-3, International Classification of Childhood Cancer (third edition)[20]; CNS, central nervous system. [Extracted from the article]

Folate, vitamins B12, B6, and riboflavin are required for one‐carbon metabolism and may affect bone health, but no previous randomized trial has investigated all four nutrients in this context. We investigated the effect of low‐dose B‐vitamins for 2 years on bone mineral density (BMD) in a dual‐centered, 2‐year randomized controlled trial (RCT) in adults aged ≥50 years. Eligible participants not consuming B‐vitamin supplements or fortified foods >4 times weekly were randomized to receive daily either combined folic acid (200 μg), vitamin B12 (10 μg), vitamin B6 (10 mg), and riboflavin (5 mg), or "active" placebo, whereby both the intervention and placebo groups received vitamin D (10 μg). BMD was assessed before and after intervention using dual‐energy X‐ray absorptiometry (DXA) scanning of the total hip, femoral neck, and lumbar spine (L1 to L4). Of 205 eligible participants randomized, 167 completed the trial in full. B‐vitamin intervention resulted in increases in serum folate (p < 0.001), serum B12 (p < 0.001), and plasma pyridoxal‐5‐phosphate (p < 0.001) and decreases in functional biomarkers of B‐vitamin status, erythrocyte glutathione reductase activation coefficient (p < 0.001), serum methylmalonic acid (MMA; p < 0.001), and serum total homocysteine (p < 0.001). B‐vitamin intervention had no overall effect on BMD, which declined in both treatment groups by approximately 1% (ranging from −0.7% to −1.4%). However, in participants with lower baseline B12 status (serum B12 <246 pmol/L or MMA ≥0.22 μmol/L), B‐vitamin intervention reduced the 2‐year BMD decline versus placebo: adjusted mean (95% confidence interval [CI]) change of −0.003 (−0.008, 0.002) versus −0.015 (−0.021, −0.010) g/cm2 at the total hip and −0.004 (−0.010, 0.001) versus −0.013 (−0.018, −0.007) g/cm2 at the femoral neck. In conclusion, the findings indicate that although low‐dose B‐vitamin intervention for 2 years had no overall effect on BMD, improving B‐vitamin status appears to have specific benefits for bone health in adults with lower B12 status. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Context Aberrant DNA methylation is linked to various diseases. The supply of methyl groups for methylation reactions is mediated by S -adenosylmethionine, which depends on the availability of folate and related B vitamins. Objectives To investigate the influence of key nutrients involved in 1-carbon metabolism on DNA methylation in adults. Data sources Systematic literature searches were conducted in the Cochrane Library, Medline, Embase, Cumulative Index to Nursing and Allied Health Literature Plus, Scopus, and Web of Science databases. Studies that met the inclusion criteria and were published in English were included. Data extraction The first author, study design, sample size, population characteristics, type and duration of intervention, tissue type or cells analyzed, molecular techniques, and DNA methylation outcomes. Data synthesis A meta-analysis of randomized, controlled trials (RCTs) was conducted to investigate the effect of 1-carbon metabolism nutrients on global DNA methylation. Functional analysis and visualization were performed using BioVenn software. Results From a total of 2620 papers screened by title, 53 studies met the inclusion criteria. Qualitative analysis indicated significant associations between 1-carbon metabolism nutrients and DNA methylation. In meta-analysis of RCTs stratified by method of laboratory analysis, supplementation with folic acid alone or in combination with vitamin B12 significantly increased global DNA methylation in studies using liquid chromatography–mass spectrometry, which had markedly lower heterogeneity (n  = 3; Z  =   3.31; P  =   0.0009; I2  = 0%) in comparison to other methods. Functional analysis highlighted a subset of 12 differentially methylated regions that were significantly related to folate and vitamin B12 biomarkers. Conclusion This study supports significant associations between 1-carbon metabolism nutrients and DNA methylation. However, standardization of DNA methylation techniques is recommended to reduce heterogeneity and facilitate comparison across studies. Systematic Review registration PROSPERO registration number: CRD42018091898. [ABSTRACT FROM AUTHOR]

Recent advances in epigenetic research have enabled the development of epigenetic clocks, which have greatly enhanced our ability to investigate molecular processes that contribute to aging and age-related disease. These biomarkers offer the potential to measure the effect of environmental exposures linked to dynamic changes in DNA methylation, including nutrients, as factors in age-related disease. They also offer a compelling insight into how imbalances in the supply of nutrients, particularly B-vitamins, or polymorphisms in regulatory enzymes involved in 1-carbon metabolism, the key pathway that supplies methyl groups for epigenetic reactions, may influence epigenetic age and interindividual disease susceptibility. Evidence from recent studies is critically reviewed, focusing on the significant contribution of the epigenetic clock to nutritional epigenomics and its impact on health outcomes and age-related disease. Further longitudinal studies and randomized nutritional interventions are required to advance the field. [ABSTRACT FROM AUTHOR]

Background: Incidence rates of dementia appear to be declining in high-income countries according to several large epidemiological studies. We aimed to describe declining incident dementia rates across successive birth cohorts in a U.S. population-based sample and to explore the influences of sex and education on these trends.Methods: We pooled data from two community-sampled prospective cohort studies with similar study aims and contiguous sampling regions: the Monongahela Valley Independent Elders Survey (1987-2001) and the Monongahela-Youghiogheny Healthy Aging Team (2006-Ongoing). We identified four decade-long birth cohorts spanning birth years 1902-1941. In an analysis sample of 3,010 participants (61% women, mean baseline age = 75.7 years, mean follow-up = 7.1 years), we identified 257 cases of incident dementia indicated by a Clinical Dementia Rating of 1.0 or higher. We used Poisson regression to model incident dementia rates by birth cohort, age, sex, education, and interactions of Sex × Cohort and Sex × Education. We further examined whether cohort effects varied by education, testing a Cohort × Education interaction and stratifying the models by education.Results: Compared to the earliest birth cohort (1902-1911), each subsequent cohort had a significantly lower incident dementia rate (1912-1921: incidence rate ratio [IRR] = 0.655, 95% confidence interval [95% CI] = 0.477-0.899; 1922-1931: IRR = 0.387, 95% CI = 0.265-0.564; 1932-1941: IRR = 0.233, 95% CI = 0.121-0.449). We observed no significant interactions of either sex or education with birth cohort.Conclusions: A decline in incident dementia rates was observed across successive birth cohorts independent of sex, education, and age. [ABSTRACT FROM AUTHOR]

The U.S. Environmental Protection Agency (EPA) is faced with the challenge of efficiently and credibly evaluating chemical safety often with limited or no available toxicity data. The expanding number of chemicals found in commerce and the environment, coupled with time and resource requirements for traditional toxicity testing and exposure characterization, continue to underscore the need for new approaches. In 2005, EPA charted a new course to address this challenge by embracing computational toxicology (CompTox) and investing in the technologies and capabilities to push the field forward. The return on this investment has been demonstrated through results and applications across a range of human and environmental health problems, as well as initial application to regulatory decision-making within programs such as the EPA's Endocrine Disruptor Screening Program. The CompTox initiative at EPA is more than a decade old. This manuscript presents a blueprint to guide the strategic and operational direction over the next 5 years. The primary goal is to obtain broader acceptance of the CompTox approaches for application to higher tier regulatory decisions, such as chemical assessments. To achieve this goal, the blueprint expands and refines the use of high-throughput and computational modeling approaches to transform the components in chemical risk assessment, while systematically addressing key challenges that have hindered progress. In addition, the blueprint outlines additional investments in cross-cutting efforts to characterize uncertainty and variability, develop software and information technology tools, provide outreach and training, and establish scientific confidence for application to different public health and environmental regulatory decisions. [ABSTRACT FROM AUTHOR]

2,4,6-tribromophenol (TBP, CAS No. 118-79-6) is widely used as a brominated flame retardant and wood antifungal agent. TBP is frequently detected in environmental matrices, biota, and humans. In female SD rats, systemically available TBP (10 µmol/kg, IV) was rapidly excreted primarily via urine, with approximately 61% of the dose recovered after 4 h, and 89%–94% in 24 h; 5% was recovered in feces; and 1%–2% in blood/tissues. TBP administered to female SD rats (0.1–1000 µmol/kg) by gavage was well absorbed, with approximately 25% eliminated via urine after 4 h and approximately 88% after 24 h. Approximately 11% of a single oral dose was recovered in bile. Male SD rats and B6C3F1/J mice of both sexes had similar disposition profiles when administered a single oral dose of TBP (10 µmol/kg). Following administration, fecal recoveries varied only slightly by dose, sex, or species. TBP readily passed unchanged through both human (ex vivo only) and rat skin with between 55% and 85% of a 100 nmol/cm2 passing into or through skin. Concentrations of TBP in blood fit a two-compartment model after IV-dosing and a one-compartment model after oral dosing. Urine contained a mixture of TBP, TBP-glucuronide, and TBP-sulfate. Fecal extracts contained only parent TBP whereas bile contained only TBP-glucuronide. TBP did not appear to bioaccumulate or alter its own metabolism after repeated administration. TBP was readily absorbed at all doses and routes tested with an oral bioavailability of 23%–27%; 49% of TBP is expected to be dermally bioavailable in humans. From these data, we conclude that humans are likely to have significant systemic exposure when TBP is ingested or dermal exposure occurs. [ABSTRACT FROM AUTHOR]

Most research on health systems examines contemporary problems within one, or at most a few, countries. Breaking with this tradition, we present a series of case studies in a book written by key policymakers, scholars and experts, looking at health systems and their projected successes to 2030. Healthcare Systems: Future Predictions for Global Care includes chapters on 52 individual countries and five regions, covering a total of 152 countries. Synthesised, two key contributions are made in this compendium. First, five trends shaping the future healthcare landscape are analysed: sustainable health systems; the genomics revolution; emerging technologies; global demographics dynamics; and new models of care. Second, nine main themes arise from the chapters: integration of healthcare services; financing, economics and insurance; patient-based care and empowering the patient; universal healthcare; technology and information technology; aging populations; preventative care; accreditation, standards, and policy; and human development, education and training. These five trends and nine themes can be used as a blueprint for change. They can help strengthen the efforts of stakeholders interested in reform, ranging from international bodies such as the World Health Organization, the International Society for Quality in Health Care and the World Bank, through to national bodies such as health departments, quality and safety agencies, non-government organisations (NGO) and other groups with an interest in improving healthcare delivery systems. This compendium offers more than a glimpse into the future of healthcare-it provides a roadmap to help shape thinking about the next generation of caring systems, extrapolated over the next 15 years. [ABSTRACT FROM AUTHOR]

Prioritizing the risk posed by thousands of chemicals potentially present in the environment requires exposure, toxicity, and toxicokinetic (TK) data, which are often unavailable. Relatively high throughput, in vitro TK (HTTK) assays and in vitro-to-in vivo extrapolation (IVIVE) methods have been developed to predict TK, but most of the in vivo TK data available to benchmark these methods are from pharmaceuticals. Here we report on new, in vivo rat TK experiments for 26 non-pharmaceutical chemicals with environmental relevance. Both intravenous and oral dosing were used to calculate bioavailability. These chemicals, and an additional 19 chemicals (including some pharmaceuticals) from previously published in vivo rat studies, were systematically analyzed to estimate in vivo TK parameters (e.g., volume of distribution [Vd], elimination rate). For each of the chemicals, rat-specific HTTK data were available and key TK predictions were examined: oral bioavailability, clearance, Vd and uncertainty. For the non-pharmaceutical chemicals, predictions for bioavailability were not effective. While no pharmaceutical was absorbed at less than 10%, the fraction bioavailable for non-pharmaceutical chemicals was as low as 0.3%. Total clearance was generally more underestimated for nonpharmaceuticals and Vd methods calibrated to pharmaceuticals may not be appropriate for other chemicals. However, the steady-state, peak, and time-integrated plasma concentrations of nonpharmaceuticals were predicted with reasonable accuracy. The plasma concentration predictions improved when experimental measurements of bioavailability were incorporated. In summary, HTTK and IVIVE methods are adequately robust to be applied to high throughput in vitro toxicity screening data of environmentally relevant chemicals for prioritizing based on human health risks. [ABSTRACT FROM AUTHOR]

Current strategies for predicting carcinogenic mode of action for nongenotoxic chemicals are based on identification of early key events in toxicity pathways. The goal of this study was to evaluate short-term key event indicators resulting from exposure to androstenedione (A4), an androgen receptor agonist and known liver carcinogen in mice. Liver cancer is more prevalent in men compared with women, but androgen-related pathways underlying this sex difference have not been clearly identified. Short-term hepatic effects of A4 were compared with reference agonists of the estrogen receptor (ethinyl estradiol, EE) and glucocorticoid receptor (prednisone, PRED). Male B6C3F1 mice were exposed for 7 or 28 days to A4, EE, or PRED. EE increased and PRED suppressed hepatocyte proliferation, while A4 had no detectable effects. In a microarray analysis, EE and PRED altered >3000 and >670 genes, respectively, in a dose-dependent manner, whereas A4 did not significantly alter any genes. Gene expression was subsequently examined in archival liver samples from male and female B6C3F1 mice exposed to A4 for 90 days. A4 altered more genes in females than males and did not alter expression of genes linked to activation of the mitogenic xenobiotic receptors AhR, CAR, and PPARa in either sex. A gene expression biomarker was used to show that in female mice, the high dose of A4 activated the growth hormone-regulated transcription factor STAT5b, which controls sexually dimorphic gene expression in the liver. These findings suggest that A4 induces subtle agerelated effects on STAT5b signaling that may contribute to the higher risk of liver cancer in males compared with females. [ABSTRACT FROM AUTHOR]

Current strategies for predicting adverse health outcomes of environmental chemicals are centered on early key events in toxicity pathways. However, quantitative relationships between early molecular changes in a given pathway and later health effects are often poorly defined. The goal of this study was to evaluate short-term key event indicators using qualitative and quantitative methods in an established pathway of mouse liver tumorigenesis mediated by peroxisome proliferator-activated receptor alpha (PPARα). Male B6C3F1 mice were exposed for 7 days to di (2-ethylhexyl) phthalate (DEHP), di-n-octyl phthalate (DNOP), and n-butyl benzyl phthalate (BBP), which vary in PPARα activity and liver tumorigenicity. Each phthalate increased expression of select PPARα target genes at 7 days, while only DEHP significantly increased liver cell proliferation labeling index (LI). Transcriptional benchmark dose (BMDT) estimates for dose-related genomic markers stratified phthalates according to hypothetical tumorigenic potencies, unlike BMDs for non-genomic endpoints (relative liver weights or proliferation). The 7-day BMDT values for Acot1 as a surrogate measure for PPARα activation were 29, 370, and 676 mg/kg/day for DEHP, DNOP, and BBP, respectively, distinguishing DEHP (liver tumor BMD of 35 mg/kg/day) from non-tumorigenic DNOP and BBP. Effect thresholds were generated using linear regression of DEHP effects at 7 days and 2-year tumor incidence values to anchor early response molecular indicators and a later phenotypic outcome. Thresholds varied widely by marker, from 2-fold (Pdk4 and proliferation LI) to 30-fold (Acot1) induction to reach hypothetical tumorigenic expression levels. These findings highlight key issues in defining thresholds for biological adversity based on molecular changes. [ABSTRACT FROM AUTHOR]

Due to extensive use, human exposure to multiple pyrethroid insecticides occurs frequently. Studies of pyrethroid neurotoxicity suggest a common mode of toxicity and that pyrethroids should be considered cumulatively to model risk. The objective of this work was to use a pyrethroid mixture that reflects human exposure to common pyrethroids to develop comparative toxicokinetic profiles in rats, and then model the relationship between brain concentration and motor activity. Data from a national survey of child care centers were used to make a mixture reflecting proportions of the most prevalent pyrethroids: permethrin, cypermethrin, β-cyfluthrin, deltamethrin, and esfenvalerate. The mixture was administered orally at one of two concentrations (11.2 and 27.4 mg/kg) to adult male rats. At intervals from 1 to 24h, motor activity was assessed and the animals were sacrificed. Pyrethroid concentrations were measured in the blood, liver, fat, and brain. After controlling for dose, there were no differences in any tissue concentrations, except blood at the initial time point. Elimination half-lives for all pyrethroids in all tissues were < 7h. Brain concentrations of all pyrethroids (when cis- and trans-permethrin were pooled) at the initial time point were proportional to their relative doses. Decreases in motor activity indicated dose additivity, and the relationship between pyrethroid brain concentration and motor activity was described by a four-parameter sigmoidal Emax model. This study links environmental data with toxicokinetic and neurobehavioral assays to support cumulative risk assessments of pyrethroid pesticides. The results support the additive model of pyrethroid effect on motor activity and suggest that variation in the neurotoxicity of individual pyrethroids is related to toxicodynamic rather than toxicokinetic differences. [ABSTRACT FROM PUBLISHER]

Permethrin is a broad-spectrum pyrethroid insecticide and among the most widely used insecticides in homes and crops. Managing the risks for pesticides such as permethrin depends on the ability to consider diverse exposure scenarios and their relative risks. Physiologically based pharmacokinetic models of delta methrin disposition were modified to describe permethrin kinetics in the rat and human. Unlike formulated deltamethrin which consists of a single stereoisomer, permethrin is formulated as a blend of cis- and trans-diastereomers. We assessed time courses for cis-permethrin and trans-permethrin in several tissues (brain, blood, liver, and fat) in the rat following oral administration of 1 and 10mg/kg permethrin (cis/trans: 40/60). Accurate simulation of permethrin in the rat suggests that a generic model structure is promising for modeling pyrethroids. Human in vitro data and appropriate anatomical information were used to develop a provisional model of permethrin disposition with structures for managing oral, dermal, and inhalation routes of exposure. The human permethrin model was used to evaluate dietary and residential exposures in the U.S. population as estimated by EPA’s Stochastic Human Exposure and Dose Simulation model. Simulated cis- and trans-DCCA, metabolites of permethrin, were consistent with measured values in the National Health and Nutrition Examination Survey, indicating that the model holds promise for assessing population exposures and quantifying dose metrics. [ABSTRACT FROM AUTHOR]

The metalloid arsenic is a natural environmental contaminant to which humans are routinely exposed in food, water, air, and soil. Arsenic has a long history of use as a homicidal agent, but in the past 100 years arsenic, has been used as a pesticide, a chemotherapeutic agent and a constituent of consumer products. In some areas of the world, high levels of arsenic are naturally present in drinking water and are a toxicological concern. There are several structural forms and oxidation states of arsenic because it forms alloys with metals and covalent bonds with hydrogen, oxygen, carbon, and other elements. Environmentally relevant forms of arsenic are inorganic and organic existing in the trivalent or pentavalent state. Metabolism of arsenic, catalyzed by arsenic (+3 oxidation state) methyltransferase, is a sequential process of reduction from pentavalency to trivalency followed by oxidative methylation back to pentavalency. Trivalent arsenic is generally more toxicologically potent than pentavalent arsenic. Acute effects of arsenic range from gastrointestinal distress to death. Depending on the dose, chronic arsenic exposure may affect several major organ systems. A major concern of ingested arsenic is cancer, primarily of skin, bladder, and lung. The mode of action of arsenic for its disease endpoints is currently under study. Two key areas are the interaction of trivalent arsenicals with sulfur in proteins and the ability of arsenic to generate oxidative stress. With advances in technology and the recent development of animal models for arsenic carcinogenicity, understanding of the toxicology of arsenic will continue to improve. [ABSTRACT FROM AUTHOR]

Inorganic arsenic (Asi) is a known human bladder carcinogen. The objective of this study was to examine the concentration dependence of the genomic response to Asi in the urinary bladders of mice. C57BL/6J mice were exposed for 1 or 12 weeks to arsenate in drinking water at concentrations of 0.5, 2, 10, and 50 mg As/l. Urinary bladders were analyzed using gene expression microarrays. A consistent reversal was observed in the direction of gene expression change: from predominantly decreased expression at 1 week to predominantly increased expression at 12 weeks. These results are consistent with evidence from in vitro studies of an acute adaptive response that is suppressed on longer exposure due to downregulation of Fos. Pathways with the highest enrichment in gene expression changes were associated with epithelial-to-mesenchymal transition, inflammation, and proliferation. Benchmark dose (BMD) analysis determined that the lowest median BMD values for pathways were above 5 mg As/l, despite the fact that pathway enrichment was observed at the 0.5 mg As/l exposure concentration. This disparity may result from the nonmonotonic nature of the concentration-responses for the expression changes of a number of genes, as evidenced by the much fewer gene expression changes at 2 mg As/l compared with lower or higher concentrations. Pathway categories with concentration-related gene expression changes included cellular morphogenesis, inflammation, apoptosis/survival, cell cycle control, and DNA damage response. The results of this study provide evidence of a concentration-dependent transition in the mode of action for the subchronic effects of Asi in mouse bladder cells in the vicinity of 2 mg Asi/l. [ABSTRACT FROM AUTHOR]

Mirfazaelian et al. developed a physiologically based pharmacokinetic (PBPK) model for the pyrethroid pesticide deltamethrin in the rat. This model describes gastrointestinal (GI) tract absorption as a saturable process mediated by phase III efflux transporters which pump deltamethrin out of the intestinal enterocytes into the GI tract lumen, resulting in minimal net absorption at low concentrations and increasing absorption at higher concentrations. In the present study, the dose dependency in absorption of deltamethrin was examined in male Long Evans rats using po exposures predicted by the Mirfazaelian model to yield different po bioavailability values. No difference in the bioavailability from single po doses of 0.3 and 3.0 mg/kg deltamethrin was observed. Based on this finding, the Mirfazaelian PBPK model was modified to exclude a saturable absorption process. Other changes to the Mirfazaelian model included describing all tissue compartments with diffusion-limited kinetics and a single blood compartment. These changes improved model predictions of deltamethrin tissue concentration data from the present study and the literature. The rat model was then scaled to humans. The model predicted a twofold greater peak deltamethrin brain concentration and threefold greater area under the curve (AUC0–48 h) for humans following an po exposure of 1 mg/kg. Based on this model, humans would have greater distribution of deltamethrin to the brain for the same administered po dose compared to rats. The relative sensitivity to deltamethrin between rats and humans depends on both pharmacokinetic and pharmacodynamic differences. Species differences in the pharmacodynamic responses to deltamethrin between rats and humans remain uncharacterized. [ABSTRACT FROM PUBLISHER]

Reduced insulin sensitivity and glucose intolerance have been long suspected of having important involvement in aging. Here we report that in studies of calorie restriction (CR) effects in mutant (Propldf and growth hormone receptor knockout [GHIRKO]) and normal mice, insulin sensitivity was strongly associated with longevity. Of particular interest was enhancement of the already increased insulin sensitivity in CR df/df mice in which longevity was also further extended and the lack of changes in insulin sensitivity in calorically restricted GHRKO mice in which there was no further increase in average life span. We suggest that enhanced insulin sensitivity, in conjunction with reduced insulin levels, may represent an important (although almost certainly not exclusive) mechanism of increased longevity in hypopituitary, growth hormone (GH)-resistant, and calorie-restricted animals. We also report that the effects of GH treatment on insulin sensitivity may be limited to the period of OH administration. [ABSTRACT FROM AUTHOR]

We examined associations between multiple aspects of social resources and 5-year change in performance on different domains of cognitive function. Results indicated that lower satisfaction with support was associated with decline in episodic memory performance over 5 years. We also found significant interactions between age and social networks of family and friends and satisfaction with support for the separate cognitive domains. The results suggest that social resources may be differentially important for cognitive change but that different cognitive domains respond in a similar pattern to social resources. [ABSTRACT FROM AUTHOR]

Little is known about potential longitudinal relationships between participation in social, physical, and intellectual activities and later cognitive performance. Data from the Victoria Longitudinal Study (n = 530) were used to test whether baseline and change in lifestyle engagement were related to corresponding indicators of cognitive speed (measured by mean-level and intraindividual variability). Regressions based on random effects model estimates showed that cross-sectional activity participation predicted corresponding values of both mean-level and intraindividual variability, but few longitudinal relationships were significant. Overall, a higher frequency of participation in cognitively complex activities was related to faster response times and lower intraindividual variability. Findings suggest that activity level at one point in time may be a more important predictor of cognition than an individual's changes in activity level. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to investigate the antibacterial activity of candles containing specific-antibacterial compounds, such as essential oils and their constituent compounds. The importance of the ionization products from the flame and the aerial concentration of the volatile compounds were investigated. Methods and Results: Agar plates inoculated with Escherichia coli (DH5 α) or Staphylococcus aureus (NCTC strain number 8532) were exposed in a large air-tight chamber to candle flames combined with the volatile bactericidal compounds β-pinene and orange oil. A steady decline in E. coli numbers was observed over time because of the effect of a candle flame. This was significantly increased by the addition of volatile oils. The number of S. aureus colonies was not reduced by a plain candle, but significant reductions were caused following exposure to β-pinene and orange oil candles. As aerial concentration of the volatiles was increased the viability of E. coli and S. aureus declined. Ionization products from the flame made a significant contribution to the observed effects, as intercepting the ions on a grounded grid over the agar plates allowed at least 20% more cells to survive. Conclusions: This study demonstrates the antibacterial properties of ionization products from a candle flame, and that this effect can be significantly increased by the addition of specific-antibacterial compounds, such as orange oil and β-pinene. The role of both the ionization products from the candle flame and the concentration of volatile compounds released are important to the effect. Significance and Impact of the Study: The technique described here offers a new and novel technique for reducing the concentration of bacteria on surfaces. [ABSTRACT FROM AUTHOR]

HERV elements make up a significant fraction of the human genome and, as jnterspersed repetitive elements, have the capacity to provide substrates for ectopic recombination and gene conversion events. To understand the extent to which these events occur and gain further insight into the complex evolutionary history of these elements in our genome, we undertook a phylogenetic study of the long terminal repeat sequences of 15 HERV-K(HML-2) elements in various primate species. This family of human endogenous retroviruses first entered the primate genome between 35 and 45 million years ago. Throughout primate evolution, these elements have undergone bursts of amplification. From this analysis, which is the largest-scale study of HERV sequence dynamics during primate evolution to date, we were able to detect intraelement gene conversion and recombination at five HERV-K loci. We also found evidence for replacement of an ancient element by another HERV-K provirus, apparently reflecting an occurrence of retroviral integration by homologous recombination. The high frequency of these events casts doubt on the accuracy of integration time estimates based only on divergence between retroelement LTRs. [ABSTRACT FROM AUTHOR]

The relationship of exposure dose and tissue concentration of parent chemical and metabolites is a critical issue in cases where toxicity may be mediated by a metabolite or by parent chemical and metabolite acting together. This has emerged as an issue for inorganic arsenic (iAs), because both its trivalent and pentavalent methylated metabolites have unique toxicities; the methylated trivalent metabolites also exhibit greater potency than trivalent inorganic arsenic (arsenite, AsIII) for some endpoints. In this study, the time-course tissue distributions for iAs and its methylated metabolites were determined in blood, liver, lung, and kidney of female B6C3F1 mice given a single oral dose of 0, 10, or 100 μmol As/kg (sodium arsenate, AsV). Compared to other organs, blood concentrations of iAs, mono- (MMA), and dimethylated arsenic (DMA) were uniformly lower across both dose levels and time points. Liver and kidney concentrations of iAs were similar at both dose levels and peaked at 1 h post dosing. Inorganic As was the predominant arsenical in liver and kidney up to 1 and 2 h post dosing, with 10 and 100 μmol As/kg, respectively. At later times, DMA was the predominant metabolite in liver and kidney. By 1 h post dosing, concentrations of MMA in kidney were 3- to 4-fold higher compared to other tissues. Peak concentrations of DMA in kidney were achieved at 2 h post dosing for both dose levels. Notably, DMA was the predominant metabolite in lung at all time points following dosing with 10 μmol As/kg. DMA concentration in lung equaled or exceeded that of other tissues from 4 h post dosing onward for both dose levels. These data demonstrate distinct organ-specific differences in the distribution and methylation of iAs and its methylated metabolites after exposure to AsV that should be considered when investigating mechanisms of arsenic-induced toxicity and carcinogenicity. [ABSTRACT FROM AUTHOR]

A study to analyse the effects of left ventricular diastolic pressure on coronary pressure-flow relations during physiological vasodilatation was carried out in 14 anaesthetised dogs. The left circumflex artery was perfused at controlled pressures via an extracorporeal circuit and vasodilatation induced by 15 s occlusion of coronary flow. The relation between end diastolic coronary perfusion pressure and flow at peak hyperaemia was linear above 40 mmHg (group 1, n = 7) and became curvilinear at perfusion pressures below 40 mmHg (group 2, n = 7). At a mean left ventricular end diastolic pressure of 8.6(0.8) mmHg the mean zero flow intercept (Pint) in group 1 was 22.5(2.3) mmHg. Graded increases in left ventricular end diastolic pressure by infusion of blood resulted in a parallel rightward shift of the vasodilated pressure-flow relation (Pint = 1.06×LVEDP+13.8 mmHg, r = 0.87). The curvilinear relations at low perfusion pressures in group 2 had lower zero flow intercept pressures (Pint = 4.8(0.7) mmHg at left ventricular end diastolic pressure 6.6(1.5) mmHg). As with group 1, graded increases in left ventricular end diastolic pressure caused a rightward shift of the pressure-flow relation, with a direct relation between left ventricular end diastolic pressure and zero flow intercept (Pint = 0.93×LVEDP+3.9 mmHg, r = 0.89). Diastolic coronary pressure-flow relations during physiological vasodilatation are essentially linear at perfusion pressures >40 mmHg but are appreciably curved at lower pressures. Increases in left ventricular end diastolic pressure cause a parallel rightward shift of the linear region of the pressure-flow relation. Left ventricular diastolic pressure appears to be a major determinant of the zero flow intercept extrapolated from the curved low pressure region. [ABSTRACT FROM PUBLISHER]

The left anterior descending coronary artery was ligated in 58 open-chest anaesthetised dogs; 23 were controls, 15 were given intravenous propranolol 1 mg·kg−1 before and at 6 h intervals after coronary ligation, nine had bilateral cervical vagal nerve stimulation (VS) before and for 4 to 6 h after coronary ligation, and 11 had both VS and propranolol. None of the 20 dogs undergoing VS developed ventricular fibrillation within the first hour after coronary ligation compared to nine of the remaining 38 (P<0.05). Compared to controls, myocardial creatine kinase (CK) depletion in the epicardial layer of the infarct centre measured 24 h after coronary ligation was significantly less in the groups treated separately with vagal nerve stimulation and propranolol. Myocardial blood flow (MBF) measured at 15 min after coronary ligation was reduced to the normal myocardium by the interventions, but was unchanged at the infarct centre. Severely ischaemic myocardium (MBF ≤ 20% of normal) was better protected by the interventions than was moderately ischaemic myocardium. At 15 min after coronary ligation, the heart rate — blood pressure product (RPP) was reduced compared with controls by propranolol (18% reduction, P<0.05), reduced more by vagal stimulation (by 37%, P<0.001) and still more by vagal stimulation with propranolol (by 43%, P<0.001). Preservation of CK in myocardium with MBF ≤20% of normal was improved by VS and propranolol given separately roughly in proportion to reduction in RPP, but further reduction in RPP by VS and propranolol together did not improve CK levels further. We conclude that there may be an optimum level of indices of oxygen demand for preservation of very ischaemic myocardium in experimental infarction. [ABSTRACT FROM PUBLISHER]

The lipoxygenase catalyzed epoxidation of 7,8-dihydroxy-7,8-dihydrobenzo[α]pyrene (BP-7,8-diol) was examined. Epoxidation of the BP-7,8-diol was catalyzed by 5- and 15-lipoxygenase in the presence of either arachidonic acid, γ-linolenic add, or 15-hydroperoxyeicosatetraenoic acid (15-HPETE). The anti-9,10-epoxy-7,8-dihydroxy-7,8-dihydro benzo[α]pyrene isomer was formed in greater quantities than the isomer, indicative of peroxyl radical mediated epoxidation. Epoxidation was dependent on time, enzyme and fatty acid concentration. There was no difference in the time course of epoxidation with either arachidonic acid or 15-HPETE, although the initial rate of oxygen consumption was ∼55-fold greater with arachidonic acid. The lipoxygenase inhibior and anit-oxidant nordihydroguaiaretic acid inhibitor and anti-oxidant nordihydroguaiaretic acid inhinited epoxidation in a dose-dependent manner inincubations initiated with either arachidonic acid or 15-HPETE. The anti-oxidant butylated hydroxyanisole also inhibited the epoxidation. Incubations conducted under anaerobic conditions with 15-lipoxygenase and either arachidonic acid or 15-HPETE significantly decreased qpoxidation. This suggests that the oxygen inserted into BP-7-8-diol is derived from the atmosphere. The epoxidixing peroxyl radicals could not be detected by using the ESR spin trapping technique in incubations of 15-lipoxygenase with 15-HPETE. This radical. formed by reduction and rearrangement of the hydroperoxide, may trap oxygen toe form a peroxyl radical We propose that the epoxidizing species is a peroxyl radical derived from 15-HPETE rather than from arachidonic acid. This proposal is based on the similar amounts of epoxidation, but dissimilar amount of oxygen consumed with both fatty acids. Since lipoxygenases are widely distributed , especially in areas where tumors arise such as the pulmonary epithelium, peroxyl radical formation by these enxymes may have an important role in chemical carcinogenesis. [ABSTRACT FROM PUBLISHER]

The peroxidase-catalyzed metabolism of (bi) sulfite (hydrated sulfur dioxide) in the presence of (±)-7, 8-dihydroxy-7, 8-dihydrobenzo()pyrene (BP-7, 8-diol) was examined. Both horseradish peroxidase and prostaglandian peroxidase catalyze the one-election oxidation of (bi)sulfite. This results in the formation of a sulfurtrioxide radical anion which then reacts with molecular oxygen to form a peroxyl radical. This (bi)sulfite-derived peroxyl radical then reacts with BP-7, 8-diol to form BP-7, 8-diol-9, 10-epoxides, the ultimate carcinogenic form of benzo()pyrene (BP). Addition of (bi)sulfite to incubations containing BP-7, 8-diol and an active peroxidase resulted in significantly increased levels of BP diol-epoxide formation. This result may, in part, explain the reported co-carcinogenic effect of sulfur dioxide on BP-induced tumors in the respiratory tracts of rats and hamsters. The sulfur trioxide radical anion also reacts directly with BP-7, 8-diol to form a sulfonate adduct. This reaction was particularly significant under conditions where molecular oxygen was depleted from the incubations. While the significance of this particular adduct is not known, its formation suggests that the sulfur trioxide radical anion generated during the peroxidase-catalyzed oxidation of (bi)sulfite could react with a wide assortment of compounds to form sulfonate adducts. [ABSTRACT FROM PUBLISHER]

The metabolism of the carcinogenic nitrosamine, N'-nitrosonornicotine (NNN), to reactive intermediates which bind covalently was assessed using male Sprague-Dawley rat liver microsomes. The NADPH-dependent covalent binding of [C]NNN was linear with time up to 90 min and protein concentration up to 3.0 mg/ml. The apparent and of the binding were determined from the initial velocities and found to be 0.91 mM and 4.7 pmol/min/mg protein, respectively. Although NNN is not a hepatocarcinogen, this amount of NADPH-dependent covalent binding is 7-fold greater than that reported for dimethylnitrosamine, a potent hepatocarcinogen. Extensive covalent binding of [C]NNN to liver and muscle microsomal protein was also present in the absence of an NADPH-generating system and in the presence of 50% methanol, indicating a non-enzymatically mediated reaction. Addition of the nucleophiles glutathione, cysteine and N-acetylcysteine significantly decreased ( <0.01) the non-NADPH-dependent binding, but did not affect NADPH-dependent binding. addition of the cytochrome P-450 inhibitors metyrapone, piperonyl butoxide and SKF-525A significantly decreased ( <0.05) NADPH-dependent binding of [C]NNN by 27–40%. NADH did not replace NADPH in supporting covalent binding. Replacement of an air atmosphere with nitrogen or CO: O(8: 2) significantly decreased ( <0.05) NADPH-dependent binding of [C]NNN by 40 and 27%, respectively. Aroclor 1254 pre-treatment of the rats did not enhance the NADPH-dependent binding of [C]NNN. These data indicate that cytochrome P-450 is at least in part responsible for the metabolic activation of the carcinogen NNN but also suggest additional mechanisms of activation. [ABSTRACT FROM PUBLISHER]

We validated a commercial enzyme-linked immunosorbent assay (ELISA), Helico-G, in diagnosing H. pylori in 129 patients (mean age 50 years, range 15-86). We analysed the results of endoscopy against serology to see whether there was a possibility of adopting the strategy of not endoscoping dyspeptic subjects under the age of 45. H. pylori infection was considered present if either histology and/or culture were positive. The ELISA had a sensitivity of 88%, specificity of 72%, positive predictive value of 85%, negative predictive value of 77% and accuracy of 82% in detecting H. pylori. In a subgroup of 52 subjects aged 45 or less (mean age 35 years, range 15-45), 17 out of 25 patients with positive endoscopic findings were H. pylori seropositive while 16 out of 27 patients had normal endoscopic findings. Eighteen out of the 52 patients (35%) were H. pylori seronegative and normal endoscopically except for five patients (10%) who had mild to moderate oesophagitis and two who had non-erosive gastritis (4%). All patients with duodenal ulcer disease (7) were seropositive giving predictive values of positive and negative serology for a diagnosis of duodenal ulcer disease as 28% and 100%, respectively. Therefore adopting a strategy of endoscoping subjects under the age of 45 only if they were H. pylori seropositive would have saved 35% of endoscopies in this age group but missed oesophagitis in 10%. Negative serology would tend to exclude duodenal ulcer disease while positive serology discriminates poorly for it. Serology may be a useful adjunct in screening to reduce endoscopy workload provided that patients with gastro-oesophageal reflux symptoms are excluded. [ABSTRACT FROM PUBLISHER]

The effect of dose on arsenate disposition was studied in adult female B6C3FI mice, dosed po with 0.5 to 5000 μ/kg [As]-arsenate in water. Urine was collected at 1, 2, 4, 8, 12, 24, and 48 hr and feces at 24 and 48 hr postexposure. The mice were euthanized at 48 hr and tissues were removed. Recovery of ar senate-derived radioactivity ranged from 83 to 89%; 66–79% of the dose was excreted in urine, 10–18% in feces, and <1% remained in the tissues. Although dose had no effect on the 48-hr excretion of radioactivity, the level of radioactivity in several tissues increased significantly with dose. The urine was analyzed for arsenic metabolites by using ion chromatography to analyze for arsenate, methylarsonic acid (MMA), and dimethylarsinic acid (DMA); ion-pairing high-performance liquid chromatogra phy was used for arsenite analysis. Arsenate elimination ranged from 3 to 15%. DMA was the predominant metabolite excreted (51-64% of dose), but no effect of dose on its elimination was detected. As the dose of arsenate increased, the amount of MMA excreted (0.1-1.0% of dose) significantly increased. At 5000 μg/kg arsenate, a significant increase in arsenite excretion was observed. At doses of arsenate <500 μg/kg, peak elimina tion of DMA occurred within 4 hr postexposure. At the 5000 μg/kg dose, DMA peak elimination shifted to 8 hr and a lower amount was excreted. In addition, at the 5000 sg/kg dose, there was an increase of arsenate and arsenite in the 1- and 2-hr urines. These results suggest that an acute dose of arsenate can affect the metabolism of arsenicals. High doses lead to the accumulation of intermediates that are more reactive than DMA, and this response may lead to increased toxicity. [ABSTRACT FROM PUBLISHER]

[C]Dinoseb was applied to previously clipped back skin of 33- and 82-day-old female Fischer 344 rats at a dosage range of 210–2680 nmol/cm. Radioactivity in the treated skin, tissues, urine, and feces was determined at 1, 6, 24, 48, 72, and 120 hr following dermal application. dermal absorption of [C]dinoseb was also measured in rats of the same age by static and flow-through methods. dermal absorption in both young and adults appeared biphasic with 55.6 and 82.7% of the recovered dose, respectively, penetrating in 72 hr. measurements of skin absorption at 72 hr with static cells showed higher values in young and lower values in the adult compared to in vivo dermal absorption values, flow-through measurements at 72 hr gave lower dermal absorption values for both young and adult rats, compared to values. Following application, adults excreted about 70% of the total recovered dose in urine, 16% in feces, and retained 7% in the body at 120 hr. HPLC analysis of urine collected at 24 hr from adults administered [C]dinoseb showed extensive metabolism of parent. Excretion and retention results for young were about 80% of the adult values, which also was the young to adult ratio of dermal penetration. Blood had the highest concentration of dinoseb-derived radioactivity of the tissues examined. The kidney to blood ratio averaged 0.60 in young and 0.41 in adults, while the liver and carcass to blood ratio averaged 0.18 in young and 0.11 in adult. Dermal absorption in young rats was slightly less than that in adults, and the subsequent kinetics of retention and excretion appeared different, dermal penetration of dinoseb was usually lower than absorption. [ABSTRACT FROM PUBLISHER]

Hypertension in adulthood is recognized as the leading risk factor contributing to mortality worldwide, primarily from cardiovascular disease, whereas hypertension in pregnancy leads to serious adverse fetal and maternal outcomes. This article explores the under-recognized role of one-carbon metabolism in blood pressure (BP) and the potential for folate-related B vitamins to protect against hypertension. Genome-wide association studies and clinical studies provide evidence linking the 677C→T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) with BP and increased risk of hypertension and hypertension in pregnancy. A novel role for riboflavin (the MTHFR cofactor) has recently emerged, however, with evidence from randomized trials that supplemental riboflavin can lower BP specifically in adults with the variant MTHFR 677TT genotype. Further studies are required to elucidate the biological mechanisms linking one-carbon metabolism with BP and explore the effect of riboflavin in modulating the genetic risk of hypertension in early and later life. [ABSTRACT FROM AUTHOR]

The author examines the connection between arsenic methylation, oxidative stress and cancer. He describes how methylation of arsenic used to be considered as a detoxification mechanism. He cites a study conducted by Kojima, et al which appeared in the December 16, 2009 issue of the "Journal of the National Cancer Institute" and reports on the role of arsenic methylation in arsenic-induced oxidative DNA damage (ODD) and the acquisition of cancer phenotypes.

The case is reported of a young woman with the Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI) who presented with rapidly progressive dyspnoea due to mitral stenosis. Mitral valve replacement was performed and the appearance of the valve was typical of mucopolysaccharide infiltration. Dyspnoea in patients with the Maroteaux-Lamy syndrome may be due primarily to cardiac valve involvement, and in this setting, valve surgery is safe and effective. [ABSTRACT FROM PUBLISHER]