bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of an Antimutagenic 1,4‐Dihydropyridine AV‐153 on Expression of Nitric Oxide Synthases and DNA Repair‐related Enzymes and Genes in Kidneys of Rats with a Streptozotocin Model of Diabetes Mellitus
Authors: Ošiņa Kristīne , Rostoka Evita , Isajevs Sergejs , Sokolovska Jelizaveta , Sjakste Tatjana , Sjakste Nikolajs 
Published: May 2016

AbstractDevelopment of complications of diabetes mellitus (DM), including diabetic nephropathy, is a complex multi‐stage process, dependent on many factors including the modification of nitric oxide (NO) production and an impaired DNA repair. The goal of this work was to study in vivo effects of 1,4‐dihydropyridine AV‐153, known as antimutagen and DNA binder, on the expression of several genes and proteins involved in NO metabolism and DNA repair in the kidneys of rats with a streptozotocin (STZ)‐induced model of DM. Transcription intensity was monitored by means of real‐time RT‐PCR and the expression of proteins by immunohistochemistry. Development of DM significantly induced PARP1 protein expression, while AV‐153 (0.5 mg/kg) administration decreased it. AV‐153 increased the expression of Parp1 gene in the kidneys of both intact and diabetic animals. Expression of H2afx mRNA and γH2AX histone protein, a marker of DNA breakage, was not changed in diabetic animals, but AV‐153 up‐regulated the expression of the gene without any impact on the protein expression. Development of DM was followed by a significant increase in iNOS enzyme expression, while AV‐153 down‐regulated the enzyme expression up to normal levels. iNos gene expression was also found to be increased in diabetic animals, but unlike the protein, the expression of mRNA was found to be enhanced by AV‐153 administration. Expression of both eNOS protein and eNos gene in the kidneys was down‐regulated, and the administration of AV‐153 normalized the expression level. The effects of the compound in the kidneys of diabetic animals appear to be beneficial, as a trend for the normalization of expression of NO synthases is observed.
Integrated But Not Whole? Applying an Ontological Account of Human Organismal Unity to the Brain Death Debate
Authors: Moschella Melissa 
Published: May 2016

AbstractAs is clear in the 2008 report of the President's Council on Bioethics, the brain death debate is plagued by ambiguity in the use of such key terms as ‘integration’ and ‘wholeness’. Addressing this problem, I offer a plausible ontological account of organismal unity drawing on the work of Hoffman and Rosenkrantz, and then apply that account to the case of brain death, concluding that a brain dead body lacks the unity proper to a human organism, and has therefore undergone a substantial change. I also show how my view can explain hard cases better than one in which biological integration (as understood by Alan Shewmon and the President's Council) is taken to imply ontological wholeness or unity.
Marizomib irreversibly inhibits proteasome to overcome compensatory hyperactivation in multiple myeloma and solid tumour patients
Authors: Levin Nancy , Spencer Andrew , Harrison Simon J. , Chauhan Dharminder , Burrows Francis J. , Anderson Kenneth C. , Reich Steven D. , Richardson Paul G. , Trikha Mohit 
Published: May 2016

SummaryProteasome inhibitors (PIs) are highly active in multiple myeloma (MM) but resistance is commonly observed. All clinical stage PIs effectively inhibit chymotrypsin‐like (CT‐L) activity; one possible mechanism of resistance is compensatory hyperactivation of caspase‐like (C‐L) and trypsin‐like (T‐L) subunits, in response to CT‐L blockade. Marizomib (MRZ), an irreversible PI that potently inhibits all three 20S proteasome subunits with a specificity distinct from other PIs, is currently in development for treatment of MM and malignant glioma. The pan‐proteasome pharmacodynamic activity in packed whole blood and peripheral blood mononuclear cells was measured in two studies in patients with advanced solid tumours and haematological malignancies. Functional inhibition of all proteasome subunits was achieved with once‐ or twice‐weekly MRZ dosing; 100% inhibition of CT‐L was frequently achieved within one cycle at therapeutic doses. Concomitantly, C‐L and T‐L activities were either unaffected or increased, suggesting compensatory hyperactivation of these subunits. Importantly, this response was overcome by continued administration of MRZ, with robust inhibition of T‐L and C‐L (up to 80% and 50%, respectively) by the end of Cycle 2 and maintained thereafter. This enhanced proteasome inhibition was independent of tumour type and may underlie the clinical activity of MRZ in patients resistant to other PIs.
Regulatory T cell frequencies are increased in preterm infants with clinical early-onset sepsis
Authors: Pagel J , Hartz A , Figge J , Gille C , Eschweiler S , Petersen K , Schreiter L , Hammer J , Karsten C M , Friedrich D , Herting E , Göpel W , Rupp J , Härtel C 
Published: May 2016

Summary
The predisposition of preterm neonates to invasive infection is, as yet, incompletely understood. Regulatory T cells (Tregs) are potential candidates for the ontogenetic control of immune activation and tissue damage in preterm infants. It was the aim of our study to characterize lymphocyte subsets and in particular CD4+CD25+forkhead box protein 3 (FoxP3)+ Tregs in peripheral blood of well-phenotyped preterm infants (n = 117; 23 + 0 – 36 + 6 weeks of gestational age) in the first 3 days of life in comparison to term infants and adults. We demonstrated a negative correlation of Treg frequencies and gestational age. Tregs were increased in blood samples of preterm infants compared to term infants and adults. Notably, we found an increased Treg frequency in preterm infants with clinical early-onset sepsis while cause of preterm delivery, e.g. chorioamnionitis, did not affect Treg frequencies. Our data suggest that Tregs apparently play an important role in maintaining maternal-fetal tolerance, which turns into an increased sepsis risk after preterm delivery. Functional analyses are needed in order to elucidate whether Tregs have potential as future target for diagnostics and therapeutics.
Association between BMI and gene expression of anti‐Müllerian hormone and androgen receptor in human granulosa cells in women with and without polycystic ovary syndrome
Authors: Nouri Mohammad , Aghadavod Esmat , Khani Sajad , Jamilian Mehri , Amiri Siavashani Mehrnush , Ahmadi Shahnaz , Asemi Zatollah 
Published: May 2016

SummaryBackgroundAnti‐Müllerian hormone (AMH) is one of the most reliable markers of ovarian reserve. There is evidence which suggests that BMI may be associated with gene expression of AMH, AMH type II receptor (AMHR‐II) and androgen receptor (AR) in human granulosa cells (GC) in women with and without polycystic ovary syndrome (PCOS).ObjectiveTo investigate the association between BMI and gene expression of AMH, AMHR‐II and AR in human GC in women with and without PCOS.Design, Patients and MeasurementsIn a cross‐sectional study, hormonal profiles were measured among 38 patients with PCOS and 38 subjects without PCOS aged 18–40. AMH, AMHR‐II and AR mRNA levels were quantified in cumulus GC. Pearson correlation and multiple linear regressions were used to assess the relationships.ResultsQuantitative RT‐PCR demonstrated that AMH and AMHR‐II expression were negatively correlated with BMI (r = −0·39, P < 0·001 for AMH and r = −0·49, P < 0·001 for AMHR‐II), whereas AR expression was positively correlated with BMI (r = 0·46, P < 0·001).ConclusionsThere is a negative association between AMH, AMHR‐II expression and BMI, and a positive association between AR expression and BMI in the GC of PCOS and non‐PCOS women.
Sodium Sulfide, a Hydrogen Sulfide‐Releasing Molecule, Attenuates Acute Cerebral Ischemia in Rats
Authors: Shi Hao‐Qiang , Zhang Ying , Cheng Ming‐He , Fan Bo‐Shi , Tian Jia‐Sheng , Yu Jian‐Guang , Chen Bing 
Published: May 2016

SummaryAimsAcute cerebral ischemia may lead to ischemic stroke, which is a major cause of death and disability worldwide. Hydrogen sulfide (H2S) functions importantly in mammalian systems. The present work was designed to study the effect of sodium sulfide, a donor of H2S, on acute cerebral ischemia.MethodsAcute cerebral focal ischemia was produced by middle cerebral artery occlusion (MCAO) in Sprague‐Dawley (SD) rats. Bilateral vertebral arteries and common carotid arteries were blocked to establish cerebral global ischemia in SD rats. Acute cerebral anoxia was produced by hypobaric anoxia in C57BL/6 mice and hypoxic anoxia in SD rats. Nimodipine and aspirin were set as positive control separately.ResultsInfarct size after MCAO was decreased by sodium sulfide. Sodium sulfide improved cerebral energy metabolism after cerebral global ischemia and prolonged survival time of animals with acute cerebral anoxia. In addition, increased cerebral blood flow and decreased cerebrovascular resistance, blood viscosity, and thrombogenesis were observed in animals treated with sodium sulfide. In cultured neurons, sodium sulfide increased cell viability and decreased cell apoptosis induced by oxygen‐glucose deprivation.ConclusionSodium sulfide, a H2S donor, presents protective effect on acute cerebral ischemia, and might be a promising therapeutic drug.
Efficacy and safety of titrated canagliflozin in patients with type 2 diabetes mellitus inadequately controlled on metformin and sitagliptin
Authors: Rodbard H. W. , Seufert J. , Aggarwal N. , Cao A. , Fung A. , Pfeifer M. , Alba M. 
Published: May 2016

AimsTo evaluate the efficacy and safety of titrated canagliflozin, a sodium glucose co‐transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin and sitagliptin.MethodsIn this randomized, double‐blind study, patients with T2DM (N = 218) on metformin ≥1500 mg/day and sitagliptin 100 mg received canagliflozin 100 mg or placebo. After 6 weeks, the canagliflozin dose was increased from 100 to 300 mg (or from placebo to matching placebo) if all of the following criteria were met: baseline estimated glomerular filtration rate ≥70 ml/min/1.73 m2; fasting self‐monitored blood glucose ≥5.6 mmol/l (≥100 mg/dl); and no volume depletion–related adverse events (AEs) within 2 weeks before dose increase. Endpoints included change in glycated haemoglobin (HbA1c) at week 26 (primary); proportion of patients achieving HbA1c <7.0%; and changes in fasting plasma glucose (FPG), body weight and systolic blood pressure (SBP). Safety was assessed using AE reports.ResultsOverall, 85.4% of patients were titrated to canagliflozin 300 mg or matching placebo (mean ± standard deviation time to titration 6.2 ± 0.8 weeks). At week 26, canagliflozin (pooled 100 and 300 mg) demonstrated superiority in HbA1c reduction versus placebo (−0.91% vs. −0.01%; p < 0.001). Canagliflozin provided significant reductions in FPG, body weight and SBP compared with placebo (p < 0.001). The overall AE incidence was 39.8 and 44.4% for canagliflozin and placebo, respectively. Canagliflozin was associated with an increased incidence of genital mycotic infections.ConclusionsTitrated canagliflozin significantly improved HbA1c, FPG, body weight and SBP, and was generally well tolerated over 26 weeks in patients with T2DM as add‐on to metformin and sitagliptin.
Allocation of cytoplasm to macromeres in embryos of annelids and molluscs is positively correlated with egg size
Authors: Jones Caleb , Stankowich Theodore , Pernet Bruno 
Published: May 2016

SUMMARYEvolutionary transitions between feeding and nonfeeding larval development have occurred many times in marine invertebrates, but the developmental changes underlying these frequent and ecologically important transitions are poorly known, especially in spiralians. We use phylogenetic comparative methods to test the hypothesis that evolutionary changes in egg size and larval nutritional mode are associated with parallel changes in allocation of cytoplasm to macromere cell lineages in diverse annelids and molluscs. Our analyses show that embryos of species with large eggs and nonfeeding larvae tend to allocate relatively more embryonic cytoplasm to macromeres at 3rd cleavage than do embryos of species with small eggs and feeding larvae. The association between egg size and allocation to macromeres in these spiralians may be driven by constraints associated with mitotic spindle positioning and size, or may be a result of “adaptation in cleavage” to maintain rapid cell cycles in micromeres, position yolk in cell lineages where it can be most efficiently used, or adjust allocation to ectoderm to accommodate changes in embryonic surface area/volume ratio.
Competing influences on morphological modularity in biomechanical systems: a case study in mantis shrimp
Authors: Anderson Philip S. L. , Smith Danielle C. , Patek S. N. 
Published: May 2016

SUMMARYRelated species that share similar biomechanical systems and segmentation patterns may exhibit different patterns of morphological covariation. We examined morphological covariation of the potent prey capture appendage of two mantis shrimp (Stomatopoda) species—a spearer (Squilla empusa) and smasher (Gonodactylaceus falcatus). We assessed three frameworks for modularity, two based on the biomechanics of the appendage and one based on its segmentation as a proxy for shared developmental pathways. We collected morphometric data fromS. empusa, and compared morphological covariation patterns across the raptorial appendage with patterns from a new analysis of previously published morphometric data fromG. falcatus. The relative importance of the different hypothetical influences differed between the two species, and was dependent on whether specimens were analyzed all together or subdivided based on sex or sub‐populations, including one particularly distinct population in the Gulf of Mexico. We also found an intriguing handedness pattern in which right‐hand appendages had a variable number of spines, whereas the left had a constant number of spines. Overall, our findings highlight the importance of testing multiple, alternative frameworks for morphological covariation and suggest that mantis shrimp experience contrasting influences on covariation depending on their feeding mechanisms.
Mitochondrial DNA variants as genetic risk factors for Parkinson disease
Authors: Liou C. W. , Chuang J. H. , Chen J. B. , Tiao M. M. , Wang P. W. , Huang S. T. , Huang T. L. , Lee W. C. , Weng S. W. , Huang P. H. , Chen S. D. , Chen R. S. , Lu C. S. , Lin T. K. 
Published: May 2016

Background and purposeInvestigation of the relationship between mitochondrial DNA (mtDNA) variants and Parkinson disease (PD) remains an issue awaiting more supportive evidence. Moreover, an affirming cellular model study is also lacking.MethodsThe index mtDNA variants and their defining mitochondrial haplogroup were determined in 725 PD patients and 744 non‐PD controls. Full‐length mtDNA sequences were also conducted in 110 cases harboring various haplogroups. Cybrid cellular models, composed by fusion of mitochondria‐depleted rho‐zero cells and donor mitochondria, were used for a rotenone‐induced PD simulation study.ResultsMultivariate logistic regression analysis revealed that subjects harboring the mitochondrial haplogroup B5 have resistance against PD (odds ratio 0.50, 95% confidence interval 0.32–0.78; P = 0.002). Furthermore, a composite mtDNA variant group consisting of A10398G and G8584A at the coding region was found to have resistance against PD (odds ratio 0.50, 95% confidence interval 0.33–0.78; P = 0.001). In cellular studies, B4 and B5 cybrids were selected according to their higher resistance to rotenone, in comparison with cybrids harboring other haplogroups. The B5 cybrid, containing G8584A/A10398G variants, showed more resistance to rotenone than the B4 cybrid not harboring these variants. This is supported by findings of low reactive oxygen species generation and a low apoptosis rate in the B5 cybrid, whereas a higher expression of autophagy was observed in the B4 cybrid particularly under medium dosage and longer treatment time with rotenone.ConclusionsOur studies, offering positive results from clinical investigations and cybrid experiments, provide data supporting the role of variant mtDNA in the risk of PD.
Influence of commonly used pharmaceutical agents on equine bone marrow‐derived mesenchymal stem cell viability
Authors: Edmonds R. E. , Garvican E. R. , Smith R. K. W. , Dudhia J. 
Published: May 2016

SummaryReason for performing studyTo provide evidence to support recommendations regarding the co‐administration of drugs with mesenchymal stem cell (MSC) therapy.ObjectivesTo determine the influence of sedatives, local anaesthetic and corticosteroids onMSCviability and proliferation, in comparison to somatic cells derived from tendon (TDCs).Study designIn vitro cell culture.Materials and methodsMSCs (n = 3) andTDCs (n = 2) were cultured in media containing a clinically relevant dose range of xylazine, romifidine, detomidine and butorphanol, mepivacaine, methylprednisolone, or triamcinolone acetonide. Cell viability in suspension culture was assessed at intervals up to 4 h using the trypan blue dye assay.MSCs in monolayer culture were exposed to the highest concentrations of drug and proliferation was measured using the alamarBlue fluorescence assay.ResultsExposure to romifidine or mepivacaine did not significantly affect viability or proliferation rate ofMSCs orTDCs at any of the dosages tested. At the highest concentration of detomidine and butorphanol,MSCviability was significantly reduced compared to controls. Although xylazine exposure caused a significant (P < 0.001), dose‐dependent reduction inMSCviability compared to controls, overall population viability remained good. Conversely, both methylprednisolone and triamcinolone resulted in the rapid death of significant numbers ofMSCs (P < 0.001).ConclusionsClinicians can sedate horses and administer nerve blocks to assist in intratendinous or intrathecal injection ofMSCs with confidence that these drugs will not impact the viability of implanted cells. However, the concomitant use of corticosteroids is likely to have a severely detrimental effect on cell viability and should not be performed. Similarly, steroid administration into the sheath of a damaged tendon is not recommended.
Percentage of hypochromic erythrocytes and reticulocyte hemoglobin equivalent predictors of response to intravenous iron in hemodialysis patients
Authors: Urrechaga E. , Boveda O. , Aguayo F. J. , de la Hera P. , Muñoz R. I. , Gallardo I. , Escanero J. F. 
Published: May 2016

SummaryIntroductionReticulocyte hemoglobin content and percentage of hypochromic red cells are incorporated into the European best practice guidelines on anemia management in chronic kidney disease. Sysmex XN analyzer (Sysmex Corporation, Kobe, Japan) reports reticulocyte hemoglobin equivalent (Ret‐He) and the hypochromic fraction of erythrocytes (%Hypo‐He). Our aim was to assess the value of these parameters, in terms of the sensitivity and specificity for detecting functional iron deficiency, in hemodialysis (HD) patients.MethodsForty HD patients in the maintenance phase of erythropoietin therapy were included. Intravenous iron supplementation was interrupted at least 3 weeks before recruitment. Two samples were analyzed for each patient: the baseline after the iron‐free period and the second sample after 4 weeks of IV iron administration. Hemogram and biochemical parameters of the iron status were measured. Patients were classified as responders or nonresponders to an iron load; responders had an increase in Hb of at least 10 g/L after iron administration, compared to the baseline. To identify the efficiency of the test for predicting the response to iron administration, receiver operating characteristic analysis (ROC) was performed.ResultsAccording to the established criteria, 21 patients were responders and 19 nonresponders. ROC analysis results: Ret‐He area under curve (AUC) was 0.84 (95% CI 0.64–0.93), at cutoff 30.8 pg, sensitivity 78.7%, and specificity 87.2%. % Hypo‐He AUC was 0.78 (95% CI 0.64–0.91), at cutoff 2.4%, sensitivity 72.2%, and specificity 88.1%.Conclusions% Hypo‐He and Ret‐He are reliable parameters for the study of erythropoiesis status in HD patients.
Appropriateness of diagnostics tests
Authors: Cappelletti P. 
Published: May 2016

SummaryThe evolution of the concept of ‘appropriateness’, in the three past decades, from ‘no harm’ and ‘no waste’ to ‘medical decision‐making’ and ‘determining outcomes’ highlights two main points: its foundation is evidence‐based medicine, and it is a quality of every phase of the total testing process, not only for the selection of tests. Nevertheless, appropriateness in Laboratory Hematology, as well as in Laboratory Medicine, is an elusive concept: ‘Appropriateness’ interplays with ‘patient's safety’, ‘healthcare costs’, ‘clinical decision‐making’, and ‘effectiveness’, and the criteria for appropriateness, mainly adherence to clinical guidelines, are often not evidence‐based and not always consensus‐based. Moreover, practising appropriateness is a complex issue because of the ambiguity of the criteria and targets, the never‐ending work of implementing guidelines and their audit, and the uniqueness of the clinical situation of the individual patient. Authors agree on some practical rules: establishing a multidisciplinary and multiprofessional team, choosing carefully clinical targets, finding or building evidences, sharing guidelines with clinicians, choosing adequate tools for changing, working hard on implementation, identifying the ‘right’ laboratory methods and processes, checking progress indefinitely, providing information, interpretations, and consultations, and promoting feedback and audits. The success depends on the ‘right’ combination of educational, operative, and reinforcing interventions. Competences in organization, in implementation science, and in interpersonal relationship management are essential as well as knowledge and experience in Hematology, not only in Laboratory Hematology.
Single and multiple dose pharmacokinetics and pharmacodynamics of omarigliptin, a novel, once‐weekly dipeptidyl peptidase‐4 inhibitor, in healthy Japanese men
Authors: Tsuchiya Saori , Friedman Evan , Addy Carol , Wakana Akira , Tatosian Daniel , Matsumoto Yuki , Suzuki Hideyo , Kauh Eunkyung 
Published: May 2016

AbstractAims/IntroductionOmarigliptin is a novel, potent, long‐acting oral dipeptidyl peptidase‐4 inhibitor being developed as a once‐weekly (q.w.) treatment for type 2 diabetes mellitus patients, with 25 mg and 12.5 mg tablets recently being approved as market formulations in Japan.Materials and MethodsThis was a two‐part, double‐blind, randomized, placebo‐controlled study in healthy Japanese men to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of omarigliptin after single dose (5–100 mg) and multiple dose (1–50 mg q.w. for 3 weeks) administration.ResultsOmarigliptin was rapidly absorbed with a time to maximum concentration of 0.5–4 h. The pharmacokinetic profile was biphasic with a long terminal half‐life >100 h. The area under the concentration–time curve from 0 to 168 h, maximum concentration and the concentration at 168 h post‐dose increased dose‐dependently after 3 weeks of once‐weekly dosing for doses ranging 1–50 mg, with accumulation ratios ranging 1.03–1.35 and 0.87–1.36 for the area under the concentration–time curve from 0 to 168 h and maximum concentration, respectively. Plasma dipeptidyl peptidase‐4 inhibition levels 1 week post‐dose increased with dose, ranging 79.2–94.0% after 5–100 mg single dose administration and 51.3–90.2% after 1–50 mg multiple once‐weekly dose administration. Administration with food did not meaningfully alter the pharmacokinetics of omarigliptin. Omarigliptin was generally well tolerated, with no hypoglycemia being reported.ConclusionThe results of the present study in healthy Japanese men showed that omarigliptin was well tolerated and had a pharmacokinetic and dipeptidyl peptidase‐4 inhibition profile that supports once‐weekly dosing in Japanese patients with type 2 diabetes mellitus.