bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrated But Not Whole? Applying an Ontological Account of Human Organismal Unity to the Brain Death Debate
Authors: Moschella Melissa
Published: May 2016

As 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

Proteasome 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

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

Background

Anti‐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).

Objective

To 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 Measurements

In 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.

Results

Quantitative 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).

Conclusions

There 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.
Advanced diagnostic genetic testing in inherited retinal disease: experience from a single tertiary referral centre in the UK National Health Service
Authors: Khan K.N. , Chana R. , Ali N. , Wright G. , Webster A.R. , Moore A.T. , Michaelides M.
Published: May 2016

In 2013, as part of our genetic investigation of patients with inherited retinal disease, we utilized multigene panel testing of 105 genes known to cause retinal disease in our patient cohorts. This test was performed in a UK National Health Service (NHS) accredited laboratory. The results of all multigene panel tests requested between 1.4.13 and 31.8.14 were retrospectively reviewed. All patients had been previously seen at Moorfields Eye Hospital, London, UK and diagnosed with an inherited retinal dystrophy after clinical examination and detailed retinal imaging. The results were categorized into three groups: (i) Testing helped establish a certain molecular diagnosis in 45 out of 115 (39%). Variants in USH2A (n = 6) and RP1 (n = 4) were most common. (ii) Definitive conclusions could not be drawn from molecular testing alone in 13 out of 115 (11%) as either insufficient pathogenic variants were discovered or those identified were not consistent with the phenotype. (iii) Testing did not identify any pathogenic variants responsible for the phenotype in 57 out of 115 (50%). Multigene panel testing performed in an NHS setting has enabled a molecular diagnosis to be confidently made in 40% of cases. Novel variants accounted for 38% of all identified variants. Detailed retinal phenotyping helped the interpretation of specific variants. Additional care needs to be taken when assessing polymorphisms in genes that have been infrequently associated with disease, as historical techniques were not as rigorous as contemporary ones. Future iterations of sequencing are likely to offer higher sensitivity, testing a broader range of genes, more rapidly and at a reduced cost.
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

Aims

Acute 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.

Methods

Acute 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.

Results

Infarct 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.

Conclusion

Sodium sulfide, a H2S donor, presents protective effect on acute cerebral ischemia, and might be a promising therapeutic drug.
Wong‐type dermatomyositis: a mimic of many dermatoses
Authors: Mutasim Diya F. , Egesi Adaeze , Spicknall Kerith E.
Published: May 2016

Wong‐type dermatomyositis (DM) is a rare variant characterized by keratotic follicular papules that may mimic pityriasis rubra pilaris. Histopathologic examination shows follicular and non‐follicular epidermal invaginations filled with keratin. The diagnosis is often delayed. Twenty‐four cases of Wong‐type DM have been reported thus far in the literature. Herein, we report the clinical and histopathologic findings of three additional cases in order to raise awareness of the disorder.
Cutaneous autoimmune effects in the setting of therapeutic immune checkpoint inhibition for metastatic melanoma
Authors: Mochel Mark C. , Ming Michael E. , Imadojemu Sotonye , Gangadhar Tara C. , Schuchter Lynn M. , Elenitsas Rosalie , Payne Aimee S. , Chu Emily Y.
Published: May 2016

Therapeutic immune checkpoint blockade for metastatic melanoma has been associated with vitiligo, pruritus and morbilliform eruptions. Reports of other autoimmune skin disease in this setting are rare. We sought to expand the spectrum of cutaneous immune‐mediated effects related to immune checkpoint inhibitor therapy. In this report, we describe two unusual cutaneous reactions related to checkpoint inhibitor therapy, namely bullous pemphigoid (BP) and dermatitis herpetiformis. The development of BP and dermatitis herpetiformis in the context of checkpoint inhibitor therapy is consistent with previous investigations supporting the importance of effector and regulatory T cells in the pathogenesis of these diseases.
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

Aims

To 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.

Methods

In 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.

Results

Overall, 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.

Conclusions

Titrated 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

Evolutionary 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

Related 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 purpose

Investigation 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.

Methods

The 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.

Results

Multivariate 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.

Conclusions

Our 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

Reason for performing study

To provide evidence to support recommendations regarding the co‐administration of drugs with mesenchymal stem cell (MSC) therapy.

Objectives

To determine the influence of sedatives, local anaesthetic and corticosteroids onMSCviability and proliferation, in comparison to somatic cells derived from tendon (TDCs).

Study design

In vitro cell culture.

Materials and methods

MSCs (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.

Results

Exposure 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).

Conclusions

Clinicians 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

Introduction

Reticulocyte 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.

Methods

Forty 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.

Results

According 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

The 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.
Do Combined Electrocardiographic and Echocardiographic Markers of Left Ventricular Hypertrophy Improve Cardiovascular Risk Estimation?
Authors: Cuspidi Cesare , Facchetti Rita , Sala Carla , Bombelli Michele , Tadic Marijana , Grassi Guido , Mancia Giuseppe
Published: May 2016

The authors estimated the risk of cardiovascular mortality associated with echocardiographic (ECHO) left ventricular hypertrophy (LVH) and subtypes of this phenotype in patients with and without electrocardiographic (ECG)LVH. A total of 1691 representatives of the general population were included in the analysis. During a follow‐up of 211 months, 89 cardiovascular deaths were recorded. Compared with individuals with neitherECHO LVHnorECG LVH, fully adjusted risk of cardiovascular mortality increased (hazard ratio [HR], 3.36; 95% confidence interval [CI], 1.51–7.47;P=.003) in patients with bothECHO‐LVHandECG‐LVH, whereas the risk entailed byECHO‐LVHalone was of borderline statistical significance (P=.04). Combined concentric nondilatedLVHandECG‐LVH, but not concentric nondilatedLVHalone, predicted cardiovascular death (HR, 3.79; 95%CI, 1.25–11.38;P=.01). Similar findings were observed for eccentric nondilatedLVH(HR, 3.37; 95%CI, 1.05–10.78;P=.04.). The present analysis underlines the value of combiningECGandECHOin the assessment of cardiovascular prognosis related to abnormal left ventricular geometric patterns.
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

Aims/Introduction

Omarigliptin 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 Methods

This 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.

Results

Omarigliptin 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.

Conclusion

The 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.
Laboratory evaluation of predation rates of two native natural enemies on the exotic pest Bagrada hilaris
Authors: Grasswitz T. R.
Published: May 2016

Laboratory studies were conducted to determine the consumption rates of two native predators found attacking the exotic invasive stink bug Bagrada hilaris (Burmeister) (Hempitera: Pentatomidae) in field plots in New Mexico, USA. Individual field‐collected adults of the spined soldier bug, Podisus maculiventris (Say) (Hempitera: Pentatomidae) and the soft‐winged flower beetle, Collops vittatus (Say) (Coleoptera: Melyridae), were provided daily with fixed numbers of different life stages of B. hilaris under controlled conditions. Consumption rates were recorded daily for ten consecutive days for a total of 20 adult P. maculiventris and 20 adult C. vittatus per prey life stage. For P. maculiventris, predation rates were obtained in relation to adult, third and fifth instar prey, and for C. vittatus for first, second and third instar prey. On average, predation on third and fifth instar B. hilaris nymphs by P. maculiventris was 0.6 ± 0.1 and 0.9 ± 0.1 per day respectively. Predation rates on adults were slightly higher (1.3 ± 0.1 per day), with female prey being consumed at a significantly higher rate than male prey when three mating pairs of B. hilaris were provided per day (0.8 ± 0.1 females per day vs. 0.5 ± 0.1 males per day). Collops vittatus adults provisioned daily with 20 first instar B. hilaris nymphs killed a mean total of 4.7 ± 0.4 and 9.3 ± 0.6 prey each day (for male and female beetles respectively), with only approximately half that number of prey being fully consumed. Partial consumption of prey by this species was also observed with second and third instar nymphs, but to a lesser degree. Female beetles consumed significantly more prey than did male beetles when fed first and third instar B. hilaris, but not when given second instar prey.
A complete chitinolytic system in the atherinopsid pike silverside Chirostoma estor: gene expression and activities
Authors: Pohls P. , González‐Dávalos L. , Mora O. , Shimada A. , Varela‐Echavarria A. , Toledo‐Cuevas E. M. , Martínez‐Palacios C. A.
Published: May 2016

The expression and digestive activity of pike silverside Chirostoma estor endogenous chitinases were analysed in samples from four life stages: whole eggs; larvae; juvenile intestine and hepatopancreas and adult intestine and hepatopancreas. A chitinase cDNA was cloned and partially sequenced (GenBank accession number: FJ785521). It was highly homologous to non‐acidic chitinase sequences from other fish species, suggesting that it is a chitotriosidase. Quantitative PCR showed that this chitinase was expressed throughout the life span of C. estor, with maximum expression in the hepatopancreas of juveniles. Chitotriosidase and chitobiosidase activities were found at all life stages, along with a very high level of N‐acetyl glucosaminidase (NAGase). The chitotriosidase activity could be encoded by the cloned complementary (c)DNA, although additional chitinase genes may be present. The chitotriosidase activity appeared to be transcriptionally regulated only at the juvenile stage. The expression and activity of chitinases tended to increase from the early to juvenile stages, suggesting that these variables are stimulated by chitin‐rich live food. Nevertheless, the feeding of juvenile and adult fish with both live food and a balanced commercial diet seemed to provoke significant reductions in pancreatic NAGase secretion and/or synthesis in the gut. Moreover, all chitinase activities were lower in adults, probably reflecting a higher intake and use of the balanced diet. The observation of chitotriosidase and chitobiosidase activities together with a very high NAGase activity suggest the presence of a complete and compensatory chitinolytic chitinase system that enables this stomachless short‐gut fish species to use chitin as an energy substrate. These novel findings suggest that dietary inclusions of chitin‐rich ingredients or by‐products might reduce the farming costs of C. estor without impairing performance.
Hepatic flare after telbivudine withdrawal and efficacy of postpartum antiviral therapy for pregnancies with chronic hepatitis B virus
Authors: Liu Jinfeng , Wang Jing , Jin Dongfang , Qi Caijing , Yan TaoTao , Cao Furong , Jin Li , Tian Zhen , Guo Dandan , Yuan Ningxia , Feng Weihong , Zhang Shulin , Zhao Yingren , Chen Tianyan
Published: May 2016

Background and Aim

The efficacy of telbivudine for breaking vertical transmission of hepatitis B virus has been well established. Data on the risk of postpartum flare after telbivudine withdrawal and efficacy of extended antiviral therapy after delivery are limited.

Methods

Chronic hepatitis B virus‐infected women who received telbivudine beginning at week 24 or 28 of gestation were enrolled and then followed up to 52 weeks postpartum. Virological and biochemical parameters were assessed.

Results

Of the 241 women who finished 52 weeks of follow‐up, 33.6% had elevated serum alanine aminotransferase (ALT) during pregnancy. Telbivudine administration resulted in ALT normalization in 85.2% before delivery. Compared with women having a normal ALT level throughout pregnancy, those with elevated ALT had a significantly higher rate of ALT flare after telbivudine withdrawal (25.0%vs11.9%;χ2 = 4.273,P = 0.039). Multivariate analysis indicated that only ALT elevation during pregnancy correlated with postpartum flare after telbivudine withdrawal. Those women with elevated ALT during pregnancy continued antiviral treatment to 52 weeks postpartum and had a significantly higher HBeAg seroconversion rate (P = 0.001) and a notable decrease in HBsAg titers (P = 0.001).

Conclusion

It is safe for the majority of women to withdraw telbivudine after delivery, whereas exciting serological response encourages extended antiviral therapy for mother with ALT elevation during pregnancy.
Clinical utility of endoscopic ultrasound‐guided biliary drainage as a rescue of re‐intervention procedure for high‐grade hilar stricture
Authors: Ogura Takeshi , Onda Saori , Takagi Wataru , Sano Tatsushi , Okuda Atsushi , Masuda Daisuke , Yamamoto Kazuhiro , Miyano Akira , Kitano Masayuki , Takeuchi Toshihisa , Fukunishi Shinya , Higuchi Kazuhide
Published: May 2016

Background and Aim

Re‐intervention after stent placement for malignant hepatic hilum obstruction (HBO) is challenging. endoscopic ultrasound‐guided biliary drainage (EUS‐BD) has been developed as an alternative method for failed endoscopic retrograde cholangiopancreatography (ERCP). In this retrospective study, the clinical utility of EUS‐BD as a rescue drainage technique for HBO patients who failed re‐intervention under ERCP guidance was evaluated.

Methods

Between April 2012 and August 2015, patients with HBO were enrolled. Patients' characteristics, kinds of metallic stents, configuration of stent placement, overall survival, stent patency, and results of re‐intervention were reviewed, along with the re‐intervention technical success rate.

Results

The biliary stricture type was Bismuth type IV in 59% (23/39) and types IIIa and b in 20.5% (8/39) each. Biliary metallic stent placement was bilateral in 38.5% (15/39), and unilateral in 61.5% (24/39). Primary stent dysfunction was observed in 71.8% (28/39) of cases. Planned re‐intervention under ERCP guidance was attempted in 26 patients. The technical success rate was 62% (16/26). For the 10 patients who failed re‐intervention under ERCP guidance, EUS‐BD was planned. The technical success rate was 100% (10/10). The procedure time was 25.8 min. Adverse events were not seen in any patients. Stent patency after re‐intervention was not significantly different between ERCP (165 days) guidance and EUS‐BD (152 days) guidance (P = 0.463)

Conclusions

In conclusion, EUS‐BD as a re‐intervention method for metallic stent obstruction was safe and feasible. If ERCP was failed, EUS‐BD may be one of option as re‐intervention method for high‐grade hilar stricture.
Plasma renin concentration represents an independent risk factor for mortality and is associated with liver dysfunction in patients with cirrhosis
Authors: Paternostro Rafael , Reiberger Thomas , Mandorfer Mattias , Schwarzer Remy , Schwabl Philipp , Bota Simona , Ferlitsch Monika , Trauner Michael , Peck‐Radosavljevic Markus , Ferlitsch Arnulf
Published: May 2016

Background and Aim

Plasma renin concentration (PRC) is increased in patients with cirrhosis. The aims of this study were to evaluate the relation of PRC to (i) portal hypertension, (ii) degree of liver dysfunction, and (iii) survival.

Methods

Plasma renin concentration (range 2.8–39.9 μU/mL) was measured after 30 min in supine position. Also, hepatic venous pressure gradient (HVPG), Child–Pugh (CPS), model for end‐stage liver disease scores and transient elastography values (TE, Fibroscan) were evaluated at this time. Mortality was recorded during follow‐up.

Results

One hundred fifty cirrhotic patients (age 55 ± 11 years; 73% male; CPS A 41.3%/B 41.3%/C 17.3%) were included. Mean HVPG was 16.6 ± 6.5 mmHg. Median PRC according to CPS was A 15.45 μU/mL (95%CI 1.56–261.5), B 37.3 μU/mL (95%CI 4.29–1317.65), and C 175.3 μU/mL (95%CI 5.3–5684; P < 0.001). In patients with clinical significant portal hypertension (HVPG ≥ 10 mmHg, n = 123) median PRC was 31.2 μU/mL (95%CI 2.76–1345.4), in those without was 13.7 μU/mL (95%CI 2.7–428.2; P = 0.009). Significantly higher TE values (33.2 [13–75] vs 59.65 kPa [14.5–75]; P = 0.014) were found in patients with elevated PRC.

Median follow up was 711 days (95%CI 24–1152). Twenty‐two (36.1%) of the 61 patients with elevated PRC and 11 of the 89 (12.4%) with normal PRC died (P = 0.001). Median PRC was significantly higher in patients that died (83.6 μU/mL [3.39–4451.9] vs 21.5 μU/mL [2.6–1197.9]; P = 0.001). Elevated PRC (P = 0.005; HR 3.36; 95%CI 1.46–7.85), hepatocellular carcinoma (P < 0.001; HR 10.68; 95%CI 3.64–31.3), CPS B (P = 0.013; HR 3.69; 95%CI 1.31–10.4) and CPS C (P = 0.008; HR 5.36; 95%CI 1.54–18.62) emerged as independent risk factors for mortality.

Conclusions

In cirrhotic patients PRC correlates with the severity of portal hypertension and liver dysfunction. Moreover, elevated PRC represents an independent risk factor for mortality.
Heat Waves, Drugs with Anticholinergic Effects, and Outcomes in Older Hospitalized Adults
Authors: Mangoni Arduino A. , Kim Susan , Hakendorf Paul , Mayner Lidia , Woodman Richard J.
Published: May 2016

Objectives

To determine whether heat waves (HWs) affect exposure to drugs with anticholinergic effects (DACEs) on admission and the effect of such on length of stay (LOS) and in‐hospital mortality in older adults.

Design

Retrospective.

Setting

Metropolitan teaching hospital.

Participants

Individuals aged 65 and older with at least one chronic condition (n = 307) admitted to a medical ward during five consecutive HWs (≥5 consecutive days of a maximum temperature of ≥35 °C or ≥3 consecutive days of a maximum temperature of ≥40 °C) recorded between 2007 and 2009. Individuals admitted before or after each HW, matched for HW period, age, and day of the week admitted, served as controls (n = 1,114).

Measurements

Data on clinical and demographic characteristics, Charlson Comorbidity Index (CCI), total medication and DACE exposure on admission (any DACE, number of DACEs, or Anticholinergic Risk Scale (ARS) score), LOS, and in‐hospital mortality were collected using electronic medical data.

Results

No significant differences in total medications, DACE exposure, CCI, number of daily admissions, LOS, or in‐hospital mortality were observed between the HW and control groups. DACE exposure (ARS) predicted longer LOS during non‐HW (β = 0.70, standard error (SE) = 0.27, P = .01) but not HW (β = 0.02, SE = 0.46, P = .96) periods. ARS did not predict mortality during non‐HW (odds ratio (OR) = 1.02, SE = 0.12, P = .87) or HW (OR = 1.21, SE = 0.23, P = .31) periods.

Conclusion

The effect of DACE exposure on LOS, but not mortality, is different between HW and non‐HW periods in older hospitalized adults. This should be considered when assessing the effect of DACEs in pharmacoepidemiological studies.
Psychometric evaluation of the McCloskey/Mueller Satisfaction Scale
Authors: Lee Seung Eun , Dahinten Susan V. , MacPhee Maura
Published: May 2016

Aim

The aim of the study was to evaluate and refine the eight‐factor structure of the 31 item McCloskey/Mueller Satisfaction Scale, which is one of the most widely used scales for measuring job satisfaction among nurses. However, this scale was developed in 1990 for the American nursing context and its psychometric validity and utility for use with non‐American nurse populations have been questioned by various researchers.

Background

The eight‐factor, 31‐item McCloskey/Mueller Satisfaction Scale is one of the most widely used scales for measuring job satisfaction among nurses. However, this scale was developed in 1990 for the American nursing context, and its psychometric validity and utility for use with non‐American nurse populations have been questioned by various researchers.

Methods

Data from a sample of 1007 Canadian nurses who were working in hospital and community settings were analyzed by using an exploratory factor analysis with varimax rotation.

Results

The original factor structure of the McCloskey/Mueller Satisfaction Scale was unable to be replicated. The best‐fitting model that was obtained was a five‐factor model with 25 items. The Cronbach's alphas for the new McCloskey/Mueller Satisfaction Scale subscales ranged from 0.71 to 0.87, which indicated stronger internal consistency than the original subscales (α = 0.52–0.84).

Conclusion

The reliability and structural validity of the revised 25 item instrument suggest that it is a potentially sound tool for measuring nurses’ job satisfaction. As a result of its sound dimensionality, it could be particularly useful when investigating individual and work factors that impact nurse job satisfaction or when evaluating the outcomes of organizational interventions that are aimed at increasing job satisfaction.
Training for Connection: Students' Perceptions of the Effects of the Person‐of‐the‐Therapist Training on Their Therapeutic Relationships
Authors: Niño Alba , Kissil Karni , Cooke Laura
Published: May 2016

The Person‐of‐the‐Therapist Training (POTT) is a program designed to facilitate clinicians' ability to consciously and purposefully use their selves to effectively connect, assess, and intervene with clients. This study exploredCFTstudents' perceptions of the effects ofPOTTon their ability to create positive therapeutic relationships. Course papers and final reflections were collected from 70CFTstudents. Directed content analysis looking for evidence‐supported elements of positive therapeutic relationships revealed 5 elements: empathy, management of countertransference, balancing multiple alliances, positive regard, and bond. Findings support the idea that a structured program focused on the training of the personal aspects of the therapists, likePOTT, can promote the evidence‐supported elements that make a therapeutic relationship effective.
Distress in long‐term head and neck cancer carers: a qualitative study of carers' perspectives
Authors: Balfe Myles , Maguire Rebecca , Hanly Paul , Butow Phyllis , O'Sullivan Eleanor , Timmons Aileen , Gooberman‐Hill Rachael , Sharp Linda
Published: May 2016

Aims and objectives

To identify and describe the triggers of emotional distress among long‐term caregivers (more than 1 year postdiagnosis) of people with head and neck cancer.

Background

Limited research has been conducted on the factors that cause head and neck cancer caregivers to become distressed.

Design

Qualitative cross‐sectional.

Methods

In‐depth semi‐structured interviews. Interviews were conducted via telephone. The study setting was the Republic of Ireland.

Results

Interviews were conducted with 31 long‐term caregivers (mean time since diagnosis 5·7 years, SD 2·9 years). Head and neck cancer caregivers experienced significant distress. Six key triggers of emotional distress were identified: understandings and fears of illness, lifestyle restrictions and competing demands, facial disfigurement, financial problems, comorbid health problems and witnessing suffering. Cutting across all of these individual causes of distress was a strong feeling of loss caused by head and neck cancer.

Conclusions

Some head and neck cancer caregivers became considerably distressed by their caring role. Although distress appears to decline with time for many caregivers, some continue to be distressed for years following the patient's diagnosis. It would be useful for future research to explicitly investigate caregivers' experiences of loss.

Relevance to clinical practice

Health professionals may be able to reduce distress in this group if they can help caregivers to access resources that can be used to buffer financial problems. Health professionals may also be able to reduce distress if they can work with caregivers to help them to obtain something of personal value or significance from their experience of loss and suffering.
COOPERATIVE GAME THEORY APPLIED TO IEAS: A COMPARISON OF SOLUTION CONCEPTS
Authors: Rogna Marco
Published: May 2016

This paper aims at providing a critical overview of the main solution concepts adopted by the cooperative game theoretical approach in analysing the constitution of an international environmental agreement (IEA). The first part is mainly descriptive and focuses on the basic features of the ‘global warming game’ characterizing the differences of the cooperative and non‐cooperative approaches to deal with this theme. It then presents the most adopted cooperative solution concepts critically analysing their ratio. Furthermore, two alternative solutions, the Rawlsian Nucleolus and a ‘revisited’ Nash Bargaining solution are proposed, both based on the concept of Minimum Feasible Core. The second part is dedicated to a numerical exercise based on a standard emissions game in order to compare the mentioned concepts with particular focus on their redistributive properties and on their capability to minimize the potential losses caused by free riding. The Rawlsian Nucleolus is, among the considered solutions, the one with the highest redistributive properties, outperforming, on this regard, the Chander and Tulkens solution that still tends to prioritize polluted countries. The ability of avoiding losses from free riding is shown to be strongly correlated with the redistributive properties of solution concepts till the point that their ranking perfectly coincides.
Polymorphism Detection by Microsatellite Markers in a Magnaporthe oryzae Population From Different Geographical Areas of Brazil
Authors: Gonçalves Fábio José , Corsi de Filippi Marta Cristina , Silva Lobo Valácia Lemes , Araújo Leila Garcês , Silva Gisele Barata , Coelho Alexandre Siqueira Guedes , Prabhu Anne Sitarama
Published: May 2016

This study aimed to examine Brazilian M. oryzae populations using 18 microsatellites. Fifty cultivars were sown in plastic trays for the pathotyping of 847 isolates. The DNA of 494 isolates was extracted and purified using the modified Doyle and Doyle method, the genetic structure was determined by the software Structure, and the actual number was selected from the prediction method based on the K values. Nei's genetic distance among the subpopulations was determined with the aid of the program Genetix, and the amova was performed with the program Arlequin. Out of 847 inoculated monosporic isolates, 528 infected their respective cultivars; of the 528 isolates pathotyped, there was a prevalence of group IA and pathotype IF‐1, which was the most frequent pathotype in the rice production areas of Brazil. The Bayesian clustering analysis indicated that 19 was the optimal value of K; this value was the lowest standard deviation and log (ln K) closest to zero, which predicted the 494 isolates of M. oryzae that were selected for molecular studies to be grouped into 19 subpopulations. The AMOVA detected a 37.13% variability within the 19 subpopulations and 62.87% variability among the subpopulations. The polymorphic information content (PIC) ranged from 0 to 0.756. Thirty three rare alleles were found distributed among 15 out of 19 subpopulations. The Margalef index ranged from 38.69 to 79.21 for all 18 analysed locus. The results indicated that the identification of different blast resistance genes must consider the composition of each subpopulation and that the identification is most effective when performed within a subpopulation and then between subpopulations.