Skeletal muscle pH assessed by biochemical and 31P-MRS methods during exercise and recovery in men.
The present study was designed to compare evaluation of skeletal muscle metabolism (vastus lateralis) evaluated by 31P-magnetic resonance spectroscopy (MRS) and biochemical analysis. During identical isometric knee extensor exercise protocols to fatigue in eight men, biopsy samples were taken at rest, peak exercise, and 32 s postexercise and 31P-MRS data were collected continuously for phosphocreatine (PCr), pH, ATP, and P(i) at 8- or 32-s intervals. There was no difference in ATP or pH measurements between the two techniques at rest, during peak exercise, or in recovery. Corresponding measurements of pH by the two techniques were closely related (r = 0.88, P < 0.01), and pH measured by 31P-MRS was closely related to muscle lactate accumulation (r = -0.84, P < 0.001). The level of PCr at peak exercise, expressed as a percentage of the baseline value, was not different between the two techniques (42 +/- 15 vs. 46 +/- 15%). The results indicate that, in skeletal muscle in normal subjects, 1) measurements of pH and PCr at rest and during exercise do not differ between the 31P-MRS and biopsy techniques and 2) muscle pH measured by 31P-MRS is closely related to lactate accumulation in men. Our data suggest that direct comparison of results of studies of exercise metabolism using these two techniques is warranted.


Mapping the optimal route between two quantum states.
A central feature of quantum mechanics is that a measurement result is intrinsically probabilistic. Consequently, continuously monitoring a quantum system will randomly perturb its natural unitary evolution. The ability to control a quantum system in the presence of these fluctuations is of increasing importance in quantum information processing and finds application in fields ranging from nuclear magnetic resonance to chemical synthesis. A detailed understanding of this stochastic evolution is essential for the development of optimized control methods. Here we reconstruct the individual quantum trajectories of a superconducting circuit that evolves under the competing influences of continuous weak measurement and Rabi drive. By tracking individual trajectories that evolve between any chosen initial and final states, we can deduce the most probable path through quantum state space. These pre- and post-selected quantum trajectories also reveal the optimal detector signal in the form of a smooth, time-continuous function that connects the desired boundary conditions. Our investigation reveals the rich interplay between measurement dynamics, typically associated with wavefunction collapse, and unitary evolution of the quantum state as described by the Schrödinger equation. These results and the underlying theory, based on a principle of least action, reveal the optimal route from initial to final states, and may inform new quantum control methods for state steering and information processing.


The association between frailty and quality of life among rural community-dwelling older adults in Kegalle district of Sri Lanka: a cross-sectional study.
The objective of this study was to estimate the cross-sectional association of frailty status with overall and domain-specific quality of life (QoL) in rural community-dwelling older adults in Kegalle district of Sri Lanka. A population-based cross-sectional study was conducted with 746 community-dwelling older adults aged ≥ 60 years living in the rural areas of Kegalle district of Sri Lanka in 2016. A three-stage probability sampling design was used to recruit participants. Frailty and QoL were assessed using the Fried phenotype and Older People's Quality of Life Questionnaire, respectively. Multivariable linear regression was used to estimate the association of frailty with QoL after accounting for the complex sampling design. The median (IQR) age of the sample was 68 (64:75) years and comprised of 56.7% women. 15.2% (95% CI 12.4%, 18.7%) were frail and 48.5% (95% CI 43.9%, 53.2%) were pre-frail. The unadjusted means (SE) of the total QoL score for the robust, pre-frail and frail groups were 139.2 (0.64), 131.8 (1.04) and 119.2 (1.35), respectively. After adjusting for covariates in the final multivariable model, the estimated differences in mean QoL were lower for both frail and pre-frail groups versus robust. The estimated reduction in the total QoL score was 7.3% for those frail and 2.1% for those pre-frail. All QoL domains apart from 'social relationships and participation', 'home and neighbourhood' and 'financial circumstances' were associated with frailty. Frailty was associated with a small but significant lower quality of life in this rural Sri Lankan population, which appears largely explained by 'health' and 'independence, control over life and freedom' QoL domains. Interventions aiming to improve quality of life in frail older adults should consider targeting these aspects.


Regularly consuming a green/roasted coffee blend reduces the risk of metabolic syndrome.
Preventive health effects of coffee could have a widespread impact on public health. Green coffee has more phenols than roasted, and thus is healthier, although with less acceptable organoleptic properties. Therefore, the effects of regularly consuming a green/roasted coffee blend (35/65) on the main components of MetS in humans were evaluated. A crossover, randomized, controlled study was performed in 25 normocholesterolaemic and 27 hypercholesterolaemic men and women aged 18-45 years with BMI 18-25 kg/m2. Three servings/day of the blend, providing 510.6 mg hydroxycinnamic acids and 121.2 mg caffeine/day, were consumed versus a control drink, during 8 weeks each. Polyphenol and methylxanthine-rich foods were restricted along the study. At the beginning (baseline) and end of the control and coffee interventions, blood samples were collected and glucose, HDL-cholesterol, triglycerides, insulin, leptin, plasminogen activator inhibitor-1 (PAI-1), resistin and visfatin were analysed; waist circumference, %body fat, and blood pressure were measured and dietary records and physical activity questionnaires completed. Systolic and diastolic blood pressure decreased (p = 0.001 and p < 0.001, respectively) in both groups as well as %body fat (p = 0.001) which may be related to the lower leptin (p = 0.001), PAI-1 (p < 0.001) and resistin (p = 0.034) levels in the two groups after coffee consumption. Glucose concentration (p = 0.030) and insulin resistance (p = 0.011; HOMA-IR) also decreased, as well as triglyceride levels (p = 0.017), so that the reduction was much greater in the hypercholesterolaemics (group effect, p = 0.027). Regular consumption of the green/roasted coffee blend may be recommended to healthy and hypercholesterolaemic subjects to prevent MetS, as it produces positive effects on blood pressure, glucose and triglyceride levels.


Cooperation, psychological game theory, and limitations of rationality in social interaction.
Rational choice theory enjoys unprecedented popularity and influence in the behavioral and social sciences, but it generates intractable problems when applied to socially interactive decisions. In individual decisions, instrumental rationality is defined in terms of expected utility maximization. This becomes problematic in interactive decisions, when individuals have only partial control over the outcomes, because expected utility maximization is undefined in the absence of assumptions about how the other participants will behave. Game theory therefore incorporates not only rationality but also common knowledge assumptions, enabling players to anticipate their co-players' strategies. Under these assumptions, disparate anomalies emerge. Instrumental rationality, conventionally interpreted, fails to explain intuitively obvious features of human interaction, yields predictions starkly at variance with experimental findings, and breaks down completely in certain cases. In particular, focal point selection in pure coordination games is inexplicable, though it is easily achieved in practice; the intuitively compelling payoff-dominance principle lacks rational justification; rationality in social dilemmas is self-defeating; a key solution concept for cooperative coalition games is frequently inapplicable; and rational choice in certain sequential games generates contradictions. In experiments, human players behave more cooperatively and receive higher payoffs than strict rationality would permit. Orthodox conceptions of rationality are evidently internally deficient and inadequate for explaining human interaction. Psychological game theory, based on nonstandard assumptions, is required to solve these problems, and some suggestions along these lines have already been put forward.


In Silico Generation of Peptides by Replica Exchange Monte Carlo: Docking-Based Optimization of Maltose-Binding-Protein Ligands.
Short peptides can be designed in silico and synthesized through automated techniques, making them advantageous and versatile protein binders. A number of docking-based algorithms allow for a computational screening of peptides as binders. Here we developed ex-novo peptides targeting the maltose site of the Maltose Binding Protein, the prototypical system for the study of protein ligand recognition. We used a Monte Carlo based protocol, to computationally evolve a set of octapeptides starting from a polialanine sequence. We screened in silico the candidate peptides and characterized their binding abilities by surface plasmon resonance, fluorescence and electrospray ionization mass spectrometry assays. These experiments showed the designed binders to recognize their target with micromolar affinity. We finally discuss the obtained results in the light of further improvement in the ex-novo optimization of peptide based binders.


Effects of plant extracts on microbial growth, color change, and lipid oxidation in cooked beef.
The effects of butylated hydroxyanisole/butylated hydroxytoluene (BHA/BHT), grape seed extract (ActiVin), pine bark extract (Pycnogenol), and oleoresin rosemary (Herbalox) on microbial growth, color change, and lipid oxidation were investigated in cooked ground beef. When compared to the control, 1.0% ActiVin and Pycnogenol) effectively reduced the numbers of Escherichia coli O157:H7 and Salmonella Typhimurium, and retarded the growth of Listeria monocytogenes and Aeromonas hydrophila. Pycnogenol resulted in reductions of 1.7, 2.0, 0.8, and 0.4 log CFU/g, respectively, in numbers of E. coli O157:H7, L. monocytogenes, S. Typhimurium, and A. hydrophila, respectively, after 9 days of refrigerated storage. The color of cooked beef treated with ActiVin was less light (L*), more red (a*), and less yellow (b*) than those treated with BHA/BHT, Pycnogenol, and Herbalox. ActiVin and Pycnogenol effectively retained the redness in cooked beef during storage. The control showed significantly higher thiobarbituric acid-reactive substances (TBARS) and hexanal content over storage. BHA/BHT, ActiVin, Pycnogenol, and Herbalox retarded the formation of TBARS by 75%, 92%, 94%, and 92%, respectively, after 9 days, and significantly lowered the hexanal content throughout the storage period. Results of this work show that ActiVin and Pycnogenol are promising additives for maintaining the quality and safety of cooked beef.


A Nationwide, Multicenter Registry Study of Antiemesis for Carboplatin-Based Chemotherapy-Induced Nausea and Vomiting in Japan.
We previously reported the results of a prospective study of chemotherapy-induced nausea and vomiting (CINV) in a cohort of patients who received carboplatin-based chemotherapy and were selected from a nationwide registry of those scheduled for moderately (MEC) or highly emetogenic chemotherapy (HEC) by the CINV Study Group of Japan. Of 1,910 previously registered patients (HEC: 1,195; MEC: 715), 400 patients received carboplatin-based chemotherapy. The frequency of CINV was determined, and the risk factors for CINV were assessed. CINV data were collected from 7-day diaries. Risk factors for CINV were identified using logistic regression models. Of 400 patients scheduled for carboplatin-based chemotherapy, 267 patients received two antiemetics (5-hydroxytryptamine-3 receptor antagonist [5-HT3 RA] and dexamethasone [DEX]), 118 patients received three antiemetics (5-HT3 RA, DEX, and neurokinin-1 receptor antagonist [NK1 RA]), and 15 were nonadherent to the treatment. In these patients, the CINV overall, acute, and delayed phase rates of complete response (CR), defined as no vomiting with no rescue medication, were 67.0%, 98.2%, and 67.5%, respectively. The rates of no nausea were 55.6%, 94.0%, and 56.1%, respectively, and those of no vomiting were 81.3%, 99.0%, and 81.8%, respectively. Older age was associated with a decreased non-CR, whereas female sex, history of pregnancy-related emesis, and dual antiemetic therapy were associated with an increased non-CR during the overall period. In a clinical practice setting, in patients who received carboplatin-based chemotherapy, adherence is quite high and appropriate antiemetic prophylaxis requires a triple antiemetic regimen including NK1 RA. For patients receiving carboplatin-based chemotherapy, triple antiemetic therapy with 5-hydroxytryptamine-3 receptor antagonist, dexamethasone, and neurokinin-1 receptor antagonist should be given prophylactically regardless of risk factor status.


Evaluation of the D3 dopamine receptor selective antagonist PG01037 on L-dopa-dependent abnormal involuntary movements in rats.
The D3 dopamine receptor selective antagonist PG01037 has been evaluated for the ability to attenuate L-dopa-associated abnormal involuntary movements (AIMs) in unilaterally lesioned male Sprague-Dawley rats, which is a model of L-dopa-dependent dyskinesia in patients with Parkinson's Disease. The intrinsic activity of PG01037 was determined using a) a forskolin-dependent adenylyl cyclase inhibition assay with transfected HEK 293 cells expressing either the human D2Long or D3 dopamine receptor subtype and b) an assay for agonist-associated mitogenesis. For the initial experiments, the 5-HT1A receptor selective partial agonist buspirone was used as a positive control to verify our ability to quantitate changes in total AIMs and AIMs minus locomotor scores. Subcutaneous (s.c.) administration of PG01037 was found to have minimal effect on AIMs score. However, it was observed that the in vivo efficacy of PG01037 increased when administered by intraperitoneal (i.p.) injection 15 min after L-dopa/benserazide administration, as compared to a 60 min, 30 min or 0 min pretreatment. It was also found that i.p. administration of PG01037 could inhibit involuntary movements after they had achieved maximum intensity. PG01037 was found to attenuate AIM scores in these animals in a dose dependent manner with IC(50) value equal to a) 7.4 mg/kg following L-dopa/benserazide administration (8 mg/kg each, i.p.) and b) 18.4 mg/kg following the administration of apomorphine (0.05 mg/kg, s.c.). However, PG01037 did not effectively inhibit SKF 81297-dependent abnormal involuntary movements. Rotarod studies indicate that PG01037 at a dose of 10 mg/kg did not adversely affect motor coordination of the unilaterally lesioned rats. Evaluation of lesioned rats using a cylinder test behavioral paradigm indicated that PG01037 did not dramatically attenuate the beneficial effects of L-dopa. These studies suggest that D3 dopamine receptor selective antagonists are potential pharmacotherapeutic candidates for the treatment of L-dopa-associated dyskinesia in patients with Parkinson's Disease.


Defining the limits of single-molecule FRET resolution in TIRF microscopy.
Single-molecule FRET (smFRET) has long been used as a molecular ruler for the study of biology on the nanoscale (∼2-10 nm); smFRET in total-internal reflection fluorescence (TIRF) Förster resonance energy transfer (TIRF-FRET) microscopy allows multiple biomolecules to be simultaneously studied with high temporal and spatial resolution. To operate at the limits of resolution of the technique, it is essential to investigate and rigorously quantify the major sources of noise and error; we used theoretical predictions, simulations, advanced image analysis, and detailed characterization of DNA standards to quantify the limits of TIRF-FRET resolution. We present a theoretical description of the major sources of noise, which was in excellent agreement with results for short-timescale smFRET measurements (<200 ms) on individual molecules (as opposed to measurements on an ensemble of single molecules). For longer timescales (>200 ms) on individual molecules, and for FRET distributions obtained from an ensemble of single molecules, we observed significant broadening beyond theoretical predictions; we investigated the causes of this broadening. For measurements on individual molecules, analysis of the experimental noise allows us to predict a maximum resolution of a FRET change of 0.08 with 20-ms temporal resolution, sufficient to directly resolve distance differences equivalent to one DNA basepair separation (0.34 nm). For measurements on ensembles of single molecules, we demonstrate resolution of distance differences of one basepair with 1000-ms temporal resolution, and differences of two basepairs with 80-ms temporal resolution. Our work paves the way for ultra-high-resolution TIRF-FRET studies on many biomolecules, including DNA processing machinery (DNA and RNA polymerases, helicases, etc.), the mechanisms of which are often characterized by distance changes on the scale of one DNA basepair.


Biodegradation ZK50 magnesium alloy compression screws: Mechanical properties, biodegradable characteristics and implant test.
Magnesium alloy implants have lower stress load and can be absorbed gradually, but their degradation rates are too fast generally. A magnesium alloy contained 5% Zn and 0.5% Zr (ZK50) which have lower degradation rate are designed to be applied to cannulated bone screw. An oxidation heat treatment of 380 °C for 2 h proceeds to modify the ZK50 Mg alloy (ZK50-H). The microstructure observation, degradation tests and Biocompatibility analysis are proceeded between ZK50 and ZK50-H. Finally, a mini-pig implantation test is proceeded to provide a reference of implant application for future pre-clinical evaluation. The heat treatment can improve the mechanical properties. A passive ceramic layer formed after simulated body fluid (SBF) solution immersion can restrict the degradation effectively. The cytotoxicity test shows the initial biosafety of ZK50 Mg alloy. A mini-pig implantation test of bone screw has proceeded to confirm the advanced biocompatibility. The ZK50-H screws can maintain enough support at least 8 weeks which the fracture of bone can get curing. The excellent osteoinduction of ZK50-H has a positive effect to growth of new bones and help the mini-pig regain heal faster in 12 weeks. This study shows ZK50-H Mg alloy screw is a feasible degradation implant and can be carried out the next-step clinical experiments.


Identification of novel tumor antigens with patient-derived immune-selected antibodies.
The identification of tumor antigens capable of eliciting an immune response in vivo may be an effective method to identify therapeutic cancer targets. We have developed a method to identify such antigens using frozen tumor-draining lymph node samples from breast cancer patients. Immune responses in tumor-draining lymph nodes were identified by immunostaining lymph node sections for B-cell markers (CD20&CD23) and Ki67 which revealed cell proliferation in germinal center zones. Antigen-dependent somatic hypermutation (SH) and clonal expansion (CE) were present in heavy chain variable (VH) domain cDNA clones obtained from these germinal centers, but not from Ki67 negative germinal centers. Recombinant VH single-domain antibodies were used to screen tumor proteins and affinity select potential tumor antigens. Neuroplastin (NPTN) was identified as a candidate breast tumor antigen using proteomic identification of affinity selected tumor proteins with a recombinant VH single chain antibody. NPTN was found to be highly expressed in approximately 20% of invasive breast carcinomas and 50% of breast carcinomas with distal metastasis using a breast cancer tissue array. Additionally, NPTN over-expression in a breast cancer cell line resulted in a significant increase in tumor growth and angiogenesis in vivo which was related to increased VEGF production in the transfected cells. These results validate NPTN as a tumor-associated antigen which could promote breast tumor growth and metastasis if aberrantly expressed. These studies also demonstrate that humoral immune responses in tumor-draining lymph nodes can provide antibody reagents useful in identifying tumor antigens with applications for biomarker screening, diagnostics and therapeutic interventions.


Microbiota-derived compounds drive steady-state granulopoiesis via MyD88/TICAM signaling.
Neutropenia is probably the strongest known predisposition to infection with otherwise harmless environmental or microbiota-derived species. Because initial swarming of neutrophils at the site of infection occurs within minutes, rather than the hours required to induce "emergency granulopoiesis," the relevance of having high numbers of these cells available at any one time is obvious. We observed that germ-free (GF) animals show delayed clearance of an apathogenic bacterium after systemic challenge. In this article, we show that the size of the bone marrow myeloid cell pool correlates strongly with the complexity of the intestinal microbiota. The effect of colonization can be recapitulated by transferring sterile heat-treated serum from colonized mice into GF wild-type mice. TLR signaling was essential for microbiota-driven myelopoiesis, as microbiota colonization or transferring serum from colonized animals had no effect in GF MyD88(-/-)TICAM1(-/-) mice. Amplification of myelopoiesis occurred in the absence of microbiota-specific IgG production. Thus, very low concentrations of microbial Ags and TLR ligands, well below the threshold required for induction of adaptive immunity, sets the bone marrow myeloid cell pool size. Coevolution of mammals with their microbiota has probably led to a reliance on microbiota-derived signals to provide tonic stimulation to the systemic innate immune system and to maintain vigilance to infection. This suggests that microbiota changes observed in dysbiosis, obesity, or antibiotic therapy may affect the cross talk between hematopoiesis and the microbiota, potentially exacerbating inflammatory or infectious states in the host.


Risk stratification for sudden cardiac death after acute myocardial infarction.
Many patients who survive an acute myocardial infarction (AMI) remain at risk of recurrent cardiac events and sudden cardiac death after discharge, despite optimal medical treatment. Assessment of the degree of left ventricular dysfunction and residual myocardial ischaemia is useful to identify the patients at greatest risk. In addition, there is increasing evidence that a number of other cardiovascular tests can be used to detect autonomic dysfunction and myocardial substrate abnormalities postAMI that increase the risk of life-threatening ventricular arrhythmias. These investigations include ECG-based tests (signal averaged ECG and T-wave alternans), Holter-based recordings (heart rate variability and heart rate turbulence) and imaging techniques (echocardiography and cardiac magnetic resonance), as well as invasive electrophysiological testing. This article reviews the current evidence for the use of these additional cardiac investigations among survivors of AMI to aid in their risk stratification for malignant ventricular arrhythmias and sudden cardiac death.


Seek COVER: using a disease proxy to rapidly develop and validate a personalized risk calculator for COVID-19 outcomes in an international network.
We investigated whether we could use influenza data to develop prediction models for COVID-19 to increase the speed at which prediction models can reliably be developed and validated early in a pandemic. We developed COVID-19 Estimated Risk (COVER) scores that quantify a patient's risk of hospital admission with pneumonia (COVER-H), hospitalization with pneumonia requiring intensive services or death (COVER-I), or fatality (COVER-F) in the 30-days following COVID-19 diagnosis using historical data from patients with influenza or flu-like symptoms and tested this in COVID-19 patients. We analyzed a federated network of electronic medical records and administrative claims data from 14 data sources and 6 countries containing data collected on or before 4/27/2020. We used a 2-step process to develop 3 scores using historical data from patients with influenza or flu-like symptoms any time prior to 2020. The first step was to create a data-driven model using LASSO regularized logistic regression, the covariates of which were used to develop aggregate covariates for the second step where the COVER scores were developed using a smaller set of features. These 3 COVER scores were then externally validated on patients with 1) influenza or flu-like symptoms and 2) confirmed or suspected COVID-19 diagnosis across 5 databases from South Korea, Spain, and the United States. Outcomes included i) hospitalization with pneumonia, ii) hospitalization with pneumonia requiring intensive services or death, and iii) death in the 30 days after index date. Overall, 44,507 COVID-19 patients were included for model validation. We identified 7 predictors (history of cancer, chronic obstructive pulmonary disease, diabetes, heart disease, hypertension, hyperlipidemia, kidney disease) which combined with age and sex discriminated which patients would experience any of our three outcomes. The models achieved good performance in influenza and COVID-19 cohorts. For COVID-19 the AUC ranges were, COVER-H: 0.69-0.81, COVER-I: 0.73-0.91, and COVER-F: 0.72-0.90. Calibration varied across the validations with some of the COVID-19 validations being less well calibrated than the influenza validations. This research demonstrated the utility of using a proxy disease to develop a prediction model. The 3 COVER models with 9-predictors that were developed using influenza data perform well for COVID-19 patients for predicting hospitalization, intensive services, and fatality. The scores showed good discriminatory performance which transferred well to the COVID-19 population. There was some miscalibration in the COVID-19 validations, which is potentially due to the difference in symptom severity between the two diseases. A possible solution for this is to recalibrate the models in each location before use.


Effect of Plasmodium falciparum sulfadoxine-pyrimethamine resistance on the effectiveness of intermittent preventive therapy for malaria in pregnancy in Africa: a systematic review and meta-analysis.
Resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine threatens the antimalarial effectiveness of intermittent preventive treatment during pregnancy (IPTp) in sub-Saharan Africa. We aimed to assess the associations between markers of sulfadoxine-pyrimethamine resistance in P falciparum and the effectiveness of sulfadoxine-pyrimethamine IPTp for malaria-associated outcomes. For this systematic review and meta-analysis, we searched databases (from Jan 1, 1990 to March 1, 2018) for clinical studies (aggregated data) or surveys (individual participant data) that reported data on low birthweight (primary outcome) and malaria by sulfadoxine-pyrimethamine IPTp dose, and for studies that reported on molecular markers of sulfadoxine-pyrimethamine resistance. Studies that involved only HIV-infected women or combined interventions were excluded. We did a random-effects meta-analysis (clinical studies) or multivariate log-binomial regression (surveys) to obtain summarised dose-response data (relative risk reduction [RRR]) and multivariate meta-regression to explore the modifying effects of sulfadoxine-pyrimethamine resistance (as indicated by Ala437Gly, Lys540Glu, and Ala581Gly substitutions in the dhps gene). This study is registered with PROSPERO, number 42016035540. Of 1097 records screened, 57 studies were included in the aggregated-data meta-analysis (including 59 457 births). The RRR for low birthweight declined with increasing prevalence of dhps Lys540Glu (ptrend=0·0060) but not Ala437Gly (ptrend=0·35). The RRR was 7% (95% CI 0 to 13) in areas of high resistance to sulfadoxine-pyrimethamine (Lys540Glu ≥90% in east and southern Africa; n=11), 21% (14 to 29) in moderate-resistance areas (Ala437Gly ≥90% [central and west Africa], or Lys540Glu ≥30% to <90% [east and southern Africa]; n=16), and 27% (21 to 33) in low-resistance areas (Ala437Gly <90% [central and west Africa], or Lys540Glu <30% [east and southern Africa]; n=30; ptrend=0·0054 [univariate], I2=69·5%). The overall RRR in all resistance strata was 21% (17 to 25). In the analysis of individual participant data from 13 surveys (42 394 births), sulfadoxine-pyrimethamine IPTp was associated with reduced prevalence of low birthweight in areas with a Lys540Glu prevalence of more than 90% and Ala581Gly prevalence of less than 10% (RRR 10% [7 to 12]), but not in those with an Ala581Gly prevalence of 10% or higher (pooled Ala581Gly prevalence 37% [range 29 to 46]; RRR 0·5% [-16 to 14]; 2326 births). The effectiveness of sulfadoxine-pyrimethamine IPTp is reduced in areas with high resistance to sulfadoxine-pyrimethamine among P falciparum parasites, but remains associated with reductions in low birthweight even in areas where dhps Lys540Glu prevalence exceeds 90% but where the sextuple-mutant parasite (harbouring the additional dhps Ala581Gly mutation) is uncommon. Therapeutic alternatives to sulfadoxine-pyrimethamine IPTp are needed in areas where the prevalence of the sextuple-mutant parasite exceeds 37%. US Centers for Disease Control and Prevention, the Malaria in Pregnancy Consortium (funded through a grant from the Bill & Melinda Gates Foundation to the Liverpool School of Tropical Medicine), Worldwide Antimalarial Resistance Network, European and Developing Countries Clinical Trials Partnership.


The oxytocin receptor (OXTR) contributes to prosocial fund allocations in the dictator game and the social value orientations task.
Economic games observe social decision making in the laboratory that involves real money payoffs. Previously we have shown that allocation of funds in the Dictator Game (DG), a paradigm that illustrates costly altruistic behavior, is partially determined by promoter-region repeat region variants in the arginine vasopressin 1a receptor gene (AVPR1a). In the current investigation, the gene encoding the related oxytocin receptor (OXTR) was tested for association with the DG and a related paradigm, the Social Values Orientation (SVO) task. Association (101 male and 102 female students) using a robust-family based test between 15 single tagging SNPs (htSNPs) across the OXTR was demonstrated with both the DG and SVO. Three htSNPs across the gene region showed significant association with both of the two games. The most significant association was observed with rs1042778 (p = 0.001). Haplotype analysis also showed significant associations for both DG and SVO. Following permutation test adjustment, significance was observed for 2-5 locus haplotypes (p<0.05). A second sample of 98 female subjects was subsequently and independently recruited to play the dictator game and was genotyped for the three significant SNPs found in the first sample. The rs1042778 SNP was shown to be significant for the second sample as well (p = 0.004, Fisher's exact test). The demonstration that genetic polymorphisms for the OXTR are associated with human prosocial decision making converges with a large body of animal research showing that oxytocin is an important social hormone across vertebrates including Homo sapiens. Individual differences in prosocial behavior have been shown by twin studies to have a substantial genetic basis and the current investigation demonstrates that common variants in the oxytocin receptor gene, an important element of mammalian social circuitry, underlie such individual differences.


Remote Asymmetric Induction Reactions using a E, E-Vinylketene Silyl N, O-Acetal and the Wide Range Stereocontrol Strategy for the Synthesis of Polypropionates.
The construction of libraries of acyclic polyketides remains a challenging topic, mostly due to the difficulties associated with finding the right balance between diversity and brevity for the synthetic routes leading to polyketides. Recently, relatively short methods have been developed and applied to the synthesis of natural products. However, these short routes often suffer from limited diversity with respect to the arrangement of functional groups and stereochemistry, as these usually require reactions that direct multiple functional groups simultaneously in one step. Therefore, methods that combine a small number of reaction steps with structural diversity remain an attractive research target for the construction of acyclic polyketide libraries. In 2004, we reported a remote asymmetric induction reaction using chiral vinylketene silyl N, O-acetal 1, which is commensurate to an anti-selective vinylogous Mukaiyama aldol reaction. Ever since, this reaction has been applied to the synthesis of numerous natural products, as this synthetic route is short and efficient on account of the simultaneous introduction of both asymmetric centers and the multiply functionalized carbon chain. Recently, we have developed a variety of this remote asymmetric induction reaction based on the E, E-vinylketene N, O-acetal 1, which includes syn-selective vinylogous Mukaiyama aldol reactions, as well as alkylation, acylation, and bromination reaction. These reactions provide polypropionates in a highly stereoselective manner. The proposed transition states of these reactions are discussed in this Account. Additionally, we have developed a new short synthesis of polypropionates by combining reactions for the remote asymmetric induction and the functionalization of double bonds (wide-range stereocontrol, WRS). The remote asymmetric induction reaction simultaneously constructs the stereogenic centers at the central part of the products and introduces the α,β-unsaturated imide, while the new strategy is based on the initial construction of the central part of the molecule and a subsequent functionalization of the surroundings (WRS). This strategy successfully furnished stereoisomers in a few steps, and the stereodivergent synthesis of 2,4,6-trimethyloctanoic acid derivatives was accomplished. This strategy should also be feasible to construct an acyclic polyketide library. Moreover, we applied this method to the concise synthesis of natural products. In this Account, the development of remote asymmetric induction reactions and the new WRS strategy are described. Applications of the WRS strategy as well as reactions for the stereodivergent synthesis of polypropionates and natural products are also described. The aforementioned acyclic polyketide library should be constructed in the future with the help of the WRS strategy and become a powerful tool in drug discovery.


Brief intervention resource kits for Indigenous Australians: generally evidence-based, but missing important components.
Little is known about the content and quality of brief intervention kits specifically targeting SNAP risk factors (smoking, poor nutrition, alcohol misuse or physical inactivity) among Indigenous Australians. This paper reviews the type and quality of these kits. Brief intervention kits were primarily identified by contacting 74 health-related organisations in Australia between 1 February 2007 and 4 March 2007. Ten brief intervention kits met inclusion criteria: four targeted smoking; three targeted alcohol; one targeted alcohol, smoking and other drugs; one targeted alcohol, other drugs and mental health; and one targeted all SNAP risk factors. Brief intervention kits were reviewed using criteria developed from clinical guidelines for SNAP risk factors and guidelines for evaluating health promotion resources. Three kits met all review criteria. Five kits were consistent with evidence-based guidelines, but lacked a training package, patient education materials and/or behavioural change strategies. All kits used images and language identifiable with Indigenous Australia, however, their cultural appropriateness for Indigenous Australians remains unclear. The specific content of the missing components should be guided by the best-available evidence, such as established mechanisms for health care provider feedback to patients as a behaviour change strategy, as well as the needs and preferences of health care providers and patients.


Effects of single oral doses of scopoletin and aflatoxin B1 on the clotting time, serum cholesterol and phospholipid levels of chicks.
The plasma cholesterol and phospholipid levels as well as the bleeding time of chicks treated with single oral doses of scopoletin (60 micrograms/kg, body wt) and aflatoxin B1 (50 micrograms/kg, body wt) were measured at intervals for a period of one week (168 h). Both compounds generally increased the bleeding time (AFB1 0.8-28.7%, Scopoletin 0.5-38.2%), serum total and free cholesterol, and the serum phospholipid levels but decreased the levels of the serum esterified cholesterol fraction relative to control throughout the period of study. The extent of these changes elicited by the respective compounds and the variation in the differences between their respective effects varied with the measured parameters. The importance of the similarities in the effects elicited by aflatoxin B1 and Scopoletin was highlighted.


Effects of Cranberry Juice Supplementation on Cardiovascular Disease Risk Factors in Adults with Elevated Blood Pressure: A Randomized Controlled Trial.
Emerging cardiovascular disease (CVD) risk factors, including central vascular function and HDL efflux, may be modifiable with food-based interventions such as cranberry juice. A randomized, placebo-controlled, crossover trial was conducted in middle-aged adults with overweight/obesity (n = 40; mean BMI: 28.7 ± 0.8 kg/m2; mean age: 47 ± 2 years) and elevated brachial blood pressure (mean systolic/diastolic BP: 124 ± 2/81 ± 1 mm Hg). Study participants consumed 500 mL/d of cranberry juice (~16 fl oz; 27% cranberry juice) or a matched placebo juice in a randomized order (8-week supplementation periods; 8-week compliance break), with blood samples and vascular measurements obtained at study entry and following each supplementation period. There was no significant treatment effect of cranberry juice supplementation on the primary endpoint of central systolic blood pressure or central or brachial diastolic pressure. Cranberry juice significantly reduced 24-h diastolic ambulatory BP by ~2 mm Hg compared to the placebo (p = 0.05) during daytime hours. Cranberry juice supplementation did not alter LDL-C but significantly changed the composition of the lipoprotein profile compared to the placebo, increasing the concentration of large LDL-C particles (+29.5 vs. -6.7 nmol/L; p = 0.02) and LDL size (+0.073 vs. -0.068 nm; p = 0.001). There was no effect of treatment on ex vivo HDL efflux in the total population, but exploratory subgroup analyses identified an interaction between BMI and global HDL efflux (p = 0.02), with greater effect of cranberry juice in participants who were overweight. Exploratory analyses indicate that baseline C-reactive protein (CRP) values may moderate treatment effects. In this population of adults with elevated blood pressure, cranberry juice supplementation had no significant effect on central systolic blood pressure but did have modest effects on 24-h diastolic ambulatory BP and the lipoprotein profile. Future studies are needed to verify these findings and the results of our exploratory analyses related to baseline health moderators.


3-D Printed Protective Equipment during COVID-19 Pandemic.
While the number of coronavirus cases from 2019 continues to grow, hospitals are reporting shortages of personal protective equipment (PPE) for frontline healthcare workers. Furthermore, PPE for the eyes and mouth, such as face shields, allow for additional protection when working with aerosols. 3-D printing enables the easy and rapid production of lightweight plastic frameworks based on open-source data. The practicality and clinical suitability of four face shields printed using a fused deposition modeling printer were examined. The weight, printing time, and required tools for assembly were evaluated. To assess the clinical suitability, each face shield was worn for one hour by 10 clinicians and rated using a visual analogue scale. The filament weight (21-42 g) and printing time (1:40-3:17 h) differed significantly between the four frames. Likewise, the fit, wearing comfort, space for additional PPE, and protection varied between the designs. For clinical suitability, a chosen design should allow sufficient space for goggles and N95 respirators as well as maximum coverage of the facial area. Consequently, two datasets are recommended. For the final selection of the ideal dataset to be used for printing, scalability and economic efficiency need to be carefully balanced with an acceptable degree of protection.


Effects of roads on Castanopsis carlesii seedlings and their leaf herbivory in a subtropical forest in China.
The effects of a forest road on Castanopsis carlesii (Hemsley) Hayata (Fagales: Fagaceae) seedlings and their leaf herbivory were investigated in a subtropical forest at Jiulianshan National Nature Reserve, Jiangxi, China. A total of 1124 seedlings, 33949 leaves, 468 leaf mines, and 205 leaf galls were found. Generally, individual numbers, tree heights, and leaf numbers of C. carlesii seedlings became lower with increasing distances from the road. These results might indicate that old seedlings were fewer and survival rate of seedlings was lower in forest interiors. Leaf miners preferred the seedlings close to the forest road, while leaf gallers preferred the seedlings about 2 m from the road. Species diversity of leaf miners was higher in the forest interior area, while species diversity of leaf gallers was higher near the road. However, both leaf miners and leaf gallers decreased in general from the road to the interior forest. There were interspecific differences in the effects of roads on leaf miner species and leaf galler species. The effects of the road on seedlings and insects could be explained by varying microhabitat conditions and different ecological strategies.


Identification and evaluation of Galleria mellonella peptides with antileishmanial activity.
Leishmaniasis is a neglected disease, World Health Organization (WHO) declared it as high priority worldwide. Colombia is one of the 98 countries in which the disease caused more than 17.000 cases per year. There is a need to explore novel therapies to reduce the side effects of the current treatments. For this reason, this study was aimed to evaluate Galleria mellonella hemolymph for potential peptides with anti-parasitic activity. Larvae were challenged with Leishmania (V) panamensis promastigotes and hemolymph was analyzed using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), reversed-phase chromatography (RP-HPLC), two-dimensional gel electrophoresis and liquid chromatography-mass spectroscopy (LC/MS). The immunological response of Galleria mellonella was followed by SDS-PAGE, immunized hemolymph was fractionated by RP-HPLC where fractions 5 and 11 showed the highest antileishmanial activity. From these fractions 15 spots were isolated by 2D gel electrophoresis and evaluated by LC/MS to identify the peptides present in the spots. After the analysis Moricin-B, Moricin-C4, Cecropin-D and Anionic Peptide 2 were identified due to the immune challenge with Leishmania promastigotes. Anionic peptide 2 and Cecropin-D were synthesized and evaluated for antileishmanial activity. The results showed that Anionic peptide 2 presented more anti-parasitic activity. This study showed for the first time the anti-parasitic potential of peptides derived from hemolymph of Galleria mellonella.


Computerized adaptive testing of symptom severity: a registry-based study of 924 patients with trapeziometacarpal arthritis.
We aimed to develop a computerized adaptive testing (CAT) version of the 11 item Patient Evaluation Measure (PEM), using an item response theory model. This model transformed the ordinal scores into ratio-interval scores. We obtained PEM responses from 924 patients with trapeziometacarpal osteoarthritis to build a CAT model and tested its performance on a simulated cohort of 1000 PEM response sets. The CAT achieved high precision (median standard error or measurement 0.26) and reduced the number of questions needed for accurate scoring from 11 to median two. The CAT scores and item-response-theory-based 15-item PEM scores were similar, and a Bland-Altman analysis demonstrated a mean score difference of 0.2 between the CAT and the full-length PEM scores on a scale from 0 to 100. We conclude that the CAT substantially reduced the burden of the PEM while also harnessing the validity of item response theory scoring.


Predicting IVF Outcome: A Proposed Web-based System Using Artificial Intelligence.
To propose a functional in vitro fertilization (IVF) prediction model to assist clinicians in tailoring personalized treatment of subfertile couples and improve assisted reproduction outcome. Construction and evaluation of an enhanced web-based system with a novel Artificial Neural Network (ANN) architecture and conformed input and output parameters according to the clinical and bibliographical standards, driven by a complete data set and "trained" by a network expert in an IVF setting. The system is capable to act as a routine information technology platform for the IVF unit and is capable of recalling and evaluating a vast amount of information in a rapid and automated manner to provide an objective indication on the outcome of an artificial reproductive cycle. ANNs are an exceptional candidate in providing the fertility specialist with numerical estimates to promote personalization of healthcare and adaptation of the course of treatment according to the indications.


Understanding 6th-century barbarian social organization and migration through paleogenomics.
Despite centuries of research, much about the barbarian migrations that took place between the fourth and sixth centuries in Europe remains hotly debated. To better understand this key era that marks the dawn of modern European societies, we obtained ancient genomic DNA from 63 samples from two cemeteries (from Hungary and Northern Italy) that have been previously associated with the Longobards, a barbarian people that ruled large parts of Italy for over 200 years after invading from Pannonia in 568 CE. Our dense cemetery-based sampling revealed that each cemetery was primarily organized around one large pedigree, suggesting that biological relationships played an important role in these early medieval societies. Moreover, we identified genetic structure in each cemetery involving at least two groups with different ancestry that were very distinct in terms of their funerary customs. Finally, our data are consistent with the proposed long-distance migration from Pannonia to Northern Italy.


The utility of the aortic dissection team: outcomes and insights after a decade of experience.
Mortality rates following acute type A aortic dissection (ATAAD) repair are reduced when operations are performed by a high-volume acute aortic dissection (AAD) team, leading to efforts to centralize ATAAD care. Here, we describe our experience with ATAAD repair by our AAD team over the last 10 years, with a focus on patient selection, transfer protocols, operative approach, and volume trends over time. An AAD team was implemented at our institution in 2005, with dedicated high-volume AAD surgeons, a multidisciplinary approach to thoracic aortic disease management, and a standardized protocol for ATAAD repair. Further process improvements were made in 2013 to facilitate the rapid transfer of ATAAD patients to our institution using stream-lined triage, diagnostic, and transfer protocols for patients with suspected ATAAD (RACE-AD protocol). Volume trends and outcomes were assessed longitudinally over this period. Institutional ATAAD repair volume remained constant at 12±2 cases per year from 2005-2013, but increased nearly two-fold to 22±6 cases per year (P=0.004) from 2013-2015 following implementation of the RACE-AD protocol. To accommodate this increased volume, two additional surgeons were added to the AAD team. Surgeon ATAAD repair volume was unchanged over the 10-year interval (7.9±3.9 cases per year from 2005-2013 versus 5.5±1.5 cases per year from 2013-2015; P=0.36), and all AAD team surgeons consistently met or exceeded the high-volume surgeon threshold of 5 ATAAD repairs per year. Thirty-day/in-hospital mortality rates of less than 10% were maintained over the study period. Centralization of ATAAD care has begun to occur at our center, with maintenance of low mortality rates for ATAAD repair. These data confirm a net positive impact on regional ATAAD outcomes through transfer of patients to a high-volume center with dedicated AAD surgeons.


49,000 Avocado Cutting Injuries.
Objectives: In the United States (US), avocado consumption has increased dramatically since the year 2000. Despite media attention concerning injuries resulting from cutting or pitting avocados, such injuries have not been monitored systematically. The current study is the first to estimate the number of people with avocado cutting injuries presenting to US hospital emergency departments. Methods: We utilized cross-sectional data from the US Consumer Product Safety Commission's (CPSC) National Electronic Injury Surveillance System (NEISS). We used keyword searches of case narrative text to identify avocado cutting and pitting injuries from 2000 to 2017. Sampling weights were applied to generate national estimates of avocado cutting injuries. Results: From 2000 to 2017, there were an estimated 49,331 avocado cutting injuries presenting to US emergency departments (95% CI 34,178-64,483). The increase in these injuries appears to coincide with increases in per capita avocado consumption. Avocado cutting injuries now constitute nearly 2% of knife-related injuries presenting to US hospital emergency departments. Conclusions: Due to the increase in avocado cutting injuries and the severity of these injuries, more systematic surveillance is needed as well as improved safety measures.


Is suicidal ideation linked to working hours and shift work in Korea?
This study attempted to use the community health survey (CHS) to identify the effect of long working hours (long WHs) and night/shift work on suicidal ideation among the employed population of Korea. This study used data from 67,471 subjects who were administered the 2008 CHS which obtained information regarding sociodemographic characteristics, health behaviors and working environment, using structured questionnaires and personal interviews. We adopted multiple logistic regression models for gender and employment stratification. Among male employees, suicidal ideation was significantly associated with only moderately long WHs (51-60 hours), after controlling covariates (adjusted odds ratio [aOR], 1.30; 95% confidence interval [95%CI], 1.07 to 1.57). Self-employed/male employer populations had higher suicidal ideation when they had moderately long WHs (aOR, 1.23; 95%CI, 1.01 to 1.50) and very long WHs (over 60 hours) (aOR, 1.31; 95%CI, 1.08 to 1.59). Among the female population, suicidal ideation was significantly association with moderately long WHs in the employee group (aOR, 1.31; 95%CI, 1.08 to 1.58) and moderately (aOR, 1.35; 95%CI, 1.08 to 1.69) and very (aOR, 1.33; 95%CI, 1.07 to 1.65) long WHs in the self-employed/employer group. Shift work was a significant predictor only in the female population in the employee groups (aOR, 1.45; 95%CI, 1.23 to 1.70). Long WHs and shift work were associated with suicidal ideation when taking into account gender and employment differences. The harmful effects of exceptionally long WHs in Korea, among other Organization for Economic Co-operation and Development (OECD) countries, raise concerns about public and occupational health. To address the issue of long WHs, labor policies that reduce maximum working hours and facilitate job stability are needed.


Investigation of a new electrode array technology for a central auditory prosthesis.
Ongoing clinical studies on patients recently implanted with the auditory midbrain implant (AMI) into the inferior colliculus (IC) for hearing restoration have shown that these patients do not achieve performance levels comparable to cochlear implant patients. The AMI consists of a single-shank array (20 electrodes) for stimulation along the tonotopic axis of the IC. Recent findings suggest that one major limitation in AMI performance is the inability to sufficiently activate neurons across the three-dimensional (3-D) IC. Unfortunately, there are no currently available 3-D array technologies that can be used for clinical applications. More recently, there has been a new initiative by the European Commission to fund and develop 3-D chronic electrode arrays for science and clinical applications through the NeuroProbes project that can overcome the bulkiness and limited 3-D configurations of currently available array technologies. As part of the NeuroProbes initiative, we investigated whether their new array technology could be potentially used for future AMI patients. Since the NeuroProbes technology had not yet been tested for electrical stimulation in an in vivo animal preparation, we performed experiments in ketamine-anesthetized guinea pigs in which we inserted and stimulated a NeuroProbes array within the IC and recorded the corresponding neural activation within the auditory cortex. We used 2-D arrays for this initial feasibility study since they were already available and were sufficient to access the IC and also demonstrate effective activation of the central auditory system. Based on these encouraging results and the ability to develop customized 3-D arrays with the NeuroProbes technology, we can further investigate different stimulation patterns across the ICC to improve AMI performance.


Evaluation of the safety of C-spine clearance by paramedics: design and methodology.
Canadian Emergency Medical Services annually transport 1.3 million patients with potential neck injuries to local emergency departments. Less than 1% of those patients have a c-spine fracture and even less (0.5%) have a spinal cord injury. Most injuries occur before the arrival of paramedics, not during transport to the hospital, yet most patients are transported in ambulances immobilized. They stay fully immobilized until a bed is available, or until physician assessment and/or X-rays are complete. The prolonged immobilization is often unnecessary and adds to the burden of already overtaxed emergency medical services systems and crowded emergency departments. The goal of this study is to evaluate the safety and potential impact of an active strategy that allows paramedics to assess very low-risk trauma patients using a validated clinical decision rule, the Canadian C-Spine Rule, in order to determine the need for immobilization during transport to the emergency department.This cohort study will be conducted in Ottawa, Canada with one emergency medical service. Paramedics with this service participated in an earlier validation study of the Canadian C-Spine Rule. Three thousand consecutive, alert, stable adult trauma patients with a potential c-spine injury will be enrolled in the study and evaluated using the Canadian C-Spine Rule to determine the need for immobilization. The outcomes that will be assessed include measures of safety (numbers of missed fractures and serious adverse outcomes), measures of clinical impact (proportion of patients transported without immobilization, key time intervals) and performance of the Rule. Approximately 40% of all very low-risk trauma patients could be transported safely, without c-spine immobilization, if paramedics were empowered to make clinical decisions using the Canadian C-Spine Rule. This safety study is an essential step before allowing all paramedics across Canada to selectively immobilize trauma victims before transport. Once safety and potential impact are established, we intend to implement a multi-centre study to study actual impact.


Placental disease and the maternal syndrome of preeclampsia: missing links?
Preeclampsia remains a significant obstetric risk worldwide. The pathophysiology of preeclampsia is complex, with multiple stages involving maladaptations in both placental and maternal physiology. The placenta links the pre-clinical stage of impaired remodeling of the uterine vasculature, occurring in early pregnancy, to the later clinical stages characterised by the maternal syndrome of hypertension and proteinuria. This review focuses on some of the recent candidates for the missing links in this process.


All systems go: An ecological perspective of behavioral health for youth with type 1 diabetes.
Youth with type 1 diabetes (T1D) experiencing self-management difficulties are at risk of irreversible long-term health problems and consume a disproportionate amount of health care resources. Behavioral health interventions for this population have shown limited long-term effects, perhaps because of limited research on and intervention in relevant environments. To effectively intervene, providers must first thoroughly understand how risk factors interact with various contexts (e.g., school, home, hospital) to determine opportunities for the development of relevant interventions. This review utilized an ecological systems framework to examine the state of the literature with regard to risk factors for poor T1D outcomes and associated intervention. This review identified that, whereas risk factors in some systems (e.g., individual, family) have received disproportionate scrutiny, other environments and contexts (e.g., school, medical system) have been relatively neglected by researchers. Similarly, interventions that target understudied environments are lacking, and the majority of rigorously studied interventions only target a single context. Perhaps this accounts for the lack of interventions shown to have a long-term impact on glycemic control. Our review demonstrates that researchers and funding agencies should prioritize efforts that (a) examine the influence of underexamined environments (e.g., primary care clinics, schools) and interactions (e.g., health care provider to parent, school nurse to youth) on T1D outcomes, (b) place increased emphasis on inclusion of understudied populations (e.g., families of minority racial/ethnic backgrounds), and (c) develop and evaluate interventions that specifically are tailored for these settings, interactions, and populations. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Modelling climate change impacts on maize yields under low nitrogen input conditions in sub-Saharan Africa.
Smallholder farmers in sub-Saharan Africa (SSA) currently grow rainfed maize with limited inputs including fertilizer. Climate change may exacerbate current production constraints. Crop models can help quantify the potential impact of climate change on maize yields, but a comprehensive multimodel assessment of simulation accuracy and uncertainty in these low-input systems is currently lacking. We evaluated the impact of varying [CO2 ], temperature and rainfall conditions on maize yield, for different nitrogen (N) inputs (0, 80, 160 kg N/ha) for five environments in SSA, including cool subhumid Ethiopia, cool semi-arid Rwanda, hot subhumid Ghana and hot semi-arid Mali and Benin using an ensemble of 25 maize models. Models were calibrated with measured grain yield, plant biomass, plant N, leaf area index, harvest index and in-season soil water content from 2-year experiments in each country to assess their ability to simulate observed yield. Simulated responses to climate change factors were explored and compared between models. Calibrated models reproduced measured grain yield variations well with average relative root mean square error of 26%, although uncertainty in model prediction was substantial (CV = 28%). Model ensembles gave greater accuracy than any model taken at random. Nitrogen fertilization controlled the response to variations in [CO2 ], temperature and rainfall. Without N fertilizer input, maize (a) benefited less from an increase in atmospheric [CO2 ]; (b) was less affected by higher temperature or decreasing rainfall; and (c) was more affected by increased rainfall because N leaching was more critical. The model intercomparison revealed that simulation of daily soil N supply and N leaching plays a crucial role in simulating climate change impacts for low-input systems. Climate change and N input interactions have strong implications for the design of robust adaptation approaches across SSA, because the impact of climate change in low input systems will be modified if farmers intensify maize production with balanced nutrient management.


Carbohydrate-like composition of submicron atmospheric particles and their production from ocean bubble bursting.
Oceans cover over two-thirds of the Earth's surface, and the particles emitted to the atmosphere by waves breaking on sea surfaces provide an important contribution to the planetary albedo. During the International Chemistry Experiment in the Arctic LOwer Troposphere (ICEALOT) cruise on the R/V Knorr in March and April of 2008, organic mass accounted for 15-47% of the submicron particle mass in the air masses sampled over the North Atlantic and Arctic Oceans. A majority of this organic component (0.1-0.4 microm(-3)) consisted of organic hydroxyl (including polyol and other alcohol) groups characteristic of saccharides, similar to biogenic carbohydrates found in seawater. The large fraction of organic hydroxyl groups measured during ICEALOT in submicron atmospheric aerosol exceeded those measured in most previous campaigns but were similar to particles in marine air masses in the open ocean (Southeast Pacific Ocean) and coastal sites at northern Alaska (Barrow) and northeastern North America (Appledore Island and Chebogue Point). The ocean-derived organic hydroxyl mass concentration during ICEALOT correlated strongly to submicron Na concentration and wind speed. The observed submicron particle ratios of marine organic mass to Na were enriched by factors of approximately 10(2)-approximately 10(3) over reported sea surface organic to Na ratios, suggesting that the surface-controlled process of film bursting is influenced by the dissolved organic components present in the sea surface microlayer. Both marine organic components and Na increased with increasing number mean diameter of the accumulation mode, suggesting a possible link between organic components in the ocean surface and aerosol-cloud interactions.


Implications of genetic variation in mouse brain structure for electrode placement by stereotaxic surgery.
The spatial locations of several forebrain and midbrain fibre tracts have been compared across seven commonly used inbred, hybrid and outbred mouse strains using a series of electrolytic lesions of known positions with respect to a stereotaxic instrument. Highly significant genetic variation was found in the position of lambda, bregma and several major fibre tracts with respect to interaural zero; in the locations of fibre tracts with respect to bregma; and in the location of fibre tracts with respect to each other. It was demonstrated that stereotaxic coordinates of a structure for one strain could not be used for other strains. Errors resulting from improper alignment of the head in the instrument and histological artifact were also determined. These errors showed no significant group differences, but they revealed that within-group variation was substantially affected by such imperfections.


A microscale human liver platform that supports the hepatic stages of Plasmodium falciparum and vivax.
The Plasmodium liver stage is an attractive target for the development of antimalarial drugs and vaccines, as it provides an opportunity to interrupt the life cycle of the parasite at a critical early stage. However, targeting the liver stage has been difficult. Undoubtedly, a major barrier has been the lack of robust, reliable, and reproducible in vitro liver-stage cultures. Here, we establish the liver stages for both Plasmodium falciparum and Plasmodium vivax in a microscale human liver platform composed of cryopreserved, micropatterned human primary hepatocytes surrounded by supportive stromal cells. Using this system, we have successfully recapitulated the full liver stage of P. falciparum, including the release of infected merozoites and infection of overlaid erythrocytes, as well as the establishment of small forms in late liver stages of P. vivax. Finally, we validate the potential of this platform as a tool for medium-throughput antimalarial drug screening and vaccine development.


Tuberculosis situation among tribal population of Car Nicobar, India, 15 years after intensive tuberculosis control project and implementation of a national tuberculosis programme.
To assess the tuberculosis (TB) situation in the tribal community of Car Nicobar island 15 years after the national TB programme was implemented in this area after an intensive phase of TB control in 1986. The entire population of Car Nicobar was enumerated through a house-to-house survey. Children aged <14 years were tuberculin tested and read for reaction sizes. Individuals aged >15 years were asked about the presence of chest symptoms (cough, chest pain, and unexplained fever for two weeks or longer and haemoptysis), and sputum samples were collected from patients with chest symptoms. Sputum samples were examined for presence of acid-fast bacilli. Among the 4,543 children enumerated, 4,351 (95.8%) were tuberculin tested and read. Of the 981 children without bacille Calmette-Guerin scars, 161 (16.4%) were infected with TB. A total of 77 cases who were smear-positive for TB were detected from among 10,570 people aged >15 years; the observed smear-positive case prevalence was 728.5 per 100,000. The standardized prevalence of TB infection, annual risk of TB infection, and prevalence of cases smear-positive for TB were 17.0%, 2.5%, and 735.3 per 100,000, respectively. The prevalence of TB infection and smear-positive cases of TB increased significantly between 1986 and 2002. Such escalation took place despite the implementation of the national TB programme on this island, which was preceded by a set of special anti-TB measures that resulted in sputum conversion in a substantially large proportion of the smear-positive cases prevalent in the community. The most likely reason for the increase seems to be the absence of a district TB programme with enough efficiency to sustain the gains made from the one-time initial phase of special anti-TB measures. High risk of transmission of TB infection currently observed on this island calls for a drastic and sustained improvement in TB control measures.


Dissecting Candida Pathobiology: Post-Translational Modifications on the Candida tropicalis Proteome.
Candida tropicalis belongs to the non-albicans group of Candida, and causes epidermal, mucosal, or systemic candidiasis in immunocompromised individuals. Although the prevalence of candidiasis has increased worldwide and non-albicans Candida (NAC) are becoming more significant, there are very few studies that focus on the NAC biology. Proteins and their post-translational modifications (PTMs) are an integral aspect in the pathobiology of such medically important fungi. Previously, we had reported the largest proteomic catalog of C. tropicalis. Notably, PTMs can be identified from proteomics data without a priori enrichment for a particular PTM, thus allowing broad-scale omics analyses. In this study, we developed the "PTM-Pro," a graphical user interface-based tool for identification and summary of high-confidence PTM sites based on statistical threshold of users' choice. We mined available proteomic data of C. tropicalis, and using PTM-Pro identified nearly 600 high-confidence PTM sites. The PTMs identified include phosphorylation of serine, threonine, and tyrosine; acetylation, crotonylation, methylation, and succinylation of lysine. These PTMs reside on biologically significant molecules, including histones, enzymes, and transcription factors. To our knowledge, this is the first report of PTMs in C. tropicalis and lays a foundation for future investigations of C. tropicalis PTMs. In addition, the PTM-Pro offers a graphical user interface tool for research on PTM sites in the field of proteomics.


[Thromboembolic complications after ambulatory herniotomy].
Thromboembolism is a serious complication of surgery and prophylaxis is therefore recommended. This study examines a new aspect of the problem, the incidence of thromboembolism after day-case surgery. From 1982 to 1992, 2281 patients underwent day-case repair for inguinal hernia management. Hospital admission for thromboembolism within the first 30 days after surgery was identified by computer linkage to the National In-Patient register, which contains details of all hospital admissions in Denmark. One patient developed non-fatal pulmonary embolism. No other patients were admitted to hospital with venous thromboembolism within 30 days of herniorrhaphy. It is concluded that there is no need for routine prophylaxis for thromboembolism in day-case hernia surgery.


ELF5 and DOK7 regulation in anti-estrogen treated cells and tumors.
Most women with primary breast cancers that express estrogen receptor alpha (ER or ESR1) are treated with endocrine therapies including the anti-estrogen tamoxifen, but resistance to these anti-endocrine therapies often develops. This study characterizes the expression of hormone receptors, and the mRNA and DNA methylation levels of docking protein 7 (DOK7), and E74-like factor 5 (ELF5), in 21 novel tamoxifen-resistant cell lines and extends the findings to primary and recurrent human breast tumors. Twenty-one tamoxifen-selected cell lines were developed through cloning by limiting dilution of an MCF-7 cell culture treated with 1 μM tamoxifen for 6 months. The parent (MCF-7) and tamoxifen-selected cell lines were characterized for protein expression of ER, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) using immunohistochemistry (IHC). The mRNA levels of ER, DOK7, and ELF5 were assessed using quantitative RT-PCR. Promoter methylation levels of DOK7 and ELF5 were determined by pyrosequencing of bisulfite-modified DNA. The relationship between hormone receptor status and promoter methylation of DOK7 and ELF5 was further examined using available methylation array data (Illumina HM450) from a set of paired primary and second breast tumors from 24 women. All 21 of the novel tamoxifen-selected cell lines are ER-positive, and HER2-negative, and 18 of the cell lines are PR-negative while the MCF-7 cells were scored as ER-positive, modestly PR-positive and HER2 negative. Expression of DOK7 and ELF5 is significantly up-regulated in half of the tamoxifen-selected cell lines as compared to the parental MCF-7. In contrast, the previously established ER-negative TMX2-28 cell line has decreased expression of both DOK7 and ELF5 and increased DNA methylation in the transcriptional start site region of these genes. ELF5 methylation was lower in second versus primary tumors in women who received anti-estrogen treatment, in PR-negative versus PR-positive tumors, and in the subset of PR-positive first tumors from the group of women who had second PR-negative tumors as compared to those who had second PR-positive tumors. The distinct ELF5 methylation of PR-positive primary tumors from women who had a PR-negative recurrence indicates the possibility of stratification of women for tailored treatment in the early stages of disease.


Assessment of damage in vasculitis: expert ratings of damage.
Current measures of damage in vasculitis do not account for the possibility that some forms of damage may exert greater impact than others. As part of an international effort to revise how damage is quantified in vasculitis clinical research, an exercise was performed to measure expert ratings of damage items. Members of the Vasculitis Clinical Research Consortium and European Vasculitis Study Group were given a list of 129 items of damage related to WG and microscopic polyangiitis (MPA). Participants were asked to rate each item of damage on an integer scale from 0 to 10, where 10 represented the most severe form of damage and 0 indicated 'no impact'. A multidisciplinary panel of 50 investigators from North America, Europe and Australia-New Zealand participated. The highest median ratings (8-10) were assigned to items of damage associated with malignancy, tissue ischaemia, the central nervous system and cardiopulmonary manifestations. The mean scores ranged from 1.3 to 9.5. The highest s.d.s (>or=2.5) were associated with forms of damage that may benefit from surgical intervention or may not be causally associated with WG or MPA. Lower scores were assigned by nephrologists in comparison with rheumatologists and by Americans in comparison to Europeans, although the difference in median ranks used by these groups was not statistically significant (P > 0.05 for the comparisons). This exercise represents an important step in the development of a weighting system that may increase the utility of damage index scores for the assessment of patients with vasculitis.


Intestinal microbiota and its effects on the immune system.
The microbiota colonizes every surface exposed to the external world and in the gut, it plays important roles in physiological functions such as the maturation of the immune system, the degradation of complex food macromolecules and also behaviour. As such, the immune system has developed tools to cohabit with the microbiota, but also to keep it under control. When this control is lost, dysbiosis, i.e. deregulation in bacterial communities, can occur and this can lead to inflammatory disorders, including inflammatory bowel disease, obesity, diabetes and autism. For these reasons, the analysis of the microbiota, its interactions with the host and its composition in disease, have been intensively investigated in the last few years. In this review, we summarize the major findings in the interaction of the microbiota with the host immune system.


Identification and characterization of receptors for secretagogues on pancreatic acinar cells.
Acinar cells from guinea pig pancreas possess six different classes of receptors that mediate the actions of various secretagogues on enzyme secretion. Four classes of receptors stimulate enzyme secretion by causing mobilization of adenylate cyclase and increased cellular cyclic AMP. This paper summarizes the results of studies that have employed radiolabeled secretagogues of high specific activity and have measured directly the interaction of secretagogues with their receptors on pancreatic acinar cells.


Serological diagnosis of typhoid fever by counterimmunoelectrophoresis.
The sensitivity and specificity of counterimmunoelectrophoresis using three antigenic preparations obtained from Salmonella typhi were compared with those of the Widal test in the serological diagnosis of typhoid fever. A veronal buffer extract yielded precipitation lines against 50 (96%) out of 52 sera collected from patients with typhoid but against none out of 62 sera obtained from control subjects who did not have typhoid. Less satisfactory results were obtained by counterimmunoelectrophoresis when two other preparations, a protein extract (Barber antigen) and an ultrasonic lysate, were used as the antigens. By Widal test the rate of detection in patients' sera was 73% and the false-positive rate for control sera 16%. It is concluded that in an area where typhoid is endemic counterimmunoelectrophoresis using veronal buffer extract as the antigen is superior to the Widal test for serological diagnosis of typhoid fever. An additional advantage of counterimmunoelectrophoresis is that results may be obtained on the same day that the serum specimens are received.


A mother's feelings for her infant are strengthened by excellent breastfeeding counseling and continuity of care.
Continuous support during the childbirth process ultimately may strengthen the mother's self-esteem and her capacity to interact with and nurture her infant and also may improve paternal involvement in general. In the present study, we investigated whether mothers, who were attended by midwives and nurses who had had a process-oriented training program in breastfeeding counseling, perceived stronger maternal feelings for their infant than mothers who had received only routine care. In a previous study, an intervention that included a process-oriented program on breastfeeding counseling for health professionals and continuity in family classes through childbirth was conducted. The 10 largest municipalities were classified in pairs that were similar in size and had similar figures of breastfeeding duration. The municipalities were randomized pairwise to either an intervention or a control group. The present study is a follow-up study on women's feelings for their infants in relation to the kind of care that they had had and was undertaken between April 2000 and January 2003. The sampling frame was based on women who were cared for at either the intervention clinic or control clinics. The mothers at the control clinics had received standard routine care and had attended family classes through the point of birth. Data collection for control group A started before effects of the intervention could be studied. Data for control group B were collected simultaneously with data collection for the intervention group (n = 540). The mothers responded to 3 questionnaires at 3 days and at 3 and 9 months postpartum. Background data of the mothers were collected. The perception of support that was provided by the health professionals and the perception of mother-infant relationship and feelings for the infant were rated on Likert scales. At 3 days postpartum, both the intervention group and control group B versus the control group A thought that their understanding of the infant was better, they perceived more strongly that the infant as their own, and they enjoyed more breastfeeding and resting with the infant. Although there was no significant difference between the intervention group and control group B at 3 days and 3 months observation, mothers in the intervention group talked more to their infant, perceived their infant to be more beautiful than other infants, and perceived more strongly that the infant was their own than did the mothers in control group B at 9 months observation. In addition, the mothers in the intervention group felt significantly more confident with the infant and felt the infant to be closer than did the mothers in control group B. A process-oriented breastfeeding training program for antenatal midwives and postnatal nurses that included an intervention that guaranteed continuity of care strengthened the maternal relationship with the infant and the feelings for the infant.


Gaussian processes for machine learning.
Gaussian processes (GPs) are natural generalisations of multivariate Gaussian random variables to infinite (countably or continuous) index sets. GPs have been applied in a large number of fields to a diverse range of ends, and very many deep theoretical analyses of various properties are available. This paper gives an introduction to Gaussian processes on a fairly elementary level with special emphasis on characteristics relevant in machine learning. It draws explicit connections to branches such as spline smoothing models and support vector machines in which similar ideas have been investigated. Gaussian process models are routinely used to solve hard machine learning problems. They are attractive because of their flexible non-parametric nature and computational simplicity. Treated within a Bayesian framework, very powerful statistical methods can be implemented which offer valid estimates of uncertainties in our predictions and generic model selection procedures cast as nonlinear optimization problems. Their main drawback of heavy computational scaling has recently been alleviated by the introduction of generic sparse approximations.13,78,31 The mathematical literature on GPs is large and often uses deep concepts which are not required to fully understand most machine learning applications. In this tutorial paper, we aim to present characteristics of GPs relevant to machine learning and to show up precise connections to other "kernel machines" popular in the community. Our focus is on a simple presentation, but references to more detailed sources are provided.


Importance of respiratory rate as an indicator of respiratory dysfunction in patients with cystic fibrosis.
Bedside measurement of respiratory frequency is commonly performed in a cursory manner and judged to be of little clinical importance. However, in a recent study of patients being weaned from mechanical ventilation, we found that tachypnea was quite accurate in predicting an unsuccessful weaning outcome. The present study was undertaken to examine the relationship between nonobtrusive measurements of respiratory frequency, using a calibrated inductive plethysmograph, and detailed measurements of pulmonary function in 11 adult patients with cystic fibrosis of varying severity. Respiratory frequency was increased in the patients with cystic fibrosis compared with a group of healthy control subjects, as was minute ventilation and mean inspiratory flow. Respiratory frequency was a sensitive predictor of respiratory dysfunction, being significantly (p less than 0.05) correlated with airway obstruction (r = 0.76), hyperinflation (r = 0.52), arterial oxygenation (r = -0.59), rib cage-abdominal discoordination (r = 0.54), and maximum ventilation during exercise (r = 0.66). Despite the presence of tachypnea, the patients did not display shallow breathing; indeed, tidal volume was not correlated with any of the above abnormalities. In conclusion, respiratory rate was a useful indicator of respiratory dysfunction in this group of patients with cystic fibrosis.


Current markers and their value in the era of immuno-oncology.
Immunotherapy in urothelial cancer is a quickly evolving field as new agents are being investigated in multiple clinical trials and various clinical settings. The purpose of this review is to provide an insight into the mechanism of these treatments, potential targets to evaluate treatment response and to give an update on the current status of clinical trials. Urothelial cancer is a polyclonal disease with a substantial tumor heterogeneity and a high mutational load which may be beneficial as this may trigger a stronger T-cell mediated immune response. PD-1 expression has been shown to correlate with stage, grade, progression and poorer survival but it appears challenging to be utilized as a predictor for treatment response in urothelial cancer. Another important concept is immune cell (IC) infiltration, which is a reflection of the activated immune response within the target tissue. Marker genes may represent signaling pathways involved in T-cell recognition and lysis of T-cells. The complexity of the tumor and host interaction requires multiple concepts to be integrated into a future model to assess treatment response. We have evaluated multiple biomarker approaches currently investigated in clinical trials in urothelial cancer.


On the relation of white matter brain abnormalities and the asociality symptoms in schizophrenia outpatients - a DTI study.
Recent MRI studies have shown that abnormal functional connections in schizophrenia coexist with subtle changes in the structure of axons in the brain. However, there is a discrepancy in the literature concerning the relationship between white matter abnormalities and the occurrence of negative psychopathological symptoms. In the present study, we investigate the relationship between the altered white matter structure and specific psychopathology symptoms, i.e., subscales of Positive and Negative Syndrome Scale (PANSS) and Brief Negative Symptoms Scale (BNSS) in a sample of schizophrenia outpatients. For investigation on white matter abnormalities in schizophrenia, the diffusion tensor imaging analysis of between-group differences in main diffusion parameters by tract-based spatial statistics was conducted on schizophrenia outpatients and healthy controls. Hence, the correlation of PANSS and BNSS psychopathology subscales in the clinical group with fractional anisotropy was analyzed in the 17 selected cortical regions of interest. Presented between-group results revealed widespread loss of white matter integrity located across the brain in schizophrenia outpatients. Results on the white matter relationship with psychopathology revealed the negative correlation between fractional anisotropy in the left orbital prefrontal cortex, right Heschl's gyrus, bilateral precuneus and posterior cingulate cortex and the severity of asociality, as assessed with the BNSS. In conclusion, the presented study confirms the previous evidence on the widespread white matter abnormalities in schizophrenia outpatients and indicates the existence of the subtle but specific association between fractional anisotropy in the fronto-temporo-parietal regions with the asociality. Recent MRI studies have shown that abnormal functional connections in schizophrenia coexist with subtle changes in the structure of axons in the brain. However, there is a discrepancy in the literature concerning the relationship between white matter abnormalities and the occurrence of negative psychopathological symptoms. In the present study, we investigate the relationship between the altered white matter structure and specific psychopathology symptoms, i.e., subscales of Positive and Negative Syndrome Scale (PANSS) and Brief Negative Symptoms Scale (BNSS) in a sample of schizophrenia outpatients. For investigation on white matter abnormalities in schizophrenia, the diffusion tensor imaging analysis of between-group differences in main diffusion parameters by tract-based spatial statistics was conducted on schizophrenia outpatients and healthy controls. Hence, the correlation of PANSS and BNSS psychopathology subscales in the clinical group with fractional anisotropy was analyzed in the 17 selected cortical regions of interest. Presented between-group results revealed widespread loss of white matter integrity located across the brain in schizophrenia outpatients. Results on the white matter relationship with psychopathology revealed the negative correlation between fractional anisotropy in the left orbital prefrontal cortex, right Heschl's gyrus, bilateral precuneus and posterior cingulate cortex and the severity of asociality, as assessed with the BNSS. In conclusion, the presented study confirms the previous evidence on the widespread white matter abnormalities in schizophrenia outpatients and indicates the existence of the subtle but specific association between fractional anisotropy in the fronto-temporo-parietal regions with the asociality.


Spatial and temporal variations of malaria epidemic risk in Ethiopia: factors involved and implications.
The aim of this study was to describe spatial and temporal variations in malaria epidemic risk in Ethiopia and to examine factors involved in relation to their implications for early warning and interpretation of geographical risk models. Forty-eight epidemic episodes were identified in various areas between September 1986 and August 1993 and factors that might have led to the events investigated using health facility records and weather data. The study showed that epidemics in specific years were associated with specific geographical areas. A major epidemic in 1988 affected the highlands whereas epidemics in 1991 and 1992 affected highland-fringe areas on the escarpments of the Rift Valley and in southern and north-western parts of the country. Malaria epidemics were significantly more often preceded by a month of abnormally high minimum temperature in the preceding 3 months than based on random chance, whereas frequency of abnormally low minimum temperature prior to epidemics was significantly lower than expected. Abnormal increases of maximum temperature and rainfall had no positive association with the epidemics. A period of low incidence during previous transmission seasons might have aggravated the events, possibly due to low level of immunity in affected populations. Epidemic risk is a dynamic phenomenon with changing geographic pattern based on temporal variations in determinant factors including weather and other eco-epidemiological characteristics of areas at risk. Epidemic early warning systems should take account of non-uniform effects of these factors by space and time and thus temporal dimensions need to be considered in spatial models of epidemic risks.


Symptom burden in malignant and non-malignant disease on admission to a palliative care unit.
There is increasing recognition that patients with non-malignant diseases have comparable physical and psychosocial symptom burden to patients with cancer. There is currently limited data directly comparing symptom burden between these patient groups. To investigate differences in symptom burden between patients with malignant and non-malignant conditions admitted to a palliative care unit (PCU). A cross-sectional study involving 186 patients admitted to a PCU was undertaken. Patients were dichotomised into malignant or non-malignant disease categories. Symptom burden at admission was assessed using the Symptom Assessment Scale and Palliative Care Problem Severity Score. Group differences in symptoms were analysed using univariate and multivariate approaches. One hundred patients (53.8%) had cancer, with upper gastrointestinal the most common type (18.0%). Among the 86 patients with non-malignant disease, neurological conditions were most prevalent (40.7%). Patients admitted with non-malignant diseases were older, more functionally impaired and more likely to be deteriorating or terminal. A malignant diagnosis was associated with a higher likelihood of clinician-assessed pain, patient-assessed pain, fatigue, psychological/spiritual symptoms and other symptoms. However, when adjusted for confounders, disease category ceased to be a significant predictor of symptom burden. Younger patients experienced worse pain and patients in terminal phase experienced less symptom burden. Symptom burden was similar between patients with malignant and non-malignant disease after adjustment for confounders. Further research is needed to understand the palliative care needs of patients with non-malignant disease.


Fluid shear stress induces endothelial transforming growth factor beta-1 transcription and production. Modulation by potassium channel blockade.
The endothelium has the capacity to modulate vascular structure in response to hemodynamic stimuli. We tested the hypothesis that exposure of the endothelium to increased laminar shear stress induces the expression of TGF beta 1 via a signal transduction pathway modulated by K+ channel currents. Although TGF beta 1 is normally secreted in a latent, inactive form, exposure of cultured endothelial cells to steady laminar shear stress (20 dynes/cm2) induced increased generation of biologically active TGF beta 1. This increase in active TGF beta 1 was associated with a sustained increase in TGF beta 1 mRNA expression within 2 h of stimulation. TGF beta 1 mRNA levels increased in direct proportion to the intensity of the shear stress within the physiologic range. The effect of shear stress on TGF beta 1 mRNA expression was regulated at the transcriptional level as defined by nuclear run-off studies and transient transfection of a TGF beta 1 promoter-reporter gene construct. Blockade of endothelial K+ channels with tetraethylammonium significantly inhibited: activation of TGF beta 1 gene transcription; increase in steady state mRNA levels; and generation of active TGF beta 1 in response to shear stress. These data suggest that endothelial K+ channels and autocrine-paracrine TGF beta 1 may be involved in the mechanotransduction mechanisms mediating flow-induced vascular remodeling.


Human IAPP-induced pancreatic β cell toxicity and its regulation by autophagy.
Pancreatic islets in patients with type 2 diabetes mellitus (T2DM) are characterized by loss of β cells and formation of amyloid deposits derived from islet amyloid polypeptide (IAPP). Here we demonstrated that treatment of INS-1 cells with human IAPP (hIAPP) enhances cell death, inhibits cytoproliferation, and increases autophagosome formation. Furthermore, inhibition of autophagy increased the vulnerability of β cells to the cytotoxic effects of hIAPP. Based on these in vitro findings, we examined the pathogenic role of hIAPP and its relation to autophagy in hIAPP-knockin mice. In animals fed a standard diet, hIAPP had no toxic effects on β cell function; however, hIAPP-knockin mice did not exhibit a high-fat-diet-induced compensatory increase in β cell mass, which was due to limited β cell proliferation and enhanced β cell apoptosis. Importantly, expression of hIAPP in mice with a β cell-specific autophagy defect resulted in substantial deterioration of glucose tolerance and dispersed cytoplasmic expression of p62-associated toxic oligomers, which were otherwise sequestrated within p62-positive inclusions. Together, our results indicate that increased insulin resistance in combination with reduced autophagy may enhance the toxic potential of hIAPP and enhance β cell dysfunction and progression of T2DM.


Improved implantation and ongoing pregnancy rates after single-embryo transfer with an optimized protocol for in vitro oocyte maturation in women with polycystic ovaries and polycystic ovary syndrome.
To describe an optimized protocol for oocyte in vitro maturation (IVM) that achieves improved implantation and ongoing pregnancy rates in women with polycystic ovaries (PCO) and polycystic ovary syndrome (PCOS). Prospective cohort study. Hospital fertility unit. Women with PCO and PCOS undergoing treatment for infertility. Follicle-stimulating hormone (FSH) priming, IVM, blastocyst culture, hormone replacement therapy. Clinical pregnancy rates. Our optimized IVM protocol achieves implantation and ongoing pregnancy rates comparable to in vitro fertilization. From 66 oocyte collections, 844 oocytes were collected (12.8 oocytes/cycle), 588 oocytes matured after IVM (69.7% maturation rate), 420 oocytes fertilized after ICSI (71.4% fertilization rate), and 175 blastocyst-stage embryos resulted (41.7% blastocyst-development rate). Of these, 62 blastocyst-stage embryos were transferred as single embryos, resulting in 29 clinical pregnancies (43.9%/oocyte collection, 46.7%/embryo transfer) and 28 live births (42.4%/oocyte collection, 45.2%/embryo transfer). In women with PCO or PCOS, improved implantation, clinical pregnancy, and live-birth rates can be achieved after single-embryo transfer by the use of an optimized IVM protocol.


Legionella drozanskii sp. nov., Legionella rowbothamii sp. nov. and Legionella fallonii sp. nov.: three unusual new Legionella species.
Seven strains of Legionella-like amoebal pathogens (LLAPs) were characterized on the basis of their cultural and staining characteristics, biochemical reactions, serology, cellular fatty acids (CFAs), isoprenoid quinone composition, total DNA relatedness, analysis of 16S rRNA and macrophage infectivity potentiator (mip) gene sequence analyses. All seven strains exhibited limited growth on buffered charcoal yeast extract alpha (BCYE) agar, required cysteine for growth and contained branched-chain CFAs and quinones typical of Legionella species. The bacilli were Gram-negative and catalase-positive. There were varying degrees of serological cross-reactions between these LLAP strains and other previously described Legionella species. Results from the various tests revealed that four LLAP strains represent three unusual new species of Legionella: Legionella drozanskii sp. nov., type strain LLAP-1T; Legionella rowbothamii sp. nov., type strain LLAP-6T; and Legionella fallonii sp. nov., type strain LLAP-10T. Three other LLAP strains, designated LLAP-7FL, LLAP-7NF and LLAP-9, were shown to be members of the species Legionella lytica. The deductions made from the phenetic characteristics of these bacteria were consistent with the phylogenetic relationships inferred from 16S rRNA and mip gene sequence analyses. This study is the first to speciate LLAP strains on the basis of data including quantitative DNA hybridization.


Magnetic micro-macro biocatalysts applied to industrial bioprocesses.
The use of magnetic biocatalysts is highly beneficial in bioprocesses technology, as it allows their easy recovering and enhances biocatalyst lifetime. Thus, it simplifies operational processing and increases efficiency, leading to more cost-effective processes. The use of small-size matrices as carriers for enzyme immobilization enables to maximize surface area and catalysts loading, also reducing diffusion limitations. As highly expensive nanoparticles (nm size) usually aggregate, their application at large scale is not recommended. In contrast, the use of magnetic micro-macro (µm-mm size) matrices leads to more homogeneous biocatalysts with null or very low aggregation, which facilitates an easy handling and recovery. The present review aims to highlight recent trends in the application of medium-to-high size magnetic biocatalysts in different areas (biodiesel production, food and pharma industries, protein purification or removal of environmental contaminants). The advantages and disadvantages of these above-mentioned magnetic biocatalysts in bioprocess technology will be also discussed.