Use of 5α-reductase inhibitors for lower urinary tract symptoms and risk of prostate cancer in Swedish men: nationwide, population based case-control study.
To assess the association between 5α-reductase inhibitor (5-ARI) use in men with lower urinary tract symptoms and prostate cancer risk. Nationwide, population based case-control study for men diagnosed with prostate cancer in 2007-09 within the Prostate Cancer data Base Sweden 2.0. The National Prostate Cancer Register, National Patient Register, census, and Prescribed Drug Register in Sweden, from which we obtained data on 5-ARI use before date of prostate cancer diagnosis. 26,735 cases and 133,671 matched controls; five controls per case were randomly selected from matched men in the background population. 7815 men (1499 cases and 6316 controls) had been exposed to 5-ARI. 412 men had been exposed to 5-ARI before the diagnosis of a cancer with Gleason score 8-10. Risk of prostate cancer calculated as odds ratios and 95% confidence intervals by conditional logistic regression analyses. Risk of prostate cancer overall decreased with an increasing duration of exposure; men on 5-ARI treatment for more than three years had an odds ratio of 0.72 (95% confidence interval 0.59 to 0.89; P<0.001 for trend). The same pattern was seen for cancers with Gleason scores 2-6 and score 7 (both P<0.001 for trend). By contrast, the risk of tumours with Gleason scores 8-10 did not decrease with increasing exposure time to 5-ARI (for 0-1 year of exposure, odds ratio 0.96 (95% confidence interval 0.83 to 1.11); for 1-2 years, 1.07 (0.88 to 1.31); for 2-3 years, 0.96 (0.72 to 1.27); for >3 years, 1.23 (0.90 to 1.68); P=0.46 for trend). Men treated with 5-ARI for lower urinary tract symptoms had a decreased risk of cancer with Gleason scores 2-7, and showed no evidence of an increased risk of cancer with Gleason scores 8-10 after up to four years' treatment.


Advances in radiotherapy techniques and delivery for non-small cell lung cancer: benefits of intensity-modulated radiation therapy, proton therapy, and stereotactic body radiation therapy.
The 21st century has seen several paradigm shifts in the treatment of non-small cell lung cancer (NSCLC) in early-stage inoperable disease, definitive locally advanced disease, and the postoperative setting. A key driver in improvement of local disease control has been the significant evolution of radiation therapy techniques in the last three decades, allowing for delivery of definitive radiation doses while limiting exposure of normal tissues. For patients with locally-advanced NSCLC, the advent of volumetric imaging techniques has allowed a shift from 2-dimensional approaches to 3-dimensional conformal radiation therapy (3DCRT). The next generation of 3DCRT, intensity-modulated radiation therapy and volumetric-modulated arc therapy (VMAT), have enabled even more conformal radiation delivery. Clinical evidence has shown that this can improve the quality of life for patients undergoing definitive management of lung cancer. In the early-stage setting, conventional fractionation led to poor outcomes. Evaluation of altered dose fractionation with the previously noted technology advances led to advent of stereotactic body radiation therapy (SBRT). This technique has dramatically improved local control and expanded treatment options for inoperable, early-stage patients. The recent development of proton therapy has opened new avenues for improving conformity and the therapeutic ratio. Evolution of newer proton therapy techniques, such as pencil-beam scanning (PBS), could improve tolerability and possibly allow reexamination of dose escalation. These new progresses, along with significant advances in systemic therapies, have improved survival for lung cancer patients across the spectrum of non-metastatic disease. They have also brought to light new challenges and avenues for further research and improvement.


Increasing Hepatitis B Testing and Linkage to Care of Foreign-Born Asians, Sacramento, California, 2012-2013.
Without medical intervention, about one-quarter of the 1.4-2.2 million Americans chronically infected with the hepatitis B virus (HBV) will die of HBV-associated conditions, including liver failure and hepatocellular carcinoma. We report on a program in Sacramento County, California, that offered HBV screening to at-risk adults, referred infected individuals to care, and vaccinated uninfected adults who were susceptible to HBV infection (i.e., individuals who tested negative for hepatitis B surface antigen and who were never vaccinated against HBV). We engaged organizations linked to Chinese, Hmong, Korean, and Vietnamese communities to cosponsor HBV screenings of Asian Americans as part of the Hepatitis Testing and Linkage to Care initiative, which promoted viral hepatitis B and hepatitis C screening, posttest counseling, and linkage to care at 34 U.S. sites. We held 28 hepatitis B community screening events throughout Sacramento County, California, in collaboration with these groups from September 2012 to September 2013. We screened 1,004 Asian American adults (i.e., 283 Koreans, 242 Chinese, 233 Vietnamese, 223 Hmong, and 23 people from other Asian communities) for HBV, of whom 98% were foreign born and 87% had a language preference other than English. Of the 76 participants who tested positive for HBV (31 Hmong, 23 Vietnamese, 17 Chinese, two Koreans, and three from other Asian communities), we provided posttest counseling to 51 participants. By collaborating with community groups and addressing barriers to screening, we highlighted the importance of disaggregating chronic HBV infection rates by Asian ethnicity and sex vs. aggregated Asian American rates. Future HBV screening initiatives should target Hmong and Vietnamese men.


Oxidative stress augments secretion of endothelium-derived relaxing peptides, C-type natriuretic peptide and adrenomedullin.
Excess oxidative stress is one of the major metabolic abnormalities on vascular walls in hypertension and atherosclerosis. In order to further elucidate the endothelial function under oxidative stress, the effect of hydrogen peroxide (H2O2) on expression of two novel endothelium-derived vasorelaxing peptides, C-type natriuretic peptide (CNP) and adrenomedullin (AM) from bovine carotid artery endothelial cells (BCAECs) was examined. BCAECs were treated with H2O2 (0.1-1.0 mmol/ l) and/or an antioxidant, N-acetylcysteine (NAC) (5-10 mmol/l), and incubated for 48 h. The concentrations of CNP and AM were measured with the specific radioimmuno assays that we originally developed. CNP and AM mRNA expressions were also examined by reverse transcription-polymerase chain reaction (RT-PCR). Treatment of BCAECs with 0.5 and 1 mmol/l H2O2 induced 9-and 10-fold increases of CNP concentration in the media. Addition of 10 mmol/l NAC significantly suppressed the effect of H2O2 by 52%. RT-PCR analysis showed that CNP mRNA expression in BCAECs was also rapidly augmented within 1 h with H2O2 (1 mmol/l) treatment, and reached a peak at 3 h to show a 10-fold increase. AM secretion from BCAECs also increased to two-fold with exposure to 0.5 mmol/l H2O2, accompanied with the augmented level of AM mRNA. NAC 10 mmol/l completely suppressed the effect of H2O2 on AM secretion. In this study, it has been demonstrated that H2O2 augments endothelial secretion of the two endothelium-derived relaxing peptides, CNP and AM. Our findings suggest the increased secretion of CNP and AM from endothelium under oxidative stress may function to compensate the impaired nitric oxide-dependent vasorelaxation in hypertension and atherosclerosis.


Universal invariants of quantum-mechanical and optical systems.
We give a brief review of the theory of quantum and optical universal invariants, i.e., certain combinations of the second- and higher-order moments (variances) of quantum-mechanical operators or the transverse phase-space coordinates of optical paraxial beams that are preserved in time (or along the axis of the beam) independently of the concrete form of the coefficients of the Hamiltonian or the parameters of the optical system, provided that the effective Hamiltonian is either a generic quadratic form of the generalized coordinate-momenta operators or a linear combination of generators of certain finite-dimensional algebras. Using the phase-space representation of quantum mechanics (paraxial optics) in terms of the Wigner function, we elucidate the relation between the quantum invariants and the classical universal integral invariants of Poincaré and Cartan. The specific features of the Gaussian beams are discussed as examples.


A history of vitamin E.
Vitamin E (α-tocopherol) was discovered nearly 100 years ago because it was required to prevent fetal resorption in pregnant, vitamin E-deficient rats fed lard-containing diets that were easily oxidizable. The human diet contains eight different vitamin E-related molecules synthesized by plants; despite the fact that all of these molecules are peroxyl radical scavengers, the human body prefers α-tocopherol. The biological activity of vitamin E is highly dependent upon regulatory mechanisms that serve to retain α-tocopherol and excrete the non-α-tocopherol forms. This preference is dependent upon the combination of the function of α-tocopherol transfer protein (α-TTP) to enrich the plasma with α-tocopherol and the metabolism of non-α-tocopherols. α-TTP is critical for human health because mutations in this protein lead to severe vitamin E deficiency characterized by neurologic abnormalities, especially ataxia and eventually death if vitamin E is not provided in large quantities to overcome the lack of α-TTP. α-Tocopherol serves as a peroxyl radical scavenger that protects polyunsaturated fatty acids in membranes and lipoproteins. Although specific pathways and specific molecular targets have been sought in a variety of studies, the most likely explanation as to why humans require vitamin E is that it is a fat-soluble antioxidant.


Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations. We assayed myosin ATP binding to define the proportion of myosins in the super relaxed state (SRX) conformation or the disordered relaxed state (DRX) conformation in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology, we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants of unknown clinical significance that were identified in patients with HCM, predicted functional consequences and associations with heart failure and arrhythmias. Myosins undergo physiological shifts between the SRX conformation that maximizes energy conservation and the DRX conformation that enables cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacological modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased the proportion of myosins in the SRX conformation, whereas pathogenic variants destabilized these and increased the proportion of myosins in the DRX conformation, which enhanced cardiomyocyte contractility, but impaired relaxation and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify variants of unknown clinical significance, we showed that the variants that destabilized myosin conformations were associated with higher rates of heart failure and arrhythmias in patients with HCM. Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy-conserving states promotes contractile abnormalities, morphological and metabolic remodeling, and adverse clinical outcomes in patients with HCM. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in patients with HCM.


Quality assurance: a Tri-Level model.
A Tri-Level Quality Assurance Model consisting of state, local, and national levels of organization is described. Quality assurance is defined as a broad concept integrating traditional quality assurance activities with professional education and credentialing. The Iowa Occupational Therapy Association Professional Standards Review System is described as an example of the Tri-Level Model. Components of the Tri-Level model include professional education, professional credentialing, development of standards of practice, liaison activities with the Professional Standards Review Organizations and the Joint Commission on Accreditation of Hospitals, continuing education, external review, and internal review. It is recommended that, with the growth in quality assurance activities, state associations consider the Tri-Level Quality Assurance Model as a valuable tool for professional development.


Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays.
Alternative pre-messenger RNA (pre-mRNA) splicing plays important roles in development, physiology, and disease, and more than half of human genes are alternatively spliced. To understand the biological roles and regulation of alternative splicing across different tissues and stages of development, systematic methods are needed. Here, we demonstrate the use of microarrays to monitor splicing at every exon-exon junction in more than 10,000 multi-exon human genes in 52 tissues and cell lines. These genome-wide data provide experimental evidence and tissue distributions for thousands of known and novel alternative splicing events. Adding to previous studies, the results indicate that at least 74% of human multi-exon genes are alternatively spliced.


Resonance micro-Raman investigations of the rat medial preoptic nucleus: effects of a low-iron diet on the neuroglobin content.
The aim of this study was to investigate the medial preoptic nucleus (MPN) of the anterior hypothalamus by resonance Raman spectroscopy (514.5 nm) to determine if it is possible to enhance the Raman scattering of hemoproteins in fresh brain tissue slices. The resonance effect was compared with near-infrared Raman spectra. Two groups of male Sprague Dawley rats were studied, one control group on a normal diet and one group on a low-iron diet to evoke iron deficiency. Each group consisted of four rats, 38-41 days old. The diets lasted for 11, 12, and 15 days. The MPN regions of brain tissue slices were analyzed by monitoring raw and pre-processed mean data, by cluster analysis, and by deriving difference spectra from pre-processed mean spectra. Cluster analysis of the resonance Raman spectra could identify different hemoprotein groups, namely, hemoglobin (Hb) and neuroglobin (Ngb). Spectra from randomly distributed spots revealed high Hb content, whereas Ngb was evenly distributed in the MPN. The different spectra showed a decrease of the Ngb and lipid content for the animals on the low-iron diet. The Ngb decrease was approximately 20%. The data show that resonance Raman spectroscopy is well suited to study hemoproteins in fresh brain tissue.


Paediatric extracranial germ-cell tumours.
Management of paediatric extracranial germ-cell tumours carries a unique set of challenges. Germ-cell tumours are a heterogeneous group of neoplasms that present across a wide age range and vary in site, histology, and clinical behaviour. Patients with germ-cell tumours are managed by a diverse array of specialists. Thus, staging, risk stratification, and treatment approaches for germ-cell tumours have evolved disparately along several trajectories. Paediatric germ-cell tumours differ from the adolescent and adult disease in many ways, leading to complexities in applying age-appropriate, evidence-based care. Suboptimal outcomes remain for several groups of patients, including adolescents, and patients with extragonadal tumours, high tumour markers at diagnosis, or platinum-resistant disease. Survivors have significant long-term toxicities. The challenge moving forward will be to translate new insights from molecular studies and collaborative clinical data into improved patient outcomes. Future trials will be characterised by improved risk-stratification systems, biomarkers for response and toxic effects, rational reduction of therapy for low-risk patients and novel approaches for poor-risk patients, and improved international collaboration across paediatric and adult cooperative research groups.


Optimization of Electronic Medical Records for Data Mining Using a Common Data Model.
The increasing use of electronic health records (EHRs) in veterinary medicine creates an opportunity to utilize the high volume of electronic patient data for mining and data-driven analytics with the goal of improving patient care and outcomes. A central focus of the Clinical and Translational Science Award One Health Alliance (COHA) is to integrate efforts across multiple disciplines to better understand shared diseases in animals and people. The ability to combine veterinary and human medical data provides a unique resource to study the interactions and relationships between animals, humans, and the environment. However, to effectively answer these questions, veterinary EHR data must first be prepared in the same way it is now commonly being done in human medicine to enable data mining and development of analytics to facilitate knowledge formation and solutions that advance our understanding of disease processes, with the ultimate goal of improving outcomes for veterinary patients and their owners. As a first step, COHA member institutions implemented a Common Data Model to standardize EHR data. Herein we present the approach executed within the COHA framework to prepare and optimize veterinary EHRs for data mining and knowledge formation based on the adoption of the Observational Health Data Sciences and Informatics' Observational Medical Outcomes Partnership Common Data Model.


Langerhans' cells, veiled cells, and interdigitating cells in the mouse recognized by a monoclonal antibody.
An mAb, NLDC-145, is described that specifically reacts with a group of nonlymphoid dendritic cells including Langerhans cells (LC), veiled cells (VC), and interdigitating cells (IDC). The antibody does not react with precursor cells in bone marrow and blood. Macrophages are not stained by the antibody, but a subpopulation of Ia+ peritoneal exudate cells is recognized. Possible relationships of the various nonlymphoid dendritic cell (NLDC) types are discussed.


The interaction of Kinesin-1 with its adaptor protein JIP1 can be regulated via proteins binding to the JIP1-PTB domain.
The regulatory mechanisms of motor protein-dependent intracellular transport are still not fully understood. The kinesin-1-binding protein, JIP1, can function as an adaptor protein that links kinesin-1 and other JIP1-binding "cargo" proteins. However, it is unknown whether these "cargo" proteins influence the JIP1-kinesin-1 binding. We show here that JIP1-kinesin-1 binding in Neuro2a cells was dependent on conserved amino acid residues in the JIP1-phosphotyrosine binding (PTB) domain, including F687. In addition, mutation of F687 severely affected the neurite tip localization of JIP1. Proteomic analysis revealed another kinesin-1 binding protein, JIP3, as a major JIP1 binding protein. The association between JIP1 and JIP3 was dependent on the F687 residue in JIP1, and this association induced the formation of a stable ternary complex with kinesin-1. On the other hand, the binding of JIP1 and JIP3 was independent of kinesin-1 binding. We also show that other PTB binding proteins can interrupt the formation of the ternary complex. The formation of the JIP1-kinesin-1 complex depends on the protein binding-status of the JIP1 PTB domain. This may imply a regulatory mechanism of kinesin-1-dependent intracellular transport.


Limitation of imaging in identifying iatrogenic aortic coarctation following thoracic endovascular aortic repair.
A 21-year-old male suffered blunt trauma from a motor vehicle accident causing thoracic aorta tear. The smallest available stent graft was deployed. Definitive repair was later performed using a 22 × 22 × 116 mm Talent Thoracic Stent Graft. The postoperative course was uneventful. Seventeen months later, he presented with dizziness, chest pain, acute renal failure, malignant hypertension, and troponin elevation. Computed tomography (CT) angiogram and transesophageal echocardiogram did not reveal any dissection, stent stenosis or collapse. Cardiac catheterization showed normal coronary arteries but a 117 mm Hg gradient across the stent graft. Iatrogenic coarctation of the aorta was confirmed with a second measurement during arch angiogram. A Palmaz stent was deployed over the distal end of the previous stent graft with complete resolution of symptoms and gradual normalization of kidney function. This case report demonstrates a need for wider availability and selecting appropriate stent graft in treating traumatic aortic injuries in young patients. It is the first case report of the inability of current imaging modalities in confirming stent collapse. Pressure gradient is a useful tool in confirming stent collapse when clinical scenario does not match CT findings.


Epidemiology and risk factors: intrahepatic cholangiocarcinoma.
Intrahepatic cholangiocarcinoma (ICC) is a rare entity with a distinct clinical course and epidemiology from hilar and extrahepatic cholangiocarcinoma. ICC makes up 8-10% of cholangiocarcinomas and 10-20% of all primary liver tumors. There remains a considerable amount of geographic variation in the incidence of ICC worldwide; however, the overall incidence of this malignancy appears to be rising. Several risk factors have been identified, such as infectious causes (liver flukes, viral hepatitis), biliary tract disease [primary sclerosing cholangitis (PSC), hepaticolithiasis, biliary cystic diseases], metabolic syndrome, lifestyle choices (alcohol abuse, tobacco use), and cirrhosis. Despite this, a substantial number of ICC patients do not have any identifiable risk factors, underlining the need for further work into the pathogenesis of this malignancy.


Predictors of rehospitalization after admission for pneumonia in the veterans affairs healthcare system.
Although some factors associated with rehospitalization after community-acquired pneumonia have been identified, other factors such as medical care utilization and medication usage have not been previously studied. We investigated novel predictors of rehospitalization in patients admitted with pneumonia. Using Department of Veteran Affairs (VA) administrative data from October 2001 to September 2007, we examined a cohort of patients 65 years old and older, who were hospitalized with pneumonia, in 150 VA acute care hospitals. The cohort was randomly split into derivation and validation samples, and then logistic regression models were used to identify and validate predictors of all-cause rehospitalization within 30 days. Of the 45,134 subjects, 13% were rehospitalized within 30 days. No significant differences were noted between the derivation and validation cohorts. Factors associated with readmission included age, marital status, chronic renal disease, prior malignancy, nursing home residence, congestive heart failure, use of oral corticosteroids, number of emergency department visits a year prior, prior admission, number of outpatient clinic visits in a year prior, and length of hospital stay. The C statistics for the derivation and validation models were 0.615 and 0.613, respectively. Factors associated with readmission were largely unrelated to the underlying pneumonia, but were related to demographics, comorbidities, healthcare utilization, and length of stay on index admission.


Clinical and cellular phenotypes associated with sequestosome 1 (SQSTM1) mutations.
Familial Paget's disease of bone has been shown to be associated with mutations in the ubiquitin-associated (UBA) domain of the sequestosome 1 (SQSTM1) gene. We have clinical findings on five families with diverse racial and ethnic backgrounds who all harbor SQSTM1 UBA domain mutations (P387L, P392L, D391fsX394, P392fsX394). Intrafamilial expressivity was highly variable. The probands in two of the families had early-onset disease involving a large number of bones and highly elevated prediagnostic levels of serum alkaline phosphatase. Affected siblings in these same families had limited bone involvement and were only diagnosed by technetium-99m methylene diphosphonate (MDP) bone scans. Furthermore, there was at least one subject in each family with no evidence of Paget's disease, although they carried one mutated copy of the SQSTM1 gene. A total of 18 such individuals were identified across the five kindreds. Thus, the gene seems to have highly variable expressivity, as well as incomplete penetrance, supporting the role of this gene as a predisposition gene for familial Paget's disease of the bone. Molecular studies of the SQSTM1 protein showed different cellular aggregation phenotypes depending on the nature of the mutation. In general, the point mutations formed larger cytoplasmic aggregates than the wildtype or truncation mutations. This aggregation phenotype was not altered on removal of the N-terminal PB1 dimerization domain, implying that aggregate formation is not wholly mediated by interaction through the PB1 domain. Although there was a genotype/phenotype correlation on the cellular level, this was not apparent on the clinical level. This supports the argument that other nongenetic factors play an important role in the pathogenesis of the disease.


A versatile system for the neuronal subtype specific expression of lentiviral vectors.
Lentiviral expression vectors are powerful tools for gene therapy and long-term gene expression/repression in the mammalian brain. However, no specificity of transduction has been reported so far in the central nervous system. Here we have developed a novel system to achieve a neuronal subtype specific expression in either dopaminergic (DA) or GABAergic neurons. We employed a delivery strategy by which the transgene is not expressed until its activation by Cre recombinase. We successfully tested the system in vitro and then used this novel lentivector, containing loxP sites, in 2 different transgenic mouse lines expressing Cre either in DA or in GABAergic neurons. In both lines the reporter gene was detected exclusively in Cre-positive cells, demonstrating that with this experimental approach we were able to achieve completely specific expression of transgenes delivered by lentiviral vectors. This universal system can be applied to all neural subtypes making use of the growing number of specific Cre driver lines.- Tolu, S., Avale, M. E., Nakatani, H., Pons, S., Parnaudeau, S., Tronche, F., Vogt, A., Monyer, H., Vogel, R., de Chaumont, F., Olivo-Marin, J.-C., Changeux, J.-P., Maskos, U. A versatile system for the neuronal subtype specific expression of lentiviral vectors.


Efficacy of Solifenacin on Irritable Bowel Syndrome With Diarrhea: Open-label Prospective Pilot Trial.
Solifenacin, a muscarinic type 3 receptor antagonist, is used to treat overactive bladder in adults. The aim of this study is to examine the efficacy of solifenacin on the symptomatic relief of diarrhea predominant irritable bowel syndrome (IBS-D). A total of 20 patients with IBS-D were enrolled. After a 2-week observation period, all participants received solifenacin for 6 weeks. Subsequently, the administration of solifenacin was discontinued and ramosetron, a serotonin 3 receptor antagonist, was administered for 4 weeks. Overall improvement, the IBS-symptom severity scale (IBS-SSS), and frequency of defecation were assessed. Six weeks after initiation of solifenacin treatment and 4 weeks after initiation of ramosetron treatment, overall improvement was observed in 19 out of 20 (95%) and 17 out of 20 (85%) participants, respectively. At 2 weeks after initiation of solifenacin, overall improvement was observed in 16 out of 20 participants (80%). Total IBS-SSS scores at 2 and 6 weeks after the administration of solifenacin, and at 4 weeks after administration of ramosetron, were significantly lower than those at week 0. Compared to before administration, the participants' quality of life and frequency of defecation were significantly lower in all participants at 2 and 6 weeks after the administration of solifenacin and at 4 weeks after administration of ramosetron. The efficacy of solifenacin in the treatment of IBS with diarrhea was not inferior to that of ramosetron. Further placebo-controlled parallel studies are needed.


Hoarding and emotional reactivity: the link between negative emotional reactions and hoarding symptomatology.
Hoarding disorder (HD) is characterized by difficulty discarding, clutter, and frequently excessive acquiring. Theories have pointed to intense negative emotional reactions (e.g., sadness) as one factor that may play a critical role in HD's etiology. Preliminary work with an analogue sample indicated that more intense negative emotions following emotional films were linked with greater hoarding symptoms. Symptom provocation imaging studies with HD patients have also found evidence for excessive activation in brain regions implicated in processing emotions. The current study utilized a sample with self-reported serious hoarding difficulties to examine how hoarding symptoms related to both general and hoarding-related emotional reactivity, taking into account the specificity of these relationships. We also examined how two cognitive factors, fear of decision-making and confidence in memory, modified this relationship. 628 participants with self-identified hoarding difficulties completed questionnaires about general emotional reactivity, depression, anxiety, decision-making, and confidence in memory. To assess hoarding-related emotional reactivity, participants reported their emotional reactions when imagining discarding various items. Heightened general emotional reactivity and more intense emotional reactions to imagined discarding were associated with both difficulty discarding and acquisition, but not clutter, controlling for age, gender, and co-occurring mood and anxiety symptoms. Fear of decision-making and confidence in memory interacted with general emotional reactivity to predict hoarding symptoms. These findings provide support for cognitive-behavioral models of hoarding. Experimental research should be conducted to discover whether emotional reactivity increases vulnerability for HD. Future work should also examine whether emotional reactivity should be targeted in interventions for hoarding.


ECO, the Evidence & Conclusion Ontology: community standard for evidence information.
The Evidence and Conclusion Ontology (ECO) contains terms (classes) that describe types of evidence and assertion methods. ECO terms are used in the process of biocuration to capture the evidence that supports biological assertions (e.g. gene product X has function Y as supported by evidence Z). Capture of this information allows tracking of annotation provenance, establishment of quality control measures and query of evidence. ECO contains over 1500 terms and is in use by many leading biological resources including the Gene Ontology, UniProt and several model organism databases. ECO is continually being expanded and revised based on the needs of the biocuration community. The ontology is freely available for download from GitHub (https://github.com/evidenceontology/) or the project's website (http://evidenceontology.org/). Users can request new terms or changes to existing terms through the project's GitHub site. ECO is released into the public domain under CC0 1.0 Universal.


The Effect of Educational Program Based on Belief, Attitude, Subjective Norm, and Enabling Factors Model on Changing the Metabolic Indices in Elderly Patients with Type II Diabetes.
Diabetes is the most common disease related to metabolism disorders. Today, diabetes in the elderly is one of the major epidemics of the century. This study aimed to investigate the effect of nutrition and jogging-based Belief, Attitude, Subjective Norm, and Enabling Factors (BASNEF) model in changes in metabolic parameters that performed in elderly patients with type II diabetes in Fasa city. This study was a randomized clinical trial on 108 elderly patients with type II diabetes (54 patients in the experimental group and 54 in control group) referred to the diabetes center in Fasa City, Fars Province, Iran, in 2016. Data were collected using a valid self-reported questionnaire including demographic variables and BASNEF Model (knowledge, attitudes, subjective norms, and enabling factors), checklist for patient's practices nutrition and jogging based on self-reporting patients, assess the level of fasting blood sugar (FBS), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG), and HbAlc patients which was completed by both groups before and 3 months after the intervention. The experimental group received the training in eight sessions; each session lasted for 70 min. Then, the data were entered into the SPSS 22 software (SPSS Inc., IBM, Chicago, IL, USA) and were analyzed using descriptive statistics, Chi-square test, independent t-test, and paired t-test. P <0.05 was considered as statistically significant. The results showed that the mean scores of the BASNEF components (knowledge, attitudes, subjective norms, and enabling factors) in two experimental and control groups after intervention were a significant difference. After training program, nutritional and jogging performance in the experimental group was better than the control group. Furthermore, FBS (P < 0.001), LDL (P < 0.001), HDL (P < 0.001), TG (P < 0.001), and HbAlc (P < 0.001) improved significantly in the experimental group compared to the control group. Plan and implement nutrition and jogging education using the BASNEF model to improve metabolic parameters in diabetic patients are very effective and beneficial. Moreover, in the implementation of these programs, control, monitoring, and follow-up educational are recommended.


Physicochemical characteristics and anti-inflammatory activities of antrodan, a novel glycoprotein isolated from Antrodia cinnamomea mycelia.
Antrodia cinnamomea (AC) is a unique fungus found inhabiting the rotten wood of Cinnamomum kanehirai. A submerged liquid culture of AC has been developed and its bioproducts have been used to meet the market demand for natural fruiting bodies. AC exhibits anti-inflammatory, antitumor, antioxidant, and immunomodulatory effects. Previously, we isolated polysaccharide AC-2 from AC mycelia by means of alkali extraction with subsequent acid precipitation and found it had a pronounced anti-inflammatory effect. In this study, a novel polysaccharide named "antrodan" was obtained by further purification of AC-2 using Sepharose CL-6B column chromatography. Antrodan exhibited a molecular weight of 442 kD and contained a particularly high content of uronic acid (152.6±0.8 mg/g). The protein content was 71.0%, apparently, higher than the carbohydrate content (14.1%), and thus antrodan was characterized as a glycoprotein. Its total glucan content was 15.65%, in which β-glucan (14.20%) was prominently higher than α-glucan (1.45%). Its FTIR confirmed the presence of β-linkages between sugars, and intramolecular amide bonds between sugars and amino acids. Its 1H-NMR spectrum showed that antrodan was a complex union of α- and β-glucans, which had (1→4)-linked α-Glcp and (1→3)-linked β-Glcp linkages to the carbohydrate chains via asparagine linked to protein site. Biologically, antrodan was confirmed to be totally non-detrimental to RAW 264.7 cell line even at dose as high as 400 μg/mL. It showed potent suppressing effect on the lipopolysaccharide-induced inflammatory responses in RAW 264.7 cell line. Moreover, antrodan significantly reduced the nitrogen oxide production at doses as low as 18.75 μg/mL.


Taylor's power law captures the effects of environmental variability on community structure: An example from fishes in the North Sea.
Taylor's power law (TPL) describes the relationship between the mean and variance in abundance of populations, with the power law exponent considered a measure of aggregation. However, the usefulness of TPL exponents as an ecological metric has been questioned, largely due to its apparent ubiquity in various complex systems. The aim of this study was to test whether TPL exponents vary systematically with potential drivers of animal aggregation in time and space and therefore capture useful ecological information of the system of interest. We derived community TPL exponents from a long-term, standardised and spatially dense data series of abundance and body size data for a strongly size-structured fish community in the North Sea. We then compared TPL exponents between regions of contrasting environmental characteristics. We find that, in general, TPL exponents vary more than expected under random conditions in the North Sea for size-based populations compared to communities considered by species. Further, size-based temporal TPL exponents are systematically higher (implying more temporally aggregated distributions) along hydrographic boundaries. Time series of size-based spatial TPL exponents also differ between hydrographically distinct basins. These findings support the notion that TPL exponents contain ecological information, capturing community spatio-temporal dynamics as influenced by external drivers.


The study of infectious intestinal disease in England: risk factors for cases of infectious intestinal disease with Campylobacter jejuni infection.
This is a case-control study aimed at identifying risk factors for intestinal infection with Campylobacter jejuni. Cases were defined as subjects with diarrhoea occurring in community cohorts or presenting to General Practitioners (GPs) with Campylobacter jejuni in stools. Controls were selected from GP lists or cohorts, matched by age, sex, and GP practice. Travel abroad and consumption of chicken in a restaurant were statistically significantly associated with being a case. There was no statistically significant risk associated with consumption of chicken other than in restaurants nor with reported domestic kitchen hygiene practices. Consumption of some foods was associated with a lower risk of being a case. Most cases remained unexplained. We suggest that infection with low numbers of micro-organisms, and individual susceptibility may play a greater role in the causation of campylobacter infection than previously thought. It is possible that in mild, sporadic cases infection may result from cross contamination from kitchen hygiene practices usually regarded as acceptable. Chicken may be a less important vehicle of infection for sporadic cases than for outbreaks, although its role as a source of infection in both settings requires further clarification in particular in relation to the effect of domestic hygiene practices. The potential effect of diet in reducing the risk of campylobacteriosis requires exploration.


Anatomical factors associated with predicting plantar fasciitis in long-distance runners.
The purpose of this study was to identify anatomical variables associated with plantar-fasciitis sufferers. Selected anatomical variables which were chosen for measurement were leg length, pronation of the subtalar joint, plantar and dorsiflexion ability, and arch height of the foot, as well as the variables height, weight, age, and miles run per week. The means and standard deviations revealed that leg-length inequality, pronation of the subtalar joint, and arch height were not good indicators of plantar-fasciitis sufferers. According to the discriminant-function analysis in which 64% of the subjects were assigned to the appropriate group, plantar flexion, dorsiflexion, and height were good predictors of the recovered and non-recovered sufferers, but could predict no more than 50% of the present sufferers. Therefore, a set of predictor variables was not found for the prediction of plantar-fasciitis sufferers.


Bioinformatics for next generation sequencing data.
The emergence of next-generation sequencing (NGS) platforms imposes increasing demands on statistical methods and bioinformatic tools for the analysis and the management of the huge amounts of data generated by these technologies. Even at the early stages of their commercial availability, a large number of softwares already exist for analyzing NGS data. These tools can be fit into many general categories including alignment of sequence reads to a reference, base-calling and/or polymorphism detection, de novo assembly from paired or unpaired reads, structural variant detection and genome browsing. This manuscript aims to guide readers in the choice of the available computational tools that can be used to face the several steps of the data analysis workflow.


Comparative analysis of the kinomes of three pathogenic trypanosomatids: Leishmania major, Trypanosoma brucei and Trypanosoma cruzi.
The trypanosomatids Leishmania major, Trypanosoma brucei and Trypanosoma cruzi cause some of the most debilitating diseases of humankind: cutaneous leishmaniasis, African sleeping sickness, and Chagas disease. These protozoa possess complex life cycles that involve development in mammalian and insect hosts, and a tightly coordinated cell cycle ensures propagation of the highly polarized cells. However, the ways in which the parasites respond to their environment and coordinate intracellular processes are poorly understood. As a part of an effort to understand parasite signaling functions, we report the results of a genome-wide analysis of protein kinases (PKs) of these three trypanosomatids. Bioinformatic searches of the trypanosomatid genomes for eukaryotic PKs (ePKs) and atypical PKs (aPKs) revealed a total of 176 PKs in T. brucei, 190 in T. cruzi and 199 in L. major, most of which are orthologous across the three species. This is approximately 30% of the number in the human host and double that of the malaria parasite, Plasmodium falciparum. The representation of various groups of ePKs differs significantly as compared to humans: trypanosomatids lack receptor-linked tyrosine and tyrosine kinase-like kinases, although they do possess dual-specificity kinases. A relative expansion of the CMGC, STE and NEK groups has occurred. A large number of unique ePKs show no strong affinity to any known group. The trypanosomatids possess few ePKs with predicted transmembrane domains, suggesting that receptor ePKs are rare. Accessory Pfam domains, which are frequently present in human ePKs, are uncommon in trypanosomatid ePKs. Trypanosomatids possess a large set of PKs, comprising approximately 2% of each genome, suggesting a key role for phosphorylation in parasite biology. Whilst it was possible to place most of the trypanosomatid ePKs into the seven established groups using bioinformatic analyses, it has not been possible to ascribe function based solely on sequence similarity. Hence the connection of stimuli to protein phosphorylation networks remains enigmatic. The presence of numerous PKs with significant sequence similarity to known drug targets, as well as a large number of unusual kinases that might represent novel targets, strongly argue for functional analysis of these molecules.


Vagotomy and Gastric Tumorigenesis.
Vagotomy reduces gastric acid secretion and was therefore introduced as a surgical treatment for peptic ulcers in the 1970s. Later, it was replaced by acid reducing medication, such as histamine type 2 (H2) receptor antagonists and proton pump inhibitors (PPIs). A large body of evidence has indicated that drug-induced hypochlorhydria per se does not increase the risk of gastric cancer. Early studies on the effects of vagotomy in chemically-induced rodent models of gastric cancer reported an increased risk of developing gastric cancer. This was most likely due to a delayed gastric emptying, which later has been accounted for by including an additional drainage procedure, e.g. pyloroplasty. In a recent study using three different mouse models of gastric cancer (including genetically engineered, chemically-induced and Helicobacter pylori-infected mice), either unilateral vagotomy or bilateral truncal vagotomy with pyloroplasty was found to significantly attenuate tumorigenesis in the denervated side of the stomach at early preneoplastic stages as well as at later stages of tumorigenesis. Consistently, pharmacological denervation using botulinum toxin A or muscarinic acetylcholine receptor 3 (M3R) blockade inhibited tumorigenesis. Moreover, it was found that recurrence of gastric cancer was reduced in patients following vagotomy. Thus, these new findings suggest the potential treatment strategies to target the nerve, neurotransmitters, corresponding receptors and their downstream signaling pathways for the malignancy.


Patchy population structure in a short-distance migrant: evidence from genetic and demographic data.
Species often occur in subdivided populations as a consequence of spatial heterogeneity of the habitat. To describe the spatial organization of subpopulations, existing theory proposes three main population models: patchy population, metapopulation and isolated populations. These models differ in their predicted levels of connectivity among subpopulations, and in the risk that a subpopulation will go extinct. However, spatially discrete subpopulations are commonly considered to be organized as metapopulations, even though explicit tests of metapopulation assumptions are rare. Here, we test predictions of the three models on the basis of demographic and genetic data, a combined approach so far surprisingly little used in mobile organisms. From 2002 to 2005, we studied nine subpopulations of the wetland-restricted reed bunting (Emberiza schoeniclus) in the southeastern part of the Canton Zurich (Switzerland), from which local declines of this species have been reported. Here, wetlands are as small as 2.7 ha and separated through intensively used agricultural landscapes. Demographic data consisted of dispersal of colour-banded individuals among subpopulations, immigration rates and extinction-/recolonization dynamics. Genetic data were based on the distribution of genetic variability and gene flow among subpopulations derived from the analysis of nine microsatellite loci. Both demographic and genetic data revealed that the patchy population model best described the spatial organization of reed bunting subpopulations. High levels of dispersal among subpopulations, high immigration into the patchy population, and genetic admixture suggested little risk of extinction of both subpopulations and the entire patchy population. This study exemplifies the idea that spatially discrete subpopulations may be organized in ways other than a metapopulation, and hence has implications for the conservation of subpopulations and species.


The neuronal expression of MYC causes a neurodegenerative phenotype in a novel transgenic mouse.
Many different proteins associated with the cell cycle, including cyclins, cyclin-dependent kinases, and proto-oncogenes such as c-MYC (MYC), are increased in degenerating neurons. Consequently, an ectopic activation of the cell cycle machinery in neurons has emerged as a potential pathogenic mechanism of neuronal dysfunction and death in many neurodegenerative diseases, including Alzheimer's disease. However, the exact role of cell cycle re-entry during disease pathogenesis is unclear, primarily because of the lack of relevant research models to study the effects of cell cycle re-entry on mature neurons in vivo. To address this issue, we developed a new transgenic mouse model in which forebrain neurons (CaMKII-MYC) can be induced to enter the cell cycle using the physiologically relevant proto-oncogene MYC to drive cell cycle re-entry. We show that such cell cycle re-entry results in neuronal cell death, gliosis, and cognitive deficits. These findings provide compelling evidence that dysregulation of cell cycle re-entry results in neurodegeneration in vivo. Our current findings, coupled with those of previous reports, strengthen the hypothesis that neurodegeneration in Alzheimer's disease, similar to cellular proliferation in cancer, is a disease that results from inappropriate cell cycle control.


Factors that support successful transition to the community among women leaving prison in British Columbia: a prospective cohort study using participatory action research.
In Canada, the number of women sentenced to prison has almost doubled since 1995. In British Columbia, the rate of reincarceration is 70% within 2 years. Our aim was to identify factors associated with recidivism among women in British Columbia. We prospectively followed women after discharge from provincial corrections centres in British Columbia. We defined recidivism as participation in criminal activity disclosed by participants during the year following release. To identify predictive factors, we carried out a repeated-measures analysis using a logistic mixed-effect model. Four hundred women completed a baseline interview, of whom 207 completed additional interviews during the subsequent year, contributing 395 interviews in total. Factors significantly associated in univariate analysis with recidivism included not having a family doctor or dentist, depression, not having children, less than high school education, index charge of drug offense or theft under $5000, poor general health, hepatitis C treatment, poor nutritional or spiritual health, and use of cannabis or cocaine. In multivariate analysis, good nutritional health (odds ratio [OR] 0.52 [95% confidence interval (CI) 0.35-0.76]), good spiritual health (OR 0.61 [95% CI 0.44-0.83]), high school education (OR 0.44 [95% CI 0.22-0.87]) and incarceration for a drug offence versus other crimes (OR 0.30 [95% CI 0.12-0.79]) were protective against recidivism. Our findings emphasize the relevance of health-related strategies as drivers of recidivism among women released from prison. Health assessment on admission followed by treatment for trauma and associated psychiatric disorders and for chronic medical and dental problems deserve consideration as priority approaches to reduce rates of reincarceration.


Formulation and evaluation of multiparticulate system for chronotherapeutic delivery of salbutamol sulphate.
Solution layering technique was used to prepare pellets of Salbutamol Sulphate. A multiparticulate system was prepared with pH independent and pH dependent coatings, and evaluated as pulsatile drug delivery system. Salbutamol sulphate release was studied from methacrylate coated pellets from non pareils. Morphology was studied using Scanning Electron Microscopy for the characterization of prepared pellets. Combination of Eudragit RSPO (pH independent) and Eudragit L100 (pH dependent) was used for coating of the pellets. Different concentrations of this polymeric combination were loaded on to the drug-loaded pellets. The aim of this study was to investigate the effect of physicochemical properties of the polymers on the release profile of Salbutamol sulphate from the pellets dosage form. The in-vitro study suggested that Eudragit RSPO and Eudragit L100 at 10% coating level led to an optimum pulsatile release behavior. The coated pellets prepared by solution layering technology successfully released drug after specific lag time indicating pulsatile drug delivery. It was revealed that Eudragit RSPO has the effect to retard drug release. The results generated in this study showed that proper selection of polymeric materials based on their physicochemical properties is important in designing pellets dosage form with suitable dissolution profile.


Structural Study of the C-Terminal Domain of Nonstructural Protein 1 from Japanese Encephalitis Virus.
Japanese encephalitis virus (JEV) is a mosquito-transmitted flavivirus that is closely related to other emerging viral pathogens, including dengue virus (DENV), West Nile virus (WNV), and Zika virus (ZIKV). JEV infection can result in meningitis and encephalitis, which in severe cases cause permanent brain damage and death. JEV occurs predominantly in rural areas throughout Southeast Asia, the Pacific Islands, and the Far East, causing around 68,000 cases of infection worldwide each year. In this report, we present a 2.1-Å-resolution crystal structure of the C-terminal β-ladder domain of JEV nonstructural protein 1 (NS1-C). The surface charge distribution of JEV NS1-C is similar to those of WNV and ZIKV but differs from that of DENV. Analysis of the JEV NS1-C structure, with in silico molecular dynamics simulation and experimental solution small-angle X-ray scattering, indicates extensive loop flexibility on the exterior of the protein. This, together with the surface charge distribution, indicates that flexibility influences the protein-protein interactions that govern pathogenicity. These factors also affect the interaction of NS1 with the 22NS1 monoclonal antibody, which is protective against West Nile virus infection. Liposome and heparin binding assays indicate that only the N-terminal region of NS1 mediates interaction with membranes and that sulfate binding sites common to NS1 structures are not glycosaminoglycan binding interfaces. This report highlights several differences between flavivirus NS1 proteins and contributes to our understanding of their structure-pathogenic function relationships.IMPORTANCE JEV is a major cause of viral encephalitis in Asia. Despite extensive vaccination, epidemics still occur. Nonstructural protein 1 (NS1) plays a role in viral replication, and, because it is secreted, it can exhibit a wide range of interactions with host proteins. NS1 sequence and protein folds are conserved within the Flavivirus genus, but variations in NS1 protein-protein interactions among viruses likely contribute to differences in pathogenesis. Here, we compared characteristics of the C-terminal β-ladder domain of NS1 between flaviviruses, including surface charge, loop flexibility, epitope cross-reactivity, membrane adherence, and glycosaminoglycan binding. These structural features are central to NS1 functionality and may provide insight into the development of diagnostic tests and therapeutics.


Human and Bovine Colostrum for Prevention of Necrotizing Enterocolitis: A Meta-analysis.
Human and bovine colostrum (HBC) administration has been linked to beneficial effects on morbidity and mortality associated with necrotizing enterocolitis (NEC). To determine the effectiveness and safety of HBC for reducing NEC, mortality, sepsis, time to full-feed and feeding intolerance in preterm infants. We conducted searches through Medline, Embase, Cumulative Index of Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, and gray literature. Randomized controlled trials comparing human or bovine colostrum to placebo. Two reviewers independently did screening, review, and extraction. Eight studies (385 infants) proved eligible. In comparison with placebo, HBC revealed no effect on the incidence of severe NEC (relative risk [RR]: 0.99; 95% confidence interval [CI] 0.48 to 2.02, I2 = 2.2%; moderate certainty of evidence), all-cause mortality (RR: 0.88; 95% CI 0.39 to 1.82, I2 = 0%; moderate certainty), culture-proven sepsis (RR: 0.78; 95% CI 0.53 to 1.14, I2 = 0%; moderate certainty), and feed intolerance (RR: 0.97; 95% CI 0.37 to 2.56, I2 = 55%; low certainty). HBC revealed a significant effect on reducing the mean days to reach full enteral feed (mean difference: -3.55; 95% CI 0.33 to 6.77, I2 = 41.1%; moderate certainty). The indirect comparison of bovine versus human colostrum revealed no difference in any outcome. The number of patients was modest, whereas the number of NEC-related events was low. Bovine or human colostrum has no effect on severe NEC, mortality, culture-proven sepsis, feed intolerance, or length of stay. Additional research focused on the impact on enteral feeding may be needed to confirm the findings on this outcome.


Mammalian Clusterin associated protein 1 is an evolutionarily conserved protein required for ciliogenesis.
Clusterin associated protein 1 (CLUAP1) was initially characterized as a protein that interacts with clusterin, and whose gene is frequently upregulated in colon cancer. Although the consequences of these observations remain unclear, research of CLUAP1 homologs in C. elegans and zebrafish indicates that it is needed for cilia assembly and maintenance in these models. To begin evaluating whether Cluap1 has an evolutionarily conserved role in cilia in mammalian systems and to explore the association of Cluap1 with disease pathogenesis and developmental abnormalities, we generated Cluap1 mutant mice. Cluap1 mutant embryos were generated and examined for gross morphological and anatomical defects using light microscopy. Reverse transcription PCR, β-galactosidase staining assays, and immunofluorescence analysis were used to determine the expression of the gene and localization of the protein in vivo and in cultured cell lines. We also used immunofluorescence analysis and qRT-PCR to examine defects in the Sonic hedgehog signaling pathway in mutant embryos. Cluap1 mutant embryos die in mid-gestation, indicating that it is necessary for proper development. Mutant phenotypes include a failure of embryonic turning, an enlarged pericardial sac, and defects in neural tube development. Consistent with the diverse phenotypes, Cluap1 is widely expressed. Furthermore, the Cluap1 protein localizes to primary cilia, and mutant embryos were found to lack cilia at embryonic day 9.5. The phenotypes observed in Cluap1 mutant mice are indicative of defects in Sonic hedgehog signaling. This was confirmed by analyzing hedgehog signaling activity in Cluap1 mutants, which revealed that the pathway is repressed. These data indicate that the function of Cluap1 is evolutionarily conserved with regard to ciliogenesis. Further, the results implicate mammalian Cluap1 as a key regulator of hedgehog signaling and as an intraflagellar transport B complex protein. Future studies on mammalian Cluap1 utilizing this mouse model may provide insights into the role for Cluap1 in intraflagellar transport and the association with colon cancer and cystic kidney disorders.


Nitridergic platelet pathway activation by hementerin, a metalloprotease from the leech Haementeria depressa.
Hementerin (HT) is an 80 kDa fibrino(geno)lytic metalloprotease, purified from saliva of the leech Haementeria depressa. In the present report, the effect of HT on several functional parameters of human platelets was assessed. HT inhibited platelet aggregation and ATP release induced by different agonists such as ADP, adrenaline, collagen, thrombin, and arachidonic acid. HT did neither modify the expression of platelet glycoproteins (Ib, IIb-IIIa, Ia-IIa, IV) nor intraplatelet fibrinogen levels, whereas it markedly decreased CD62P and CD63 levels after the stimulation with thrombin. HT significantly increased thrombin-induced platelet Ca2+ intracellular levels, cGMP content and nitric oxide synthase (NOS) activity. The effect of HT on platelet aggregation was reversed by two NOS inhibitors, N(omega)-Nitro-L-arginine methyl ester and 2 N(G)-Nitro-L-arginine. In summary, these results indicate that HT is an effective inhibitor of human platelet aggregation, presumably through activation of the platelet's nitridergic pathway.


Localization of sesquiterpene formation and emission in maize leaves after herbivore damage.
Maize (Zea mays L.) leaves damaged by lepidopteran herbivores emit a complex volatile blend that can attract natural enemies of the herbivores and may also have roles in direct defense and inter- or intra-plant signaling. The volatile blend is dominated by sesquiterpenes of which the majority is produced by two herbivore-induced terpene synthases, TPS10 and TPS23. However, little is known about the pattern of volatile emission within maize leaves. In this study, we restricted herbivore feeding to small sections of the maize leaf with the aim of determining the patterns of volatile sesquiterpene emission throughout the damaged leaf and in neighboring leaves. Sesquiterpene volatiles were released at high rates from damaged leaves, but at much lower rates from neighboring leaves. Release was restricted to the site of damage or to leaf sections located apical to the damage, but was not seen in sections basal to the damage or on the other side of the midrib. The emission pattern correlated well with the transcript pattern of the respective sesquiterpene synthase genes, tps10 and tps23, implying that biosynthesis likely occurs at the site of emission. The concentrations of jasmonic acid and its leucine derivative were also elevated in terpene-emitting tissues suggesting a role for jasmonates in propagating the damage signal. In contrast to other defense reactions which often occur systemically throughout the whole plant, herbivore-induced sesquiterpene production in maize is restricted to the wounding site and distal leaf parts. Since the signal mediating this reaction is directed to the leaf tip and cannot propagate parallel to the leaf axis, it is likely connected to the xylem. The increasing gradient of volatiles from the tip of the leaf towards the damage site might aid herbivore enemies in host or prey finding.


Nonobstructive coronary artery disease and risk of myocardial infarction.
Little is known about cardiac adverse events among patients with nonobstructive coronary artery disease (CAD). To compare myocardial infarction (MI) and mortality rates between patients with nonobstructive CAD, obstructive CAD, and no apparent CAD in a national cohort. Retrospective cohort study of all US veterans undergoing elective coronary angiography for CAD between October 2007 and September 2012 in the Veterans Affairs health care system. Patients with prior CAD events were excluded. Angiographic CAD extent, defined by degree (no apparent CAD: no stenosis >20%; nonobstructive CAD: ≥1 stenosis ≥20% but no stenosis ≥70%; obstructive CAD: any stenosis ≥70% or left main [LM] stenosis ≥50%) and distribution (1, 2, or 3 vessel). The primary outcome was 1-year hospitalization for nonfatal MI after the index angiography. Secondary outcomes included 1-year all-cause mortality and combined 1-year MI and mortality. Among 37,674 patients, 8384 patients (22.3%) had nonobstructive CAD and 20,899 patients (55.4%) had obstructive CAD. Within 1 year, 845 patients died and 385 were rehospitalized for MI. Among patients with no apparent CAD, the 1-year MI rate was 0.11% (n = 8, 95% CI, 0.10%-0.20%) and increased progressively by 1-vessel nonobstructive CAD, 0.24% (n = 10, 95% CI, 0.10%-0.40%); 2-vessel nonobstructive CAD, 0.56% (n = 13, 95% CI, 0.30%-1.00%); 3-vessel nonobstructive CAD, 0.59% (n = 6, 95% CI, 0.30%-1.30%); 1-vessel obstructive CAD, 1.18% (n = 101, 95% CI, 1.00%-1.40%); 2-vessel obstructive CAD, 2.18% (n = 110, 95% CI, 1.80%-2.60%); and 3-vessel or LM obstructive CAD, 2.47% (n = 137, 95% CI, 2.10%-2.90%). After adjustment, 1-year MI rates increased with increasing CAD extent. Relative to patients with no apparent CAD, patients with 1-vessel nonobstructive CAD had a hazard ratio (HR) for 1-year MI of 2.0 (95% CI, 0.8-5.1); 2-vessel nonobstructive HR, 4.6 (95% CI, 2.0-10.5); 3-vessel nonobstructive HR, 4.5 (95% CI, 1.6-12.5); 1-vessel obstructive HR, 9.0 (95% CI, 4.2-19.0); 2-vessel obstructive HR, 16.5 (95% CI, 8.1-33.7); and 3-vessel or LM obstructive HR, 19.5 (95% CI, 9.9-38.2). One-year mortality rates were associated with increasing CAD extent, ranging from 1.38% among patients without apparent CAD to 4.30% with 3-vessel or LM obstructive CAD. After risk adjustment, there was no significant association between 1- or 2-vessel nonobstructive CAD and mortality, but there were significant associations with mortality for 3-vessel nonobstructive CAD (HR, 1.6; 95% CI, 1.1-2.5), 1-vessel obstructive CAD (HR, 1.9; 95% CI, 1.4-2.6), 2-vessel obstructive CAD (HR, 2.8; 95% CI, 2.1-3.7), and 3-vessel or LM obstructive CAD (HR, 3.4; 95% CI, 2.6-4.4). Similar associations were noted with the combined outcome. In this cohort of patients undergoing elective coronary angiography, nonobstructive CAD, compared with no apparent CAD, was associated with a significantly greater 1-year risk of MI and all-cause mortality. These findings suggest clinical importance of nonobstructive CAD and warrant further investigation of interventions to improve outcomes among these patients.


Cost consequences of implementing an electronic decision support system for ordering laboratory tests in primary care: evidence from a controlled prospective study in the Netherlands.
The economic consequences of interventions to promote rational, evidence-based use of laboratory tests by physicians are not yet fully understood. We evaluated the cost consequences of a computer-based, guideline-driven decision-support system (CDSS) for ordering blood tests in primary care. We installed the CDSS in 118 practices [159 general practitioners (GPs)] throughout The Netherlands and calculated the costs of the intervention in this group. During a period of 6 months before and 6 months after installation of the CDSS, the test-ordering behavior of 87 (109 GPs) of these 118 study practices was studied and the results were compared with those of a nonhistorical control group that did not receive the CDSS. In addition the costs of laboratory requests were calculated for both groups. Total intervention costs, comprising development costs and installation costs, amounted to 79,000 euro (670 euro per practice). Whereas the introduction of the CDSS did not affect the number of order forms submitted to the laboratories, it did reduce the number of blood tests per order form. As a result, the CDSS yielded mean savings on the costs of laboratory requests of 847 euro per practice per 6 months. This study demonstrates that providing electronic decision support for ordering blood tests in primary care represents an economically promising concept. Savings on laboratory costs are achievable and not offset by disproportionally high intervention costs.


Imitating the Cherenkov radiation in backward directions using one-dimensional photonic wires.
A novel radiation emission from traveling charged particles in vacuum is theoretically demonstrated. This radiation is conical as in the Cherenkov radiation, but emerges in backward directions of the particle trajectories. The basic mechanism of the radiation is the Smith-Purcell effect via the interaction between the charged particles and a circular-symmetric photonic wire with a one-dimensionally periodic dielectric function. The wire exhibits the photonic band structure characterized with angular momentum. The charged particle can resonantly excite the photonic band modes with particular angular momentum, depending on the particle velocity. A simple kinetics of the Smith-Purcell effect enables us to design the conical radiation emitted in backward directions. Numerical results of the backward radiation are also presented for a metallic wire with aligned air holes.


Lack of importance in humans of the slow component of the response of force to an increase in cardiac muscle length.
1. An increase in length in isolated animal muscles causes an immediate increase in contractile force, which is followed by a slower further progressive increase: the slow component. However, the pressure-volume concept, used in characterizing left ventricular function, is dependent on a constant relationship between pressure and volume. 2. We therefore examined the possible occurrence of the slow inotropic component of the response to cardiac muscle stretch in man at cardiac catheterization. 3. Human subjects undergoing left heart catheterization for clinical indications were studied. The development of the slow component was studied by measurement of rate of rise in left ventricular developed pressure and the time course after an increase in end-diastolic volume. 4. No evidence for any slow component was elicited. 5. It is concluded that the slow component of force (or pressure) increase after an increase in cardiac muscle length (or volume) does not have a role in the human heart in situ.


Set7 methyltransferase roles in myocardial protection from chronic stressors.
Epigenome changes in chronic states of cardiovascular stress including diabetes, pressure overload and cardiomyopathies frequently involve changes in open chromatin and post-translation modifications of histone lysine residues at specific amino acid positions by acetylation, methylation and phosphorylation. Since the discovery of Set7 as an important regulator of histone H3 lysine 4 methylation state, there has been wide interest in its role in cardiovascular remodeling and cardiac dysfunction. Recent transcriptome and Fourier transform infrared spectroscopy analyses and in vivo assessments of cardiac function by Lunardon and colleagues now reveal a clear role of Set7 in the regulation of the extracellular matrix composition and cardiac hypertrophy in response to chronic isoproterenol induced cardiac stress.


What are the Barriers to Antenatal Care Utilization in Rufisque District, Senegal?: a Bottleneck Analysis.
This study aimed to analyze the barriers affecting the utilization of antenatal care (ANC) among Senegalese mothers. Health facility staffs were surveyed to examine the availability coverage of ANC (infrastructural capacity of health posts to handle maternal and newborn healthcare). A total of 113 women of childbearing age were surveyed to identify factors associated with the accessibility coverage (physical, economic, and information accessibility factors), acceptability coverage (socio-cultural features, social acceptance, and language), and effectiveness coverage (ratio of mothers having completed 4 visits) of ANC. Further, to identify the socio-cultural factors and the specific characteristics of the barriers, 5 focus group discussions were conducted with women of childbearing age, their husbands and mothers-in-law, community health workers, and health facility staff. The effectiveness coverage of ANC was analyzed by reviewing materials from the District Health Information System 2 of Senegal. Key barriers of ANC utilization were associated with acceptability coverage. ANC during early pregnancy was avoided owing to the negative social stigma surrounding miscarriage. The survey results indicated an extremely high miscarriage rate of 30.9% among the participants. The social stigma towards unmarried mothers caused them to hide their pregnancy, which deterred ANC utilization. The husband was the final decision maker and social supporter on ANC utilization. To promote the utilization of ANC services among pregnant women in Senegal, it is important to alleviate the social stigma towards miscarriages and unmarried mothers, and to provide greater social support for pregnancies and newborn deliveries within family.


Comparison of amlodipine/valsartan fixed-dose combination therapy and conventional therapy.
Single-pill-combination (SPC) antihypertensive drug products have been shown to improve compliance but are associated with higher acquisition costs. This study compared the clinical and economic outcomes associated with the use of an SPC of amlodipine/valsartan (trade name Exforge) with the outcomes from conventional combination therapy in patients failing to respond to initial monotherapy with either a dihydropyridine calcium channel blocker (DHP-CCB) or an angiotensin receptor blocker (ARB). We conducted a retrospective cohort study of hypertensive patients failing to respond to monotherapy with either a DHP-CCB or an ARB who were switched to an SPC of amlodipine/valsartan (SPC group) or to treatment that could not include any SPC (control group). The groups were matched for age, gender, race, baseline blood pressure (BP), and comorbidities. The primary outcomes of the study included the proportion of patients achieving BP targets, the absolute change in BP from baseline, the proportion of patients discontinuing drug therapy because of side effects, the proportion of patients non-compliant with drug therapy, and health care resource utilization and costs. Fifty-eight SPC patients achieved BP targets compared with 47 control patients (P = 0.119). The absolute reduction in BP was significantly greater in the SPC group (-22.8 +/- 6.9/-19.3 +/- 5.2 mmHg) than in the control group (-20.6 +/- 6.4/-17.8 +/- 5.6 mmHg) (P < 0.03). Significantly fewer patients discontinued anti-hypertensive therapy because of side effects and noncompliance in the SPC group compared with the control group (both P = 0.042). SPC patients accrued fewer clinic visits, laboratory tests, and electrocardiograms but had higher drug acquisition costs. Median medical therapy costs were significantly lower in the SPC group at the end of the 6-month follow-up, primarily because of lower costs for clinic visits. The use of the SPC of amlodipine/valsartan was associated with greater absolute BP reductions and fewer antihypertensive drug discontinuations because of side effects and noncompliance compared with the use of the individual drugs. Although the acquisition cost of the SPC was greater than that of the individual drugs, SPC combination therapy resulted in fewer clinic visits, laboratory tests, and electrocardiograms. As a result, the total cost of SPC therapy was significantly less than that associated with the use of the individual drug components.


Transcriptome profiling of Gossypium barbadense inoculated with Verticillium dahliae provides a resource for cotton improvement.
Verticillium wilt, caused by the fungal pathogen Verticillium dahliae, is the most severe disease in cotton (Gossypium spp.), causing great lint losses worldwide. Disease management could be achieved in the field if genetically improved, resistant plants were used. However, the interaction between V. dahliae and cotton is a complicated process, and its molecular mechanism remains obscure. To understand better the defense response to this pathogen as a means for obtaining more tolerant cultivars, we monitored the transcriptome profiles of roots from resistant plants of G. barbadense cv. Pima90-53 that were challenged with V. dahliae. In all, 46,192 high-quality expressed sequence tags (ESTs) were generated from a full-length cDNA library of G. barbadense. They were clustered and assembled into 23126 unigenes that comprised 2661 contigs and 20465 singletons. Those unigenes were assigned Gene Ontology terms and mapped to 289 KEGG pathways. A total of 3027 unigenes were found to be homologous to known defense-related genes in other plants. They were assigned to the functional classification of plant-pathogen interactions, including disease defenses and signal transduction. The branch of "SA→NPR1→TGA→PR-1→Disease resistance" was first discovered in the interaction of cotton-V. dahliae, indicating that this wilt process includes both biotrophic and necrotrophic stages. In all, 4936 genes coding for putative transcription factors (TF) were identified in our library. The most abundant TF family was the NAC group (527), followed by G2-like (440), MYB (372), BHLH (331), bZIP (271) ERF, C3H, and WRKY. We also analyzed the expression of genes involved in pathogen-associated molecular pattern (PAMP) recognition, the activation of effector-triggered immunity, TFs, and hormone biosynthesis, as well as genes that are pathogenesis-related, or have roles in signaling/regulatory functions and cell wall modification. Their differential expression patterns were compared among mock-/inoculated- and resistant/susceptible cotton. Our results suggest that the cotton defense response has significant transcriptional complexity and that large accumulations of defense-related transcripts may contribute to V. dahliae resistance in cotton. Therefore, these data provide a resource for cotton improvement through molecular breeding approaches. This study generated a substantial amount of cotton transcript sequences that are related to defense responses against V. dahliae. These genomics resources and knowledge of important related genes contribute to our understanding of host-pathogen interactions and the defense mechanisms utilized by G. barbadense, a non-model plant system. These tools can be applied in establishing a modern breeding program that uses marker-assisted selections and oligonucleotide arrays to identify candidate genes that can be linked to valuable agronomic traits in cotton, including disease resistance.


Combined treatment of Pseudomonas aeruginosa biofilm with lactoferrin and xylitol inhibits the ability of bacteria to respond to damage resulting from lactoferrin iron chelation.
With an ageing and ever more obese population, chronic wounds such as diabetic ulcers, pressure ulcers and venous leg ulcers are an increasingly relevant medical concern. Identification of bacterial biofilm contamination as a major contributor to non-healing wounds demands biofilm-targeted strategies to manage chronic wounds. Pseudomonas aeruginosa has been identified as a principal biofilm-forming opportunistic pathogen in chronic wounds. The innate immune molecule lactoferrin and the rare sugar alcohol xylitol have been demonstrated to be co-operatively efficacious against P. aeruginosa biofilms in vitro. Data presented here propose a model for the molecular mechanism behind this co-operative antimicrobial effect. Lactoferrin iron chelation was identified as the primary means by which lactoferrin destabilises the bacterial membrane. By microarray analysis, 183 differentially expressed genes of ≥ 1.5-fold difference were detected. Interestingly, differentially expressed transcripts included the operon encoding components of the pyochelin biosynthesis pathway. Furthermore, siderophore detection verified that xylitol is the component of this novel synergistic treatment that inhibits the ability of the bacteria to produce siderophores under conditions of iron restriction. The findings presented here demonstrate that whilst lactoferrin treatment of P. aeruginosa biofilms results in destabilisation of the bacterial cell membrane though iron chelation, combined treatment with lactoferrin and xylitol inhibits the ability of P. aeruginosa biofilms to respond to environmental iron restriction.


Automated virtual reality cognitive therapy versus virtual reality mental relaxation therapy for the treatment of persistent persecutory delusions in patients with psychosis (THRIVE): a parallel-group, single-blind, randomised controlled trial in England with mediation analyses.
Persecutory delusions are a major psychiatric problem that often do not respond sufficiently to standard pharmacological or psychological treatments. We developed a new brief automated virtual reality (VR) cognitive treatment that has the potential to be used easily in clinical services. We aimed to compare VR cognitive therapy with an alternative VR therapy (mental relaxation), with an emphasis on understanding potential mechanisms of action. THRIVE was a parallel-group, single-blind, randomised controlled trial across four UK National Health Service trusts in England. Participants were included if they were aged 16 years or older, had a persistent (at least 3 months) persecutory delusion held with at least 50% conviction, reported feeling threatened when outside with other people, and had a primary diagnosis from the referring clinical team of a non-affective psychotic disorder. We randomly assigned (1:1) patients to either THRIVE VR cognitive therapy or VR mental relaxation, using a permuted blocks algorithm with randomly varying block size, stratified by severity of delusion. Usual care continued for all participants. Each VR therapy was provided in four sessions over approximately 4 weeks, supported by an assistant psychologist or clinical psychologist. Trial assessors were masked to group allocation. Outcomes were assessed at 0, 2 (therapy mid-point), 4 (primary endpoint, end of treatment), 8, 16, and 24 weeks. The primary outcome was persecutory delusion conviction, assessed by the Psychotic Symptoms Rating Scale (PSYRATS; rated 0-100%). Outcome analyses were done in the intention-to-treat population. We assessed the treatment credibility and expectancy of the interventions and the two mechanisms (defence behaviours and safety beliefs) that the cognitive intervention was designed to target. This trial is prospectively registered with the ISRCTN registry, ISRCTN12497310. From Sept 21, 2018, to May 13, 2021 (with a pause due to COVID-19 pandemic restrictions from March 16, 2020, to Sept 14, 2020), we recruited 80 participants with persistent persecutory delusions (49 [61%] men, 31 [39%] women, with a mean age of 40 years [SD 13, range 18-73], 64 [80%] White, six [8%] Black, one [1%] Indian, three [4%] Pakistani, and six [8%] other race or ethnicity). We randomly assigned 39 (49%) participants assigned to VR cognitive therapy and 41 (51%) participants to VR mental relaxation. 33 (85%) participants who were assigned to VR cognitive therapy attended all four sessions, and 35 (85%) participants assigned to VR mental relaxation attended all four sessions. We found no significant differences between the two VR interventions in participant ratings of treatment credibility (adjusted mean difference -1·55 [95% CI -3·68 to 0·58]; p=0·15) and outcome expectancy (-0·91 [-3·42 to 1·61]; p=0·47). 77 (96%) participants provided follow-up data at the primary timepoint. Compared with VR mental relaxation, VR cognitive therapy did not lead to a greater improvement in persecutory delusions (adjusted mean difference -2·16 [-12·77 to 8·44]; p=0·69). Compared with VR mental relaxation, VR cognitive therapy did not lead to a greater reduction in use of defence behaviours (adjusted mean difference -0·71 [-4·21 to 2·79]; p=0·69) or a greater increase in belief in safety (-5·89 [-16·83 to 5·05]; p=0·29). There were 17 serious adverse events unrelated to the trial (ten events in seven participants in the VR cognitive therapy group and seven events in five participants in the VR mental relaxation group). The two VR interventions performed similarly, despite the fact that they had been designed to affect different mechanisms. Both interventions had high uptake rates and were associated with large improvements in persecutory delusions but it cannot be determined that the treatments accounted for the change. Immersive technologies hold promise for the treatment of severe mental health problems. However, their use will likely benefit from experimental research on the application of different therapeutic techniques and the effects on a range of potential mechanisms of action. Medical Research Council Developmental Pathway Funding Scheme and National Institute for Health and Care Research Oxford Health Biomedical Research Centre.


Short-term cardiovascular responses to rapid whole-body tilting during exercise.
Our objective was to characterize the responses of heart rate (HR) and arterial blood pressure (BP) to changes in posture during concomitant dynamic leg exercise. Ten men performed dynamic leg exercise at 50, 100, and 150 W and were rapidly and repeatedly tilted between supine (0 degrees ) and upright (80 degrees ) positions at 2-min intervals. Continuous recordings of BP and HR were made, and changes in central blood volume were estimated from transthoracic impedance. Short-lasting increases in BP were observed immediately upon tilting from the upright to the supine position (down-tilt), averaging +18 mmHg (50 W) to +31 mmHg (150 W), and there were equally short-lasting decreases in BP, ranging from -26 to -38 mmHg upon tilting from supine to upright (up-tilt). These components occurred for all pressure parameters (systolic, mean, diastolic, and pulse pressures). We propose that these transients reflect mainly tilt-induced changes in total peripheral resistance resulting from decreases and increases of the efficiency of the venous muscle pump. After 3-4 s (down-tilt) and 7-11 s (up-tilt) there were large HR transients in a direction opposite to the pressure transients. These HR transients were larger during the down-tilt (-15 to -26 beats. min(-1)) than during the up-tilt (+13 to +17 beats. min(-1)), and increased in amplitude with work intensity during the down-tilt. The tilt-induced HR fluctuations could be modelled as a basically linear function of an arterial baroreflex input from a site half-way between the heart and the carotid sinus, and with varying contributions of fast vagal and slow sympathetic HR responses resulting in attenuated tachycardic responses to hypotensive stimuli during exercise.


[Regional variations in homicide mortality in Jalisco, Mexico].
The present study describes regional variations in homicide rates in Jalisco State, Mexico, in 1989-1991, 1994-1996, and 1999-2000, analyzing the trends by gender and socioeconomic stratum. Using mortality data generated by the National Institute for Statistics, Geography, and Information Technology, homicide rates adjusted by age and gender were calculated, along with rate/female rate ratios; rate ratios by socioeconomic stratum and 95% confidence intervals were also calculated. According to the results, the homicide rate showed: a downward trend in the 1990s; a regional homicide mortality pattern, with the highest rates in peripheral regions, considered among the poorest areas in the State; municipalities with the lowest socioeconomic conditions also presenting a statistically significant excess homicide mortality; and an evident over-mortality from homicide among males. The results point to tasks and challenges for public health and law enforcement institutions, including the need to implement different inter-institutional policies that take into consideration the characteristics of homicide and violent crime in Jalisco.


Cold-sensitive cell-division-cycle mutants of yeast: isolation, properties, and pseudoreversion studies.
We isolated 18 independent recessive cold-sensitive cell-division-cycle (cdc) mutants of Saccharomyces cerevisiae, in nine complementation groups. Terminal phenotypes exhibited include medial nuclear division, cytokinesis, and a previously undescribed terminal phenotype consisting of cells with a single small bud and an undivided nucleus. Four of the cold-sensitive mutants proved to be alleles of CDC11, while the remaining mutants defined at least six new cell-division-cycle genes: CDC44, CDC45, CDC48, CDC49, CDC50 and CDC51.--Spontaneous revertants from cold-sensitivity of four of the medial nuclear division cs cdc mutants were screened for simultaneous acquisition of a temperature-sensitive phenotype. The temperature-sensitive revertants of four different cs cdc mutants carried single new mutations, called Sup/Ts to denote their dual phenotype: suppression of the cold-sensitivity and concomitant conditional lethality at 37 degrees. Many of the Sup/Ts mutations exhibited a cell-division-cycle terminal phenotype at the high temperature, and they defined two new cdc genes (CDC46 and CDC47). Two cold-sensitive medial nuclear division cdc mutants representing two different cdc genes were suppressed by different Sup/Ts alleles of another gene which also bears a medial nuclear division function (CDC46). In addition, the cold-sensitive medial nuclear division cdc mutant csH80 was suppressed by a Sup/Ts mutation yielding an unbudded terminal phenotype with an undivided nucleus at the high temperature. This mutation was an allele of CDC32. These results suggest a pattern of interaction among cdc gene products and indicate that cdc gene proteins might act in the cell cycle as complex specific functional assemblies.


Efficacy and safety of factor VIII/von Willebrand's factor concentrate (Haemate-P) in preventing bleeding during surgery or invasive procedures in patients with von Willebrand disease.
To evaluate the efficacy and safety of the factor VIII/von Willebrand factor concentrate Haemate-P as replacement therapy in patients with von Willebrand's disease (VWD) undergoing surgical or invasive procedures. Between January 1996 and October 2002, 26 patients (12 males and 14 females, median age 41.5 years, range 9-80 years), followed at three Italian Hemophilia Centers (Trento, Verona and Parma), with VWD type 1 (19 cases) and VWD type 2B (7 cases), underwent 43 surgical or invasive procedures: major surgery (14 cases), minor surgery (11 cases), dental extractions (11 cases), invasive diagnostic procedures (7 cases). Replacement therapy with factor VIII/von Willebrand factor concentrate (Haemate-P) was administered in the surgical setting as perioperative prophylaxis against excessive bleeding. The mean total dose (range) of Haemate-P used for major surgery was 284.1 IU VWF:RCo/kg (range 125.0-976.4), for minor surgery it was 120.8 IU VWF:RCo/kg (range 42.9-173.3), for dental extractions it was 38.4 IU VWF:RCo/kg (range 23.5-100.0) and for invasive procedures it was 87.3 VWF:RCo/kg (range 27.3-160.0). We recorded one bleeding episode 3 days after multiple dental extractions in a patient with severe periodontal disease; this bleeding was controlled with 2 further administrations of concentrate. We did not observe thrombotic episodes or other side effects following infusion of the concentrate. In conclusion, Haemate-P was effective and safe in preventing excessive bleeding after major and minor surgery or invasive procedures in VWD patients.


A social model for health promotion for an aging population: initial evidence on the Experience Corps model.
This report evaluates whether a program for older volunteers, designed for both generativity and health promotion, leads to short-term improvements in multiple behavioral risk factors and positive effects on intermediary risk factors for disability and other morbidities. The Experience Corps(R) places older volunteers in public elementary schools in roles designed to meet schools' needs and increase the social, physical, and cognitive activity of the volunteers. This article reports on a pilot randomized trial in Baltimore, Maryland. The 128 volunteers were 60-86 years old; 95% were African American. At follow-up of 4-8 months, physical activity, strength, people one could turn to for help, and cognitive activity increased significantly, and walking speed decreased significantly less, in participants compared to controls. In this pilot trial, physical, cognitive, and social activity increased, suggesting the potential for the Experience Corps to improve health for an aging population and simultaneously improve educational outcomes for children.


Impact of the new european paediatric regulatory framework on ethics committees: overview and perspectives.
To evaluate the impact of the new European paediatric regulatory framework on the activities of Ethics Committees operating in Europe and to assess their involvement and interest in paediatric research. Task-force in Europe for Drug Development for the Young Network of Excellence and Relating Expectations and Needs to the Participation and Empowerment of Children in Clinical Trials project set up an inventory of Ethics Committees existing in Europe and conducted a survey on their approach to paediatric trials. Ethics Committees operating in 22 European Countries participated in this survey. Results showed a high lack of knowledge, understanding and awareness of the current European paediatric regulatory framework and a lack of involvement of Ethics Committees in paediatric research, especially in terms of training and education, demonstrated also by the decreasing number of Ethics Committees answering exhaustively to the whole questionnaire. The majority of participating Ethics Committees expressed interest in future initiatives related to paediatric research. Despite a limited knowledge and understanding of the current paediatric regulatory framework, a significant number of Ethics Committees operating in Europe show interest in initiatives related to paediatric research. Networking may be an essential tool to be used to enhance Ethics Committees role in supporting paediatric research. Any initiative should be undertaken at European level in collaboration with European Union Institutions.


Removal of ammonium ions by laboratory-synthesized zeolite linde type A adsorption from water samples affected by mining activities in Ghana.
Ammonium ion adsorption by laboratory-synthesized zeolite (linde type A; LTA) was investigated in batch kinetics experiments. Synthesized zeolite LTA was characterized by X-ray diffraction, scanning electron microscopy, energy-dispersive X-ray spectroscopy, thermogravimetric analysis, Fourier transform infrared spectroscopy and particle size analysis. Water samples were taken from the Nyam and Tano rivers in Ghana, and 0.8 g of zeolite was added to 100 ml portions of each sample. Portions of the samples were withdrawn every 30 min for 150 min and the concentration of ammonia in each sample was determined. The removal efficiency of zeolite LTA was evaluated by retrieving the zeolite from the water samples and adding to a fresh sample to repeat the process. Equilibrium data were fitted by Langmuir and Freundlich isotherms. Maximum adsorption capacities were 72.99 mg g(-1) for samples from the River Nyam and 72.87 mg g(-1) for samples from the River Tano. The equilibrium kinetic data were analysed using adsorption kinetic models: pseudo-first order and pseudo-second order kinetic models. Linear regression was used to estimate the adsorption and kinetic parameters. The results showed that the adsorption followed pseudo-second order kinetics and suggest that zeolite LTA is a good adsorbent for the removal of nitrogen ammonia from water.


Current Status of Rift Valley Fever Vaccine Development.
Rift Valley Fever (RVF) is a mosquito-borne zoonotic disease that presents a substantial threat to human and public health. It is caused by Rift Valley fever phlebovirus (RVFV), which belongs to the genus Phlebovirus and the family Phenuiviridae within the order Bunyavirales. The wide distribution of competent vectors in non-endemic areas coupled with global climate change poses a significant threat of the transboundary spread of RVFV. In the last decade, an improved understanding of the molecular biology of RVFV has facilitated significant progress in the development of novel vaccines, including DIVA (differentiating infected from vaccinated animals) vaccines. Despite these advances, there is no fully licensed vaccine for veterinary or human use available in non-endemic countries, whereas in endemic countries, there is no clear policy or practice of routine/strategic livestock vaccinations as a preventive or mitigating strategy against potential RVF disease outbreaks. The purpose of this review was to provide an update on the status of RVF vaccine development and provide perspectives on the best strategies for disease control. Herein, we argue that the routine or strategic vaccination of livestock could be the best control approach for preventing the outbreak and spread of future disease.


Optimization of Protein and Peptide Drugs Based on the Mechanisms of Kidney Clearance.
Development of proteins and peptides into drugs has been considered as a promising strategy to target certain diseases. However, only few proteins and peptides have been approved as new drugs into the market each year. One major problem is that proteins and peptides often exhibit short plasma half-life times, which limits the application for their clinical use. In most cases a short half-life time is not effective to deliver sufficient amount of drugs to the target organs and tissues, which is generally caused by fast renal clearance and low plasma stability due to proteolytic degradation during systemic circulation, because that the most common clearance pathway of small proteins and peptides is through glomerular filtration by the kidneys. In this review, enzymatic degradation of proteins and peptides were discussed. Furthermore, several approaches to lengthen the half-life of peptides and proteins drugs based on the unique structures of glomerular capillary wall and the mechanisms of glomerular filtration were summarized, such as increasing the size and hydrodynamic diameter; increasing the negative charge to delay the filtration; increasing plasma protein binding to decrease plasma clearance.