Chronology of martian breccia NWA 7034 and the formation of the martian crustal dichotomy

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). The attached file is the published version of the article

Effect of antiandrogen flutamide on measures of hepatic regeneration in rats

Male rat liver undergoes a process of demasculinization during hepatic regeneration following partial hepatectomy. The possibility that antiandrogens might potentiate this demasculinization process and in so doing augment the hepatic regenerative response was investigated. Adult male Wistar rats were treated with the antiandrogen flutamide (2 mg/rat/day or 5 mg/rat/day subcutaneously) or vehicle for three days prior to and daily after a 70% partial hepatectomy. At various times after hepatectomy, the liver remnants were removed and weighed. Rates of DNA and polyamine synthesis were assessed by measuring thymidine kinase and ornithine decarboxylase activities, respectively. Hepatic estrogen receptor status and the activity of alcohol dehydrogenase, an androgen-sensitive protein, were measured. Prior to surgery, the administration of 5 mg/day flutamide reduced the hepatic cytosolic androgen receptor activity by 98% and hepatic cytosolic estrogen receptor content by 92% compared to that present in vehicle-treated controls. After hepatectomy, however, all differences in sex hormone receptor activity between the treatment groups were abolished. The rate of liver growth after partial hepatectomy in the three groups was identical. Moreover, hepatectomy-induced increases in ornithine decarboxylase activity and thymidine kinase activity were comparable. These data demonstrate that, although flutamide administration initially alters the sex hormone receptor status of the liver, these affects have no effect on the hepatic regenerative response following a partial hepatectomy. © 1989 Plenum Publishing Corporation

Test–retest stability of patient experience items derived from the national GP patient survey

PURPOSE: The validity and reliability of various items on the GP Patient Survey (GPPS) survey have been reported, however stability of patient responses over time has not been tested. The purpose of this study was to determine the test-retest reliability of the core items from the GPPS. METHODS: Patients who had recently consulted participating GPs in five general practices across the South West England were sent a postal questionnaire comprising of 54 items concerning their experience of their consultation and the care they received from the GP practice. Patients returning the questionnaire within 3 weeks of mail-out were sent a second identical (retest) questionnaire. Stability of responses was assessed by raw agreement rates and Cohen's kappa (for categorical response items) and intraclass correlation coefficients and means (for ordinal response items). RESULTS: 348 of 597 Patients returned a retest questionnaire (58.3 % response rate). In comparison to the test phase, patients responding to the retest phase were older and more likely to have white British ethnicity. Raw agreement rates for the 33 categorical items ranged from 66 to 100 % (mean 88 %) while the kappa coefficients ranged from 0.00 to 1.00 (mean 0.53). Intraclass correlation coefficients for the 21 ordinal items averaged 0.67 (range 0.44-0.77). CONCLUSIONS: Formal testing of items from the national GP patient survey examining patient experience in primary care highlighted their acceptable temporal stability several weeks following a GP consultation.Funding was provided by Health Services and Delivery Research Programme (Grant No. RP-PG-0608-10050)

Risk management of biosimilars in oncology: each medicine is a work in progress

Drug licensing and drug safety monitoring for standard chemical entities have been established and are routinely used. These have resulted in a solid foundation of knowledge from which confident therapeutic decisions can be made. For many chemical entities, this advanced level of experience is also present for the generic products. The expertise surrounding the development of biosimilar competitor versions is increasing and progress is encouraging. To address the re-engineering and comparability complexities of biosimilars, the European Union imposed a requirement that risk management plans be included in the medications’ marketing applications. This paper summarizes and discusses the circumstances complicating the public’s view of drug safety, historical incidents during the transition from innovative to competitor products, as well as retrospective assessments of the development and post-marketing experiences thus far with two biosimilars. Through assessing the market entries and post-marketing experiences of biosimilars used in oncology, the healthcare field can better prepare for the next wave of comparator-products: biosimilar monoclonal antibodies

Antenatal care and perinatal outcomes in Kwale district, Kenya

<p>Abstract</p> <p>Background</p> <p>The importance of antenatal care (ANC) for improving perinatal outcomes is well established. However access to ANC in Kenya has hardly changed in the past 20 years. This study aims to identify the determinants of attending ANC and the association between attendance and behavioural and perinatal outcomes (live births and healthy birthweight) for women in the Kwale region of Kenya.</p> <p>Method</p> <p>A Cohort survey of 1,562 perinatal outcomes (response rate 100%) during 2004–05 in the catchment areas for five Ministry of Health dispensaries in two divisions of the Kwale region. The associations between background and behavioural decisions on ANC attendance and perinatal outcomes were explored using univariate analysis and multivariate logistic regression models with backwards-stepwise elimination. The outputs from these analyses were reported as odds ratios (OR) with 95% confidence intervals (CI).</p> <p>Results</p> <p>Only 32% (506/1,562) of women reported having any ANC. Women with secondary education or above (adjusted OR 1.83; 95% CI 1.06–3.15) were more likely to attend for ANC, while those living further than 5 km from a dispensary were less likely to attend (OR 0.29; 95% CI 0.22–0.39). Paradoxically, however, the number of ANC visits increased with distance from the dispensary (OR 1.46; 95% CI 1.33–1.60). Women attending ANC at least twice were more likely to have a live birth (vs. stillbirth) in both multivariate models. Women attending for two ANC visits (but not more than two) were more likely to have a healthy weight baby (OR 4.39; 95% CI 1.36–14.15).</p> <p>Conclusion</p> <p>The low attendance for ANC, combined with a positive relationship between attendance and perinatal outcomes for the women in the Kwale region highlight the need for further research to understand reasons for attendance and non-attendance and also for strategies to be put in place to improve attendance for ANC.</p

Anticancer prodrugs of butyric acid and formaldehyde protect against doxorubicin-induced cardiotoxicity

Formaldehyde has been previously shown to play a dominant role in promoting synergy between doxorubicin (Dox) and formaldehyde-releasing butyric acid (BA) prodrugs in killing cancer cells. In this work, we report that these prodrugs also protect neonatal rat cardiomyocytes and adult mice against toxicity elicited by Dox. In cardiomyocytes treated with Dox, the formaldehyde releasing prodrugs butyroyloxymethyl diethylphosphate (AN-7) and butyroyloxymethyl butyrate (AN-1), but not the corresponding acetaldehyde-releasing butyroyloxydiethyl phosphate (AN-88) or butyroyloxyethyl butyrate (AN-11), reduced lactate dehydrogenase leakage, prevented loss of mitochondrial membrane potential (ΔΨm) and attenuated upregulation of the proapoptotic gene Bax. In Dox-treated mice, AN-7 but not AN-88 attenuated weight-loss and mortality, and increase in serum lactate dehydrogenase. These findings show that BA prodrugs that release formaldehyde and augment Dox anticancer activity also protect against Dox cardiotoxicity. Based on these observations, clinical applications of these prodrugs for patients treated with Dox warrant further investigation

A Model for Damage Load and Its Implications for the Evolution of Bacterial Aging

Deleterious mutations appearing in a population increase in frequency until stopped by natural selection. The ensuing equilibrium creates a stable frequency of deleterious mutations or the mutational load. Here I develop the comparable concept of a damage load, which is caused by harmful non-heritable changes to the phenotype. A damage load also ensues when the increase of damage is opposed by selection. The presence of a damage load favors the evolution of asymmetrical transmission of damage by a mother to her daughters. The asymmetry is beneficial because it increases fitness variance, but it also leads to aging or senescence. A mathematical model based on microbes reveals that a cell lineage dividing symmetrically is immortal if lifetime damage rates do not exceed a threshold. The evolution of asymmetry allows the lineage to persist above the threshold, but the lineage becomes mortal. In microbes with low genomic mutation rates, it is likely that the damage load is much greater than the mutational load. In metazoans with higher genomic mutation rates, the damage and the mutational load could be of the same magnitude. A fit of the model to experimental data shows that Escherichia coli cells experience a damage rate that is below the threshold and are immortal under the conditions examined. The model estimates the asymmetry level of E. coli to be low but sufficient for persisting at higher damage rates. The model also predicts that increasing asymmetry results in diminishing fitness returns, which may explain why the bacterium has not evolved higher asymmetry

Fitness Consequences of Advanced Ancestral Age over Three Generations in Humans

A rapid rise in age at parenthood in contemporary societies has increased interest in reports of higher prevalence of de novo mutations and health problems in individuals with older fathers, but the fitness consequences of such age effects over several generations remain untested. Here, we use extensive pedigree data on seven pre-industrial Finnish populations to show how the ages of ancestors for up to three generations are associated with fitness traits. Individuals whose fathers, grandfathers and great-grandfathers fathered their lineage on average under age 30 were ~13% more likely to survive to adulthood than those whose ancestors fathered their lineage at over 40 years. In addition, females had a lower probability of marriage if their male ancestors were older. These findings are consistent with an increase of the number of accumulated de novo mutations with male age, suggesting that deleterious mutations acquired from recent ancestors may be a substantial burden to fitness in humans. However, possible non-mutational explanations for the observed associations are also discussed

Orally available Mn porphyrins with superoxide dismutase and catalase activities

Superoxide dismutase/catalase mimetics, such as salen Mn complexes and certain metalloporphyrins, catalytically neutralize reactive oxygen and nitrogen species, which have been implicated in the pathogenesis of many serious diseases. Both classes of mimetic are protective in animal models of oxidative stress. However, only AEOL11207 and EUK-418, two uncharged Mn porphyrins, have been shown to be orally bioavailable. In this study, EUK-418 and several new analogs (the EUK-400 series) were synthesized and shown to exhibit superoxide dismutase, catalase, and peroxidase activities in vitro. Some also protected PC12 cells against staurosporine-induced cell death. All EUK-400 compounds were stable in simulated gastric fluid, and most were substantially more lipophilic than the salen Mn complexes EUK-189 and EUK-207, which lack oral activity. Pharmacokinetics studies demonstrate the presence of all EUK-400 series compounds in the plasma of rats after oral administration. These EUK-400 series compounds are potential oral therapeutic agents for cellular damage caused by oxidative stress

Width of Gene Expression Profile Drives Alternative Splicing

Alternative splicing generates an enormous amount of functional and proteomic diversity in metazoan organisms. This process is probably central to the macromolecular and cellular complexity of higher eukaryotes. While most studies have focused on the molecular mechanism triggering and controlling alternative splicing, as well as on its incidence in different species, its maintenance and evolution within populations has been little investigated. Here, we propose to address these questions by comparing the structural characteristics as well as the functional and transcriptional profiles of genes with monomorphic or polymorphic splicing, referred to as MS and PS genes, respectively. We find that MS and PS genes differ particularly in the number of tissues and cell types where they are expressed.We find a striking deficit of PS genes on the sex chromosomes, particularly on the Y chromosome where it is shown not to be due to the observed lower breadth of expression of genes on that chromosome. The development of a simple model of evolution of cis-regulated alternative splicing leads to predictions in agreement with these observations. It further predicts the conditions for the emergence and the maintenance of cis-regulated alternative splicing, which are both favored by the tissue specific expression of splicing variants. We finally propose that the width of the gene expression profile is an essential factor for the acquisition of new transcript isoforms that could later be maintained by a new form of balancing selection