Preexposure prophylaxis for HIV infection among African women.
Preexposure prophylaxis with antiretroviral drugs has been effective in the prevention of human immunodeficiency virus (HIV) infection in some trials but not in others. In this randomized, double-blind, placebo-controlled trial, we assigned 2120 HIV-negative women in Kenya, South Africa, and Tanzania to receive either a combination of tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) or placebo once daily. The primary objective was to assess the effectiveness of TDF-FTC in preventing HIV acquisition and to evaluate safety. HIV infections occurred in 33 women in the TDF-FTC group (incidence rate, 4.7 per 100 person-years) and in 35 in the placebo group (incidence rate, 5.0 per 100 person-years), for an estimated hazard ratio in the TDF-FTC group of 0.94 (95% confidence interval, 0.59 to 1.52; P=0.81). The proportions of women with nausea, vomiting, or elevated alanine aminotransferase levels were significantly higher in the TDF-FTC group (P=0.04, P<0.001, and P=0.03, respectively). Rates of drug discontinuation because of hepatic or renal abnormalities were higher in the TDF-FTC group (4.7%) than in the placebo group (3.0%, P=0.051). Less than 40% of the HIV-uninfected women in the TDF-FTC group had evidence of recent pill use at visits that were matched to the HIV-infection window for women with seroconversion. The study was stopped early, on April 18, 2011, because of lack of efficacy. Prophylaxis with TDF-FTC did not significantly reduce the rate of HIV infection and was associated with increased rates of side effects, as compared with placebo. Despite substantial counseling efforts, drug adherence appeared to be low. (Supported by the U.S. Agency for International Development and others; FEM-PrEP ClinicalTrials.gov number, NCT00625404.).


The anatomical distribution of plasma fibrinolytic activity in man during cardiac catheterisation.
Regional circulating plasma levels of fibrinolytic activity were assessed in 15 patients undergoing cardiac catheterisation. The euglobulin clot lysis time (ECLT) was longer in the abdominal aorta (AA) than the inferior vena cava (IVC), (median difference -17.5 min, p = 0.008). This was associated with higher inhibition of plasminogen activator activity (PAI) in the AA than IVC, -1.75 IU/ml, p = 0.002. In the venous circulation the ECLT was higher in the peripheral venous sample than in the IVC, -25.5 min, p = 0.003, with higher PAI peripherally than in the IVC, -1.9 IU/ml, p = 0.001. There were no differences in ECLT, PAI, PAI-1:Ag or t-PA:Ag throughout the arterial circulation. These results demonstrate higher fibrinolytic activity with lower inhibitor activity in the venous compared to the arterial circulation. Within the venous circulation fibrinolytic activity is lower peripherally with increased inhibitor activity.


Participation of reactive oxygen species in diabetes-induced endothelial dysfunction.
In the present study, the relationship between diabetes-induced hyperglycemia, reactive oxygen species production and endothelium-mediated arterial function was examined. The effect of antioxidant on the reactive oxygen species induced damage was tested. Diabetes was induced by streptozotocin (STZ), 3 x 30 mg/kg i.p., administered on three consecutive days. After 10 weeks of diabetes, the functional state of the endothelium of the aorta was tested, endothelemia evaluation was performed and systolic blood pressure was measured. Reactive oxygen species (ROS) formation in blood and the aorta was measured using luminol-enhanced chemiluminescence (CL). Levels of reduced glutathione (GSH) were determined in the aorta, kidney, and plasma. To study the involvement of hyperglycemia in functional impairment of the endothelium, aortal rings incubated in solution with high glucose concentration were tested in in vitro experiments. After 10 weeks of diabetes, endothelial injury was observed, exhibited by diminished endothelium-dependent relaxation of the aorta, increased endothelemia and by elevated systolic blood pressure. Using luminol-enhanced CL, a significant increase of ROS production was found in arterial tissue and blood. GSH levels were significantly increased in the kidney, while there were no GSH changes in plasma and the aorta. Incubation of aortic rings in solution with high glucose concentration led to impairment of endothelium-dependent relaxation. The synthetic antioxidant SMe1EC2 was able to restore reduced endothelium-mediated relaxation. Our results suggest an important role of hyperglycemia-induced ROS production in mediating endothelial dysfunction in experimental diabetes, confirmed by CL and the protective effect of the antioxidant SMe1EC2.


Turbo-SMT: Accelerating Coupled Sparse Matrix-Tensor Factorizations by 200×.
How can we correlate the neural activity in the human brain as it responds to typed words, with properties of these terms (like 'edible', 'fits in hand')? In short, we want to find latent variables, that jointly explain both the brain activity, as well as the behavioral responses. This is one of many settings of the Coupled Matrix-Tensor Factorization (CMTF) problem. Can we accelerate any CMTF solver, so that it runs within a few minutes instead of tens of hours to a day, while maintaining good accuracy? We introduce TURBO-SMT, a meta-method capable of doing exactly that: it boosts the performance of any CMTF algorithm, by up to 200×, along with an up to 65 fold increase in sparsity, with comparable accuracy to the baseline. We apply TURBO-SMT to BRAINQ, a dataset consisting of a (nouns, brain voxels, human subjects) tensor and a (nouns, properties) matrix, with coupling along the nouns dimension. TURBO-SMT is able to find meaningful latent variables, as well as to predict brain activity with competitive accuracy.


The effect of foot orthoses on standing foot posture and gait of young children with Down syndrome.
The purpose of this study was to determine if foot orthoses (FOs) immediately affected gait of children with Down Syndrome (DS) and excessively pronated feet. Subjects were 3--6 years old; 16 with DS and 10 without disabilities. Gait of children with DS wearing sneakers was compared with and without FOs and compared to gait of children without disabilities. Ankle moment, walking speed during stance phase, sneaker prints, center of pressure, and transverse plane foot angles were collected and compared. In standing, heel eversion was reduced when the children wore FOs (p=0.000). During gait the transverse plane foot angle decreased indicating more internal rotation with FOs (p=0.000). Trial-to-trial variability of pronation-supination index (p=0.0001), foot length contact (p=0.0001), transverse plane foot angle (p=0.0003), and walking speed (p=0.0001) all decreased with FO use. Trial-to-trial variability of normalized peak ankle moment (p=0.0001), and of phase of peak ankle moment (p=0.0001) increased when the children wore FOs.


Strength training effects of whole-body vibration?
Whole-body vibration (WBV) has been suggested to have a beneficial effect on muscle strength. Manufacturers of vibration platforms promote WBV as an effective alternative or complement to resistance training. This study aimed to review systematically the current (August 2005) scientific support for effects of WBV on muscle strength and jump performance. MEDLINE and SPORT DISCUS were searched for the word vibration in combination with strength or training. Twelve articles were included in the final analysis. In four of the five studies that used an adequate design with a control group performing the same exercises as the WBV group, no difference in performance improvement was found between groups, suggesting no or only minor additional effects of WBV as such. Proposed neural mechanisms are discussed.


Detection of bacterial contamination in food matrices by integration of quorum sensing in a paper-strip test.
There are an estimated 48 million cases of foodborne illness in the United States every year. In general, these illnesses are the result of unintentional contamination and improper food handling. Because bacterial contamination plays a major role in food spoilage and, hence, in foodborne illnesses, it is important to design easy, portable methods to detect bacteria in food. Quorum sensing (QS) enables bacteria to communicate with one another and by doing so they can modulate their behavior in a cell-density dependent manner. In bacteria, quorum sensing molecules (QSMs) are known to control several factors such as virulence factor production, antibiotic production, biofilm formation, and gene regulation. Herein, we demonstrate the applicability of whole cell biosensing systems for the early identification of food contamination via detection of QSMs. Additionally, we have developed a portable system for detection of bacterial contamination using microdots of immobilized whole cell-based biosensors on paper that boast nanomolar level detection of QSMs in two different food matrices, namely beef and milk. Limits of detection ranged from 1 × 10-7 M to 1 × 10-9 M with relative standard deviations (RSDs) of 1-16%. This rapid, easy, and portable test could be a useful tool for use in the field and during all stages of food manipulation, i.e., from farms to distribution, storage, sales, and preparation prior to consumption, to ensure that food is free of bacterial contamination.


Chronic Toxoplasma infection is associated with distinct alterations in the synaptic protein composition.
Chronic infection with the neurotropic parasite Toxoplasma gondii has been implicated in the risk for several neuropsychiatric disorders. The mechanisms, by which the parasite may alter neural function and behavior of the host, are not yet understood completely. Here, a novel proteomic approach using mass spectrometry was employed to investigate the alterations in synaptic protein composition in a murine model of chronic toxoplasmosis. In a candidate-based strategy, immunoblot analysis and immunohistochemistry were applied to investigate the expression levels of key synaptic proteins in glutamatergic signaling. A comparison of the synaptosomal protein composition revealed distinct changes upon infection, with multiple proteins such as EAAT2, Shank3, AMPA receptor, and NMDA receptor subunits being downregulated, whereas inflammation-related proteins showed an upregulation. Treatment with the antiparasitic agent sulfadiazine strongly reduced tachyzoite levels and diminished neuroinflammatory mediators. However, in both conditions, a significant number of latent cysts persisted in the brain. Conversely, infection-related alterations of key synaptic protein levels could be partly reversed by the treatment. These results provide evidence for profound changes especially in synaptic protein composition in T. gondii-infected mice with a downregulation of pivotal components of glutamatergic neurotransmission. Our results suggest that the detected synaptic alterations are a consequence of the distinct neuroinflammatory milieu caused by the neurotropic parasite.


Genetics of osteoporosis.
Osteoporosis is a common multifactorial disorder of reduced bone mass. The disorder in its most common form is generalized, affecting the elderly, both sexes, and all racial groups. Multiple environmental factors are involved in the pathogenesis. Genes also play a major role as reflected by heritability of many components of bone strength. Quantitative phenotypes in bone strength in the normal population do not conform to a monogenetic mode of inheritance. The common form of osteoporosis is generally considered to be a polygenic disorder arising from the interaction of common polymorphic alleles at quantitative trait loci, with multiple environmental factors. Finding the susceptibility genes underlying osteoporosis requires identifying specific alleles that coinherit with key heritable phenotypes in bone strength. Because of the close correspondence among mammalian genomes, identification of the genes underlying bone strength in mammals such as the mouse is likely to be of major assistance in human studies. Identification of susceptibility genes for osteoporosis is one of several important approaches toward the long-term goal of understanding the molecular biology of the normal variation in bone strength and how it may be modified to prevent osteoporosis. As with all genetic studies in humans, these scientific advances will need to be made in an environment of legal and ethical safeguards that are acceptable to the general public.


Molecular mechanism of activation and superactivation of Ret tyrosine kinases by ultraviolet light irradiation.
The catalytic activities of Ret tyrosine kinases as the products of oncogene RET with multiple endocrine neoplasia type 2A (Ret-MEN2A) or 2B (Ret-MEN2B) mutations and the hybrid gene from c-RET and RFP (Rfp-Ret) were higher than those of c-Ret. We demonstrated that ultraviolet light (UV) irradiation induced activation of c-Ret and superactivation of genetically mutated, and thereby constitutively activated, Ret-MEN2A, Ret-MEN2B, and Rfp-Ret. We found that small proportions of c-Ret and Ret-MEN2B and a large proportion of MEN2A were dimerized due to disulfide bonds and that high kinase activity resided in these fractions. The UV-induced activation of c-Ret and superactivation of Ret-MEN2A and Ret-MEN2B were then shown to be closely associated with promotion of the disulfide bond-mediated dimerization of the Ret proteins. Furthermore, we showed that a large proportion of Rfp-Ret was dimerized or polymerized and that almost all kinase activities resided in the highly polymerized but not dimerized fraction. The UV-induced superactivation of Rfp-Ret was also found to be closely associated with promotion of polymerization but not with dimerization of Rfp-Ret. Further experiments revealed that UV induced intracellular dimerization and activation of the extracellular domain-deleted mutant Ret (Ret-PTC-1). Most importantly, the levels of basal kinase activity and dimerization of Ret-TPC-1-C376A, in which cysteine 376 in the tyrosine kinase domain of Ret-TPC-1 was replaced with alanine, were low and were not increased by UV irradiation. These results suggest that the cysteine at this position works as the primary target of dimerization of Ret proteins inside the cell for both the maintenance of the basal kinase activity and its promotion by UV, possibly in co-operation with the cysteine(s) in the extracellular domain of Ret-MEN2A and Rfp-Ret, which is the target of dimerization and polymerization outside the cell. The potential biological significance of the UV-mediated superactivation of mutant Ret through the newly proposed mechanism in oncogenesis is discussed.


Heart Disease Death Rates Among Blacks and Whites Aged ≥35 Years - United States, 1968-2015.
Heart disease is the leading cause of death in the United States. In 2015, heart disease accounted for approximately 630,000 deaths, representing one in four deaths in the United States. Although heart disease death rates decreased 68% for the total population from 1968 to 2015, marked disparities in decreases exist by race and state. 1968-2015. The National Vital Statistics System (NVSS) data on deaths in the United States were abstracted for heart disease using diagnosis codes from the eighth, ninth, and tenth revisions of the International Classification of Diseases (ICD-8, ICD-9, and ICD-10) for 1968-2015. Population estimates were obtained from NVSS files. National and state-specific heart disease death rates for the total population and by race for adults aged ≥35 years were calculated for 1968-2015. National and state-specific black-white heart disease mortality ratios also were calculated. Death rates were age standardized to the 2000 U.S. standard population. Joinpoint regression was used to perform time trend analyses. From 1968 to 2015, heart disease death rates decreased for the total U.S. population among adults aged ≥35 years, from 1,034.5 to 327.2 per 100,000 population, respectively, with variations in the magnitude of decreases by race and state. Rates decreased for the total population an average of 2.4% per year, with greater average decreases among whites (2.4% per year) than blacks (2.2% per year). At the national level, heart disease death rates for blacks and whites were similar at the start of the study period (1968) but began to diverge in the late 1970s, when rates for blacks plateaued while rates for whites continued to decrease. Heart disease death rates among blacks remained higher than among whites for the remainder of the study period. Nationwide, the black-white ratio of heart disease death rates increased from 1.04 in 1968 to 1.21 in 2015, with large increases occurring during the 1970s and 1980s followed by small but steady increases until approximately 2005. Since 2005, modest decreases have occurred in the black-white ratio of heart disease death rates at the national level. The majority of states had increases in black-white mortality ratios from 1968 to 2015. The number of states with black-white mortality ratios >1 increased from 16 (40%) to 27 (67.5%). Although heart disease death rates decreased both for blacks and whites from 1968 to 2015, substantial differences in decreases were found by race and state. At the national level and in most states, blacks experienced smaller decreases in heart disease death rates than whites for the majority of the period. Overall, the black-white disparity in heart disease death rates increased from 1968 to 2005, with a modest decrease from 2005 to 2015. Since 1968, substantial increases have occurred in black-white disparities of heart disease death rates in the United States at the national level and in many states. These increases appear to be due to faster decreases in heart disease death rates for whites than blacks, particularly from the late 1970s until the mid-2000s. Despite modest decreases in black-white disparities at the national level since 2005, in 2015, heart disease death rates were 21% higher among blacks than among whites. This study demonstrates the use of NVSS data to conduct surveillance of heart disease death rates by race and of black-white disparities in heart disease death rates. Continued surveillance of temporal trends in heart disease death rates by race can provide valuable information to policy makers and public health practitioners working to reduce heart disease death rates both for blacks and whites and disparities between blacks and whites.


Clinical manifestations of actinomycosis in Southern Taiwan.
Actinomycosis is an uncommon and frequently misdiagnosed infection that may present as an acute or indolent process. Even when clinical suspicion is high, the disease is commonly confused with other chronic inflammatory diseases and malignancy. An early diagnosis helps the clinician in deciding treatment and can avoid physical morbidity such as unwarranted surgery. We retrospectively evaluated the histopathology and selected clinical information on all cases of actinomycosis that occurred at Kaohsiung Veterans General Hospital in Taiwan from 1993 to 2005. Data on the demographic characteristics, predisposing conditions, clinical presentations, diagnosis and treatment were analyzed. A total 36 cases of actinomycosis were identified and evaluated. The mean age of patients was 52.14 +/- 13.28 years, and the male-to-female ratio was 1:1.1. Only three types of actinomycosis were found in this study: cervicofacial, at an incidence of 31%; thoracic (33%); and pelvic (36%). The clinical manifestations depended upon the region of infection; the most frequent presentations of cervicofacial, thoracic and pelvic actinomycosis were cutaneous soft tissue swelling with drainage sinus formation (55%), hemotypsis (75%) and abnormal vaginal spotting (54%), respectively. The most common initial laboratory abnormalities were normochromic anemia (69%) and leukocytosis (25%). While most patients had no history of a foreign body, all pelvic actinomycotic patients had a history of intrauterine device use. Nineteen patients (53%) had no comorbid conditions and 11 patients (31%) had malignancy. Most patients were initially diagnosed as malignancy (56%). All patients with actinomycosis were diagnosed by histopathologic findings. Twenty two patients (61%) were treated by surgery combined with antibiotics, 11 patients (31%) by surgery only and 3 patients (8%) by antibiotics only. No recurrence or mortality occurred. Actinomycosis should be included in the differential diagnosis when patients present with chronic drainage sinus, chronic hemoptysis and abnormal vaginal spotting with use of intrauterine devices.


Time-varying covariates and coefficients in Cox regression models.
Time-varying covariance occurs when a covariate changes over time during the follow-up period. Such variable can be analyzed with the Cox regression model to estimate its effect on survival time. For this it is essential to organize the data in a counting process style. In situations when the proportional hazards assumption of the Cox regression model does not hold, we say that the effect of the covariate is time-varying. The proportional hazards assumption can be tested by examining the residuals of the model. The rejection of the null hypothesis induces the use of time varying coefficient to describe the data. The time varying coefficient can be described with a step function or a parametric time function. This article aims to illustrate how to carry out statistical analyses in the presence of time-varying covariates or coefficients with R.


Fate of abstracts presented at an International Commission on Occupational Health (ICOH) congress--followed by publication in peer-reviewed journals?
Presentations at international meetings offer an excellent way to disseminate current research findings. One measure of the quality of research is its subsequent publication. Our study aimed to determine the publication rate of abstracts presented at a congress of the International Commission of Occupational Health (ICOH), and to identify predictive factors of publication and differences between presented abstracts and -subsequently published papers. We identified a random sample of 318 abstracts presented at the 2000 ICOH meeting from the book of abstracts. Using Medline and Embase, we assessed their publication rate in the period ranging from 1998 to 2006 and investigated the factors associated with publication rate. Of 318 abstracts originating from 51 countries, 105 articles [33%, 95% confidence interval (95% CI) 27-38)] were subsequently published in 67 journals indexed in Medline or Embase. Mean time to publication was 17 months (95% CI 13-21). Multivariate analysis revealed that abstracts with quantitative data and written by authors originating from developed countries were significantly more published. From the time of abstract presentation to publication in a peer-reviewed journal, both the study sample size and the first author frequently changed (respectively 25% and 29%), but the overall conclusions remained stable, except in one case. Most of the abstracts presented at the 2000 ICOH congress were not subsequently published as full research reports. If this is the case for most abstracts submitted to conferences, this may limit the ability of a reader to judge the validity, reliability, and generalizability of the research presented. Caution is advised when referencing or generalizing from abstracts that have not been subsequently published in full.


Chronic stress, depressive symptoms, anger, hostility, and risk of stroke and transient ischemic attack in the multi-ethnic study of atherosclerosis.
This study investigated chronic stress, depressive symptoms, anger, and hostility in relation to incident stroke and transient ischemic attacks in middle-aged and older adults. Data were from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based cohort study of 6749 adults, aged 45 to 84 years and free of clinical cardiovascular disease at baseline, conducted at 6 US sites. Chronic stress, depressive symptoms, trait anger, and hostility were assessed with standard questionnaires. The primary outcome was clinically adjudicated incident stroke or transient ischemic attacks during a median follow-up of 8.5 years. One hundred ninety-five incident events (147 strokes; 48 transient ischemic attacks) occurred during follow-up. A gradient of increasing risk was observed for depressive symptoms, chronic stress, and hostility (all P for trend ≤0.02) but not for trait anger (P>0.10). Hazard ratios (HRs) and 95% confidence intervals indicated significantly elevated risk for the highest-scoring relative to the lowest-scoring group for depressive symptoms (HR, 1.86; 95% confidence interval, 1.16-2.96), chronic stress (HR, 1.59; 95% confidence interval, 1.11-2.27), and hostility (HR, 2.22; 95% confidence interval, 1.29-3.81) adjusting for age, demographics, and site. HRs were attenuated but remained significant in risk factor-adjusted models. Associations were similar in models limited to stroke and in secondary analyses using time-varying variables. Higher levels of stress, hostility, and depressive symptoms are associated with significantly increased risk of incident stroke or transient ischemic attacks in middle-aged and older adults. Associations are not explained by known stroke risk factors.


Acute copper exposure induces oxidative stress and cell death in lateral line hair cells of zebrafish larvae.
Numerous physical and chemical agents can destroy mechanosensory hair cells in the inner ear of vertebrates, a process that is irreversible in mammals. Few experimental systems allow the observation of hair cell death mechanisms in vivo, in the intact animal, one of these being the lateral line system in the zebrafish. In this work we characterize the behavior of dying lateral line hair cells in fish exposed to low doses of copper in the water. The concentration of copper used in our study kills hair cells in a few hours, but removal of the metal is followed by robust regeneration of new hair cells. We use a combination of membrane and nuclear live stains, ultrastructural analysis and measurement of reactive oxygen species to characterize the events leading to the death of hair cells under these conditions. Our results show that a combination of necrotic cell death, accompanied by apoptotic features such as rapid DNA fragmentation, lead to the loss of these cells. We also show that hair cells exposed to copper undergo oxidative stress and that antioxidants can protect these cells from the effects of the metal. The study of this process in the zebrafish lateral line allows rapid morphological analysis of hair cell death and may be used as an efficient end point for molecule screens aimed at preventing these effects.


Biological characteristics of three co-occurring species of armorhead from different genera vary markedly from previous results for the Pentacerotidae.
Biological characteristics of Pentaceropsis recurvirostris, Paristiopterus gallipavo and Parazanclistius hutchinsi were determined from commercial gillnet samples from temperate south-western Australian coastal waters. Growth zones in otoliths, with more than a few such zones, were readily detectable only after the otoliths had been sectioned. Visual analyses and modelling of the trends in marginal increments on sectioned otoliths demonstrate that these opaque zones are formed annually. Maximum ages of 55, 36 and 49 years, derived for P. recurvirostris, P. gallipavo and P. hutchinsi, respectively, reflect relatively low mortalities. These longevities greatly exceed those estimated, using otoliths, for Pentaceros wheeleri and Pentaceros richardsoni, which belong to the other pentacerotid subfamily. These differences may be due to the counts of 'daily' growth zones in sectioned otoliths of P. wheeleri not representing the complete age range of that species and the zones detected in whole otoliths of P. richardsoni not constituting the complete range of annually-formed zones. Pentaceropsis recurvirostris, P. gallipavo and P. hutchinsi recruited into the fishery in the sampling area as 2-3 year-old fishes. Pentaceropsis recurvirostris and P. hutchinsi exhibited little or no subsequent growth throughout the remainder of their protracted life, whereas, P. gallipavo continued to grow for c. 5 years and then underwent little further growth. Spawning of P. recurvirostris and P. hutchinsi peaked in the austral winter and autumn, respectively, but in the austral spring and summer with P. gallipavo, which is more typical of temperate species. Although the females of P. gallipavo and P. hutchinsi were mature, this did not apply to a few P. recurvirostris, some of which were >20 years old, implying that any given female of this species does not always spawn every year. Ovarian mass greatly exceeded testis mass, indicative of pair spawning, which is consistent with field observations. In contrast to P. recurvirostris and P. hutchinsi, the sex ratio was heavily biased towards males and the spawning period longer in P. gallipavo, suggesting that selection pressures for spawning success were greater for this latter species.


Long-term oral platelet glycoprotein IIb/IIIa receptor antagonism with sibrafiban after acute coronary syndromes: study design of the sibrafiban versus aspirin to yield maximum protection from ischemic heart events post-acute coronary syndromes (SYMPHONY) trial. Symphony Steering Committee.
Despite progress, atherosclerotic vascular disease remains a major cause of morbidity and mortality. Intravenous therapy with platelet glycoprotein (GP) IIb/IIIa receptor antagonists improves outcome in patients with acute coronary syndromes (ACS). Whether potent long-term antiplatelet therapy with oral GP IIb/IIIa antagonists will further improve outcome at a dose that is tolerable in long-term treatment is unknown. SYMPHONY (Sibrafiban versus aspirin to Yield Maximum Protection from ischemic Heart events post-acute cOroNary syndromes) was a randomized, double-blind, aspirin-controlled trial with 2 concentration regimens of sibrafiban, an oral peptidomimetic GP IIb/IIIa antagonist, for long-term treatment instead of aspirin in patients after an ACS. Patients were eligible for SYMPHONY if they presented within 7 days of an ACS (>/=20 minutes of ischemic symptoms), had been clinically stable for at least 12 hours, and met one of the following inclusion criteria: ST-segment depression or elevation of at least 0.5 mm or new left bundle branch block with the ACS or elevated creatinine kinase MB more than the upper limit of normal and >3% of total creatine kinase or, if creatine kinase MB was not measured, an elevated level of troponin T or I. Approximately 9000 patients post ACS were randomized 1:1:1 to treatment with either aspirin (80 mg every 12 hours) or high-dose or low-dose sibrafiban every 12 hours. Assignment of tablet strength (3, 4.5, or 6 mg) within the sibrafiban arms was based on body weight and renal function to achieve a target steady-state plasma concentration. The duration of study drug therapy was 90 days. Patients who had intracoronary stenting during the course of the study initially received a blinded stent medication assignment for 2 to 4 weeks based on their initial randomization as follows: aspirin/ticlopidine 250 mg twice daily, low-dose sibrafiban/ticlopidine placebo twice daily, and high-dose sibrafiban/ticlopidine placebo twice daily. After the second interim safety assessment by the Data and Safety Monitoring Board the stent regimen for the low-dose group was modified to include ticlopidine 250 mg twice daily. The primary efficacy end point of SYMPHONY was the 90-day incidence of a composite of all-cause mortality, myocardial infarction or reinfarction, and severe recurrent ischemia. A clinical events classification committee was established to determine the end points of reinfarction and severe recurrent ischemia. The primary safety end points were the incidence of major bleeding or minor bleeding and the combined incidence of major and minor bleeding. Bleeding classification was done by computer algorithm. Tolerability was assessed by the rate of study drug discontinuation from bleeding.


Deletion of ATG5 shows a role of autophagy in salivary homeostatic control.
Autophagy is a catabolic pathway utilized to maintain a balance among the synthesis, degradation, and recycling of cellular components, thereby playing a role in cell growth, development, and homeostasis. Previous studies revealed that a conditional knockout of essential member(s) of autophagy in a variety of tissues causes changes in structure and function of these tissues. Acinar cell-specific expression of knocked-in Cre recombinase through control of aquaporin 5 (Aqp5) promoter/enhancer (Aqp5-Cre) allows us to specifically inactivate Atg5, a protein necessary for autophagy, in salivary acinar cells of Atg5(f/f);Aqp5-Cre mice. There was no difference in apoptotic or proliferation levels in salivary glands of Atg5/Cre mice from each genotype. However, H&E staining and electron microscopy studies revealed modestly enlarged acinar cells and accumulated secretory granules in salivary glands of Atg5(f/f);Aqp5-Cre mice. Salivary flow rates and amylase contents of Atg5/Cre mice indicated that acinar-specific inactivation of ATG5 did not alter carbachol-evoked saliva and amylase secretion. Conversely, autophagy intersected with salivary morphological and secretory manifestations induced by isoproterenol administration. These results identified a role for autophagy as a homeostasis control in salivary glands. Collectively, Atg5(f/f);Aqp5-Cre mice would be a useful tool to enhance our understanding of autophagy in adaptive responses following targeted head and neck radiation or Sjögren syndrome.


Long-term effects of modest weight loss in type II diabetic patients.
Since most obese patients with type II diabetes are unable to achieve ideal body weight, this study examined whether more modest weight losses would provide a long-term benefit. Type II diabetic patients (N = 114) were treated in a behavioral weight control program and followed up for one year. Weight loss was significantly correlated with improvements in glycosylated hemoglobin values at posttreatment (r = .55) and one year (r = .51). Patients who lost more than 6.9 kg or had more than 5% reduction in body weight had significant improvements in glycosylated hemoglobin values at one year, while patients losing less weight had nonsignificant changes and those gaining weight had significant worsening. Thus, modest weight loss can have a long-term impact on glycemic control. However, the improvement in glycemic control for a given weight loss was greater initially than at one year, suggesting that energy restriction, in addition to weight loss, may contribute to initial improvement. Neither percent overweight nor diabetes treatment affected weight loss.


Self domestication and the evolution of language.
We set out an account of how self-domestication plays a crucial role in the evolution of language. In doing so, we focus on the growing body of work that treats language structure as emerging from the process of cultural transmission. We argue that a full recognition of the importance of cultural transmission fundamentally changes the kind of questions we should be asking regarding the biological basis of language structure. If we think of language structure as reflecting an accumulated set of changes in our genome, then we might ask something like, "What are the genetic bases of language structure and why were they selected?" However, if cultural evolution can account for language structure, then this question no longer applies. Instead, we face the task of accounting for the origin of the traits that enabled that process of structure-creating cultural evolution to get started in the first place. In light of work on cultural evolution, then, the new question for biological evolution becomes, "How did those precursor traits evolve?" We identify two key precursor traits: (1) the transmission of the communication system through learning; and (2) the ability to infer the communicative intent associated with a signal or action. We then describe two comparative case studies-the Bengalese finch and the domestic dog-in which parallel traits can be seen emerging following domestication. Finally, we turn to the role of domestication in human evolution. We argue that the cultural evolution of language structure has its origin in an earlier process of self-domestication.


Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis.
The Mediterranean diet has long been reported to be protective against the occurrence of several different health outcomes. We aimed to update our previous meta-analysis of published cohort prospective studies that investigated the effects of adherence to the Mediterranean diet on health status. We conducted a comprehensive literature search through electronic databases up to June 2010. The updated review process showed 7 prospective studies published in the past 2 y that were not included in the previous meta-analysis (1 study for overall mortality, 3 studies for cardiovascular incidence or mortality, 1 study for cancer incidence or mortality, and 2 studies for neurodegenerative diseases). These recent studies included 2 health outcomes not previously investigated (ie, mild cognitive impairment and stroke). The meta-analysis for all studies with a random-effects model that was conducted after the inclusion of these recent studies showed that a 2-point increase in adherence to the Mediterranean diet was associated with a significant reduction of overall mortality [relative risk (RR) = 0.92; 95% CI: 0.90, 0.94], cardiovascular incidence or mortality (RR = 0.90; 95% CI: 0.87, 0.93), cancer incidence or mortality (RR = 0.94; 95% CI: 0.92, 0.96), and neurodegenerative diseases (RR = 0.87; 95% CI: 0.81, 0.94). The meta-regression analysis showed that sample size was the most significant contributor to the model because it significantly influenced the estimate of the association for overall mortality. This updated meta-analysis confirms, in a larger number of subjects and studies, the significant and consistent protection provided by adherence to the Mediterranean diet in relation to the occurrence of major chronic degenerative diseases.


Why Does a Universal Anti-Bullying Program Not Help All Children? Explaining Persistent Victimization During an Intervention.
Although anti-bullying interventions are often effective, some children continue to be victimized. To increase knowledge of potential factors that might impede children's benefiting from an anti-bullying intervention, we examined potential reasons for individual differences in victimization trajectories during a group-based anti-bullying intervention. Data stem from a five-wave survey among 9122 children (7-12 years old; grades 2-5) who participated in the KiVa anti-bullying intervention (n = 6142) or were in control schools (n = 2980 children). Three trajectories were found in the intervention sample, representing children who experienced stable high, decreasing, or stable low/no victimization. A two-trajectory model of high and low trajectories represented the control sample best. Multinomial regressions on the intervention sample showed that children who experienced particularly high levels of peer rejection, internalizing problems, and lower quality parent-child relationships decreased less in victimization; thus these characteristics appeared to contribute to persistent victimization. The results call for tailored strategies in interventions aiming to reduce victimization for more children.


Phosphorus removal in a wetland constructed on former arable land.
Phosphorus in surface runoff water may cause eutrophication of recipient water. This study clarifies the mechanisms of P removal in the wetland of Hovi, Finland, constructed on arable land in 1998. Before the construction, the surface soil (removed in the construction) and subsoil (the current wetland bottom) were analyzed for Al and Fe oxides (Al(ox) and Fe(ox)) reactive in P sorption, and for the distribution of P between various pools as well as for P exchange properties. Retention of P from runoff water within the wetland was studied from 1999 to 2001 in situ and factors affecting the P removal (O2 availability and P concentration in water) were investigated in a laboratory microcosm. The processes taking place in the wetland diminished by 68% the total P load and by 49% the dissolved reactive P load. Desorption-sorption tests indicated that without removal of the surface soil, there would have been a risk of the wetland being a source of P, since the equilibrium P concentration of the soil removed was high compared with the mean P concentration of the inflowing water. The subsoil contained less P and high amounts of reactive oxides, which could bind P. Evidently, the P sorption by Al(ox) played an important role in a first phase removal of P, since the wetland retained P efficiently even under anoxic conditions, where Fe tends to be reduced. Fine-textured, mineral soil on the bottom of the wetland (subsoil of the former arable land) seemed to be very efficient in retaining P from agricultural runoff.


Spatial convergent cross mapping to detect causal relationships from short time series.
Recent developments in complex systems analysis have led to new techniques for detecting causal relationships using relatively short time series, on the order of 30 sequential observations. Although many ecological observation series are even shorter, perhaps fewer than ten sequential observations, these shorter time series are often highly replicated in space (i.e., plot replication). Here, we combine the existing techniques of convergent cross mapping (CCM) and dewdrop regression to build a novel test of causal relations that leverages spatial replication, which we call multispatial CCM. Using examples from simulated and real-world ecological data, we test the ability of multispatial CCM to detect causal relationships between processes. We find that multispatial CCM successfully detects causal relationships with as few as five sequential observations, even in the presence of process noise and observation error. Our results suggest that this technique may constitute a useful test for causality in systems where experiments are difficult to perform and long time series are not available. This new technique is available in the multispatialCCM package for the R programming language.


Long term effectiveness on prescribing of two multifaceted educational interventions: results of two large scale randomized cluster trials.
Information on benefits and risks of drugs is a key element affecting doctors' prescribing decisions. Outreach visits promoting independent information have proved moderately effective in changing prescribing behaviours. Testing the short and long-term effectiveness on general practitioners' prescribing of small groups meetings led by pharmacists. Two cluster open randomised controlled trials (RCTs) were carried out in a large scale NHS setting. Ad hoc prepared evidence based material were used considering a therapeutic area approach--TEA, with information materials on osteoporosis or prostatic hyperplasia--and a single drug oriented approach--SIDRO, with information materials on me-too drugs of 2 different classes: barnidipine or prulifloxacin. In each study, all 115 Primary Care Groups in a Northern Italy area (2.2 million inhabitants, 1737 general practitioners) were randomised to educational small groups meetings, in which available evidence was provided together with drug utilization data and clinical scenarios. Main outcomes were changes in the six-months prescription of targeted drugs. Longer term results (24 and 48 months) were also evaluated. In the TEA trial, one of the four primary outcomes showed a reduction (prescription of alfuzosin compared to tamsulosin and terazosin in benign prostatic hyperplasia: prescribing ratio -8.5%, p = 0.03). Another primary outcome (prescription of risedronate) showed a reduction at 24 and 48 months (-7.6%, p = 0.02; and -9,8%, p = 0.03), but not at six months (-5.1%, p = 0.36). In the SIDRO trial both primary outcomes showed a statistically significant reduction (prescription of barnidipine -9.8%, p = 0.02; prescription of prulifloxacin -11.1%, p = 0.04), which persisted or increased over time. These two cluster RCTs showed the large scale feasibility of a complex educational program in a NHS setting, and its potentially relevant long-term impact on prescribing habits, in particular when focusing on a single drug. National Health systems should invest in independent drug information programs. Controlled-Trials.com ISRCTN05866587.


[From ontological compartimentalisation to ontological complexity].
Discussions about the foundations of psychiatry show repetitive traits. Although in the disputes that arise between the three mainframes of reference (i.e. physical/naturalistic, hermeneutic-phenomenological, and socio-critical) new ideas do emerge with regard to content, hardly any changes can be detected in the basic hypotheses. In this article this stalemate is analysed in terms of the fundamental ontological theories that lie at the root of the three perspectives. An attempt is made to drive the debate forwards by the introduction of the concept of ontological complexity. Eventually it is argued that existential and moral learning processes of the psychiatrist (and in the environment of their patients) are just as important for their profession as are empirical and analytical insights, measurement scales and methods and innumerable pharmacological aids.


The prevalence of psychopathology in offspring of bipolar women from a Brazilian tertiary center.
No previous study has assessed the occurrence of psychopathology in offspring of bipolar women from South America. The objective of this study was to assess the prevalence of psychopathology in offspring of bipolar mothers from Brazil compared with two control groups. Children and adolescents aged 6 to 18 years of bipolar disorders mothers (n = 43), mothers with other mild to moderate mental disorders (n = 53) and mothers without any psychiatric disorder (n = 53) were evaluated using the Kiddie Schedule for Affective Disorders and Schizophrenia present and lifetime version, the Child Behavior Checklist and the Youth Self-Report. Raters were blind to the mothers' diagnoses, who were interviewed by means of the Structured Clinical Interview. Bipolar offspring had twice the chance of having one or more lifetime Axis I diagnoses [prevalence ratio = 2.11 (95% CI: 1.30-3.42) and p = 0.003] and 2.8 higher risk of having a lifetime anxiety disorder [prevalence ratio = 2.83 (95% CI: 1.39-5.78) e p = 0.004] than the offspring of mothers with no mental disorder. In addition, significantly higher scores on Child Behavior Checklist thought problems and Youth Self-Report social problems, as well as anxiety/depression and internalizing problems were observed. Our results confirm previous findings suggesting higher psychiatric problems in offspring of bipolar mothers and extend them to the Brazilian society.


Nop58p is a common component of the box C+D snoRNPs that is required for snoRNA stability.
Eukaryotic nucleoli contain a large family of box C+D small nucleolar RNA (snoRNA) species, all of which are associated with a common protein Nop1p/fibrillarin. Nop58p was identified in a screen for synthetic lethality with Nop1p and shown to be an essential nucleolar protein. Here we report that a Protein A-tagged version of Nop58p coprecipitates all tested box C+D snoRNAs and that genetic depletion of Nop58p leads to the loss of all tested box C+D snoRNAs. The box H+ACA class of snoRNAs are not coprecipitated with Nop58p, and are not codepleted. The yeast box C+D snoRNAs include two species, U3 and U14, that are required for the early cleavages in pre-rRNA processing. Consistent with this, Nop58p depletion leads to a strong inhibition of pre-rRNA processing and 18S rRNA synthesis. Unexpectedly, depletion of Nop58p leads to the accumulation of 3' extended forms of U3 and U24, showing that the protein is also involved in snoRNA synthesis. Nop58p is the second common component of the box C+D snoRNPs to be identified and the first to be shown to be required for the stability and for the synthesis of these snoRNAs.


Molecular cloning of a cDNA of a camptothecin-resistant human DNA topoisomerase I and identification of mutation sites.
Camptothecin (CPT), a plant alkaloid with antitumor activity, is a specific inhibitor of eukaryotic DNA topoisomerase I. We have previously isolated and characterized a CPT-resistant topoisomerase I isolated from a CPT-resistant human leukemia cell line, CPT-K5. cDNA clones of topoisomerase I were isolated from the CPT-resistant and the parental CPT-sensitive cell lines, respectively. Sequencing of the clones identified two mutations in the cDNA isolated from the resistant cells, which cause amino acid changes from aspartic acid to glycine at residues 533 and 583 of the parental topoisomerase I. When the CPT-K5 topoisomerase I was expressed in E. coli as a fusion protein with Staphylococcal Protein A fragment, the activity was resistant to CPT at a dose level up to 125 microM, whereas the parental fusion protein was sensitive to CPT as low as 1 microM. The resistance index (greater than 125) of the CPT-K5 fusion topoisomerase I is similar to that of the native CPT-K5 topoisomerase I. These results indicate that either or both of the two amino acid changes identified in the mutant enzyme is responsible for the resistance to CPT.


Modulation of Spatial Attentional Allocation by Computer-Based Cognitive Training during Lacrosse Shooting Performance.
It has been reported that repetitive execution of a stimulus-response compatibility (SRC) task attenuates the interference effect of a choice reaction time task, known as a Simon task. We investigated whether attentional control, enhanced by repetitive execution of an SRC task, would reduce the interference effect of a Simon task and could be transferred to lacrosse shooting skills, increasing the likelihood that players would shoot in the direction opposite to the goalie's initial movement. Female lacrosse players who were matched in terms of age, handedness score, competitive lacrosse playing experience, and playing position, were allocated to the SRC task group (n = 15) or the 2-back training group (n = 14). Participants underwent 10 sessions of 180 trials of a computer-based version of either a Type 2 SRC task or the 2-back task, within four consecutive weeks. Eight practice trials were completed prior to the execution of each task in every training session, during which feedback was provided to confirm accurate mapping between the stimulus and response. Before and after the training phase, both the magnitude of the Simon effect and the lacrosse shooting performance were assessed. After participating in computer-based cognitive training, players did indeed increase the number of shots toward the direction opposite to that of the movement of the goalie. In conclusion, these findings indicate that computer-based cognitive training is beneficial for improving the shooting ability of lacrosse players.


Inhibition of alveolar Na transport and LPS causes hypoxemia and pulmonary arterial vasoconstriction in ventilated rats.
Oxygen diffusion across the alveolar wall is compromised by low alveolar oxygen but also by pulmonary edema, and leads to hypoxemia and hypoxic pulmonary vasoconstriction (HPV). To test, whether inhibition of alveolar fluid reabsorption results in an increased pulmonary arterial pressure and whether this effect enhances HPV, we established a model, where anesthetized rats were ventilated with normoxic (21% O2) and hypoxic (13.5% O2) gas received aerosolized amiloride and lipopolisaccharide (LPS) to inhibit alveolar fluid reabsorption. Right ventricular systolic pressure (RVsP) was measured as an indicator of pulmonary arterial pressure. Oxygen pressure (PaO2) and saturation (SaO2) in femoral arterial blood served as indicator of oxygen diffusion across the alveolar wall. Aerosolized amiloride and bacterial LPS decreased PaO2 and SaO2 and increased RVsP even when animals were ventilated with normoxic gas. Ventilation with hypoxic gas decreased PaO2 by 35 mmHg and increased RVsP by 10 mmHg. However, combining hypoxia with amiloride and LPS did not aggravate the decrease in PaO2 and SaO2 and had no effect on the increase in RVsP relative to hypoxia alone. There was a direct relation between SaO2 and PaO2 and the RVsP under all experimental conditions. Two hours but not 1 h exposure to aerosolized amiloride and LPS in normoxia as well as hypoxia increased the lung wet-to-dry-weight ratio indicating edema formation. Together these findings indicate that inhibition of alveolar reabsorption causes pulmonary edema, impairs oxygen diffusion across the alveolar wall, and leads to an increased pulmonary arterial pressure.


The low conductance mitochondrial permeability transition pore confers excitability and CICR wave propagation in a computational model.
Mitochondria have long been known to sequester cytosolic Ca(2+) and even to shape intracellular patterns of endoplasmic reticulum-based Ca(2+) signaling. Evidence suggests that the mitochondrial network is an excitable medium which can demonstrate independent Ca(2+) induced Ca(2+) release via the mitochondrial permeability transition. The role of this excitability remains unclear, but mitochondrial Ca(2+) handling appears to be a crucial element in diverse diseases as diabetes, neurodegeneration and cardiac dysfunction that also have bioenergetic components. In this paper, we extend the modular Magnus-Keizer computational model for respiration-driven Ca(2+) handling to include a permeability transition based on a channel-like pore mechanism. We demonstrate both excitability and Ca(2+) wave propagation accompanied by depolarizations qualitatively similar to those reported in cell and isolated mitochondria preparations. These waves depend on the energy state of the mitochondria, as well as other elements of mitochondrial physiology. Our results support the concept that mitochondria can transmit state dependent signals about their function across the mitochondrial network. Our model provides the tools for predictions about the internal physiology that leads to this qualitatively different Ca(2+) excitability seen in mitochondria.


Hypnotizability, absorption and negative cognitions as predictors of dental anxiety: two pilot studies.
The authors conducted two pilot studies that investigated the roles of hypnotizability, absorption (defined as the ability to maintain focused attention on a task or stimulus) and state versus trait anxiety as predictors of dental anxiety. One of the studies also examined the effectiveness of hypnosis in managing dental anxiety. Participants in study 1 completed measures of hypnotizability and anxiety, viewed a video of a dental procedure either under hypnosis or not, and completed dental anxiety questionnaires. Participants in study 2 were told either that the video showed major dental work or a routine polishing. All subjects watched the video and then completed measures assessing their perceptions of the video and their anxiety. The authors found a positive relationship between hypnotizability and scores on the Dental Anxiety Scale (DAS) (F(1,290) = 3.45, P = .06), as well as an interaction between hypnotizability and hypnosis (F(1,290) = 6.55, P = .01). An analysis of covariance found a relationship between trait and dental anxiety (F(1,290) = 11.50; P = .001). A two-way analysis of variance found a main effect for hypnosis (F(1,290) = 3.20, P = .07). The authors found an effect for group on the DAS (F(1,228) = 3.67, P = .057), such that subjects in the negative-cognition group scored higher on the DAS. The authors found an interaction between absorption and cognition in perceptions of pain experienced by the patient in the video (F(1,228) = 3.70, P = .05) and in ratings of one's own pain level if in the same situation (F(1,228) = 4.38, P < .05). Hypnotizability or absorption, pre-existing anxiety and cognitions about dental procedures predict dental anxiety, and hypnosis may be helpful for some, but not all, patients. Characteristics such as hypnotizability, trait anxiety and negative cognitions predict which people develop dental anxiety and who will be more responsive to hypnosis. The authors provide suggestions for dentists treating anxious patients.


Prenatal and postnatal myeloid cells demonstrate stepwise progression in the pathogenesis of MLL fusion gene leukemia.
The steps to leukemia following an in utero fusion of MLL (HRX, ALL-1) to a partner gene in humans are not known. Introduction of the Mll-AF9 fusion gene into embryonic stem cells results in leukemia in mice with cell-type specificity similar to humans. In this study we used myeloid colony assays, immunophenotyping, and transplantation to evaluate myelopoiesis in Mll-AF9 mice. Colony assays demonstrated that both prenatal and postnatal Mll-AF9 tissues have significantly increased numbers of CD11b(+)/CD117(+)/Gr-1(+/-) myeloid cells, often in compact clusters. The self-renewal capacity of prenatal myeloid progenitors was found to decrease following serial replating of colony-forming cells. In contrast, early postnatal myeloid progenitors increased following replating; however, the enhanced self-renewal of early postnatal myeloid progenitor cells was limited and did not result in long-term cell lines or leukemia in vivo. Unlimited replating, long-term CD11b/Gr-1(+) myeloid cell lines, and the ability to produce early leukemia in vivo in transplantation experiments, were found only in mice with overt leukemia. Prenatal Mll-AF9 tissues had reduced total (mature and progenitor) CD11b/Gr-1(+) cells compared with wild-type tissues. Colony replating, immunophenotyping, and cytochemistry suggest that any perturbation of cellular differentiation from the prenatal stage onward is partial and largely reversible. We describe a novel informative in vitro and in vivo model system that permits study of the stages in the pathogenesis of Mll fusion gene leukemia, beginning in prenatal myeloid cells, progressing to a second stage in the postnatal period and, finally, resulting in overt leukemia in adult animals.


Roles of Src family kinase signaling during fertilization and the first cell cycle in the marine protostome worm Cerebratulus.
For eggs to generate a calcium response during fertilization, the sperm of many deuterostome animals must first activate a group of egg kinases, called Src family kinases (SFKs). However, whether SFK activation is also required for fertilization-induced calcium signals in eggs of protostomes remains unknown. Thus, in this study, unfertilized oocytes of the marine protostome worm Cerebratulus were treated with either PP2 to inhibit SFKs or with U73122 to block phospholipase C activity downstream of SFK. Compared with control fertilizations, the inhibitors significantly reduced post-insemination levels of polar body formation and cleavage, but apparently did so via different mechanisms, based on the variable effects of these drugs on sperm incorporations and pronuclear differentiation. Moreover, confocal calcium imaging revealed that repetitive calcium waves (=oscillations) were blocked by U73122, but not by PP2, even though immunoblots indicated SFK activity was inhibited by PP2. Such findings fail to support the view that SFKs are required for initiating fertilization-induced calcium oscillations in Cerebratulus, and alternative mechanisms for the observed inhibition of polar body formation and cleavage in drug-treated specimens are discussed.


Essential oil composition of five collections of Achillea biebersteinii from central Turkey and their antifungal and insecticidal activity.
The composition of the essential oils hydrodistilled from the aerial parts of five Achillea biebersteinii Afan samples, collected in central Turkey from Konya, Isparta and Ankara, were analyzed both by gas chromatography (GC-FID) and gas chromatography-mass spectrometry (GC-MS). Eighty-four components were identified, representing 87 to 99% of the total oil composition. The identified major components were 1,8-cineole (9-37%), camphor (16-30%) and p-cymene (1-27%). Two samples differed in piperitone (11%) and ascaridol (4%) content. The five A. biebersteinii essential oils were subsequently evaluated for their antifungal activity against the strawberry anthracnose-causing fungal plant pathogens Colletotrichum acutatum, C. fragariae and C. gloeosporioides using the direct overlay bioautography assay. The essential oils showed no antifungal activity at 80 and 160 microg/spot. In addition, A. biebersteinii oils and their major compounds were subsequently investigated against Aedes aegypti first instar larvae in a high throughput bioassay. Among the oils, only one sample from Ankara showed a notable larvacidal effect on Ae. aegypti larvae. The major compounds, 1,8-cineole, camphor and p-cymene, exhibited low mosquito larval activity, and thus the minor compounds are probably responsible for the observed activity against Ae. aegypti larvae. The oils showed weak activity against adult Ae. aegypti.


Tricalbins Contribute to Cellular Lipid Flux and Form Curved ER-PM Contacts that Are Bridged by Rod-Shaped Structures.
Lipid flow between cellular organelles occurs via membrane contact sites. Extended-synaptotagmins, known as tricalbins in yeast, mediate lipid transfer between the endoplasmic reticulum (ER) and plasma membrane (PM). How these proteins regulate membrane architecture to transport lipids across the aqueous space between bilayers remains unknown. Using correlative microscopy, electron cryo-tomography, and high-throughput genetics, we address the interplay of architecture and function in budding yeast. We find that ER-PM contacts differ in protein composition and membrane morphology, not in intermembrane distance. In situ electron cryo-tomography reveals the molecular organization of tricalbin-mediated contacts, suggesting a structural framework for putative lipid transfer. Genetic analysis uncovers functional overlap with cellular lipid routes, such as maintenance of PM asymmetry. Further redundancies are suggested for individual tricalbin protein domains. We propose a modularity of molecular and structural functions of tricalbins and of their roles within the cellular network of lipid distribution pathways.


Optically tunable fiber grating transmission filters.
We propose and demonstrate single- and multiple-passband fiber grating transmission filters that are remotely tunable by exploitation of the optical pump-induced thermal effects in Er/Yb-codoped fiber sections. A repeatable, wavelength-independent induced phase shift of 0.1 pi/mW is obtained without hysteresis and anisotropic effects. A transmission extinction ratio of >23 dB with a 3-mW change in pump power is achieved.


Long-chain polyunsaturated fatty acids and cognition in VLBW infants at 8 years: an RCT.
To test the hypothesis that supplementation with the long chain polyunsaturated fatty acids docosahexaenoic acid (DHA) and arachidonic acid (AA) to very low birth weight (VLBW) infants would improve long-term cognitive functions and influence neuroanatomical volumes and cerebral cortex measured by MRI. The current study is a follow-up of a randomized, double-blinded, placebo-controlled study of supplementation with high-dose DHA (0.86%) and AA (0.91%) to 129 VLBW infants fed human milk. Ninety-eight children participated at 8 years follow-up and completed a broad battery of cognitive tests. Eighty-one children had cerebral MRI scans of acceptable quality. There were no significant differences between the intervention group and the control group on any of the cognitive measures. Equally, MRI data on segmental brain volumes and cerebral cortex volume, area, and thickness suggested no overall group effect. This study is the first long-term follow-up of a randomized controlled trial with supplementation of DHA and AA to human milk fed VLBW infants investigating both cognitive functions and brain macrostructure measured by MRI. No cognitive or neuroanatomical effects of the supplementation were detected at 8 years of age.


Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium.
Tools for the prediction of atrial fibrillation (AF) may identify high-risk individuals more likely to benefit from preventive interventions and serve as a benchmark to test novel putative risk factors. Individual-level data from 3 large cohorts in the United States (Atherosclerosis Risk in Communities [ARIC] study, the Cardiovascular Health Study [CHS], and the Framingham Heart Study [FHS]), including 18 556 men and women aged 46 to 94 years (19% African Americans, 81% whites) were pooled to derive predictive models for AF using clinical variables. Validation of the derived models was performed in 7672 participants from the Age, Gene and Environment-Reykjavik study (AGES) and the Rotterdam Study (RS). The analysis included 1186 incident AF cases in the derivation cohorts and 585 in the validation cohorts. A simple 5-year predictive model including the variables age, race, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, and history of myocardial infarction and heart failure had good discrimination (C-statistic, 0.765; 95% CI, 0.748 to 0.781). Addition of variables from the electrocardiogram did not improve the overall model discrimination (C-statistic, 0.767; 95% CI, 0.750 to 0.783; categorical net reclassification improvement, -0.0032; 95% CI, -0.0178 to 0.0113). In the validation cohorts, discrimination was acceptable (AGES C-statistic, 0.664; 95% CI, 0.632 to 0.697 and RS C-statistic, 0.705; 95% CI, 0.664 to 0.747) and calibration was adequate. A risk model including variables readily available in primary care settings adequately predicted AF in diverse populations from the United States and Europe.


Automatic imitation in dogs.
After preliminary training to open a sliding door using their head and their paw, dogs were given a discrimination task in which they were rewarded with food for opening the door using the same method (head or paw) as demonstrated by their owner (compatible group), or for opening the door using the alternative method (incompatible group). The incompatible group, which had to counterimitate to receive food reward, required more trials to reach a fixed criterion of discrimination performance (85% correct) than the compatible group. This suggests that, like humans, dogs are subject to 'automatic imitation'; they cannot inhibit online the tendency to imitate head use and/or paw use. In a subsequent transfer test, where all dogs were required to imitate their owners' head and paw use for food reward, the incompatible group made a greater proportion of incorrect, counterimitative responses than the compatible group. These results are consistent with the associative sequence learning model, which suggests that the development of imitation depends on sensorimotor experience and phylogenetically general mechanisms of associative learning. More specifically, they suggest that the imitative behaviour of dogs is shaped more by their developmental interactions with humans than by their evolutionary history of domestication.


Effect of a mind-body therapeutic program for infertile women repeating in vitro fertilization treatment on uncertainty, anxiety, and implantation rate.
The study aimed to develop a mind-body therapeutic program and evaluate its effects on mitigating uncertainty, anxiety, and implantation rate of second-trial in vitro fertilization (IVF) women. This study employed a nonequivalent control group nonsynchronized design. The conceptual framework and program content were developed from a preliminary survey of eight infertile women and the extensive review of the literature. Program focuses on three uncertainty-induced anxieties in infertile women: cognitive, emotional, and biological responses. To evaluate the effect of the intervention, the infertile women with unknown cause preparing for a second IVF treatment were sampled at convenience (26 experimental and 24 control). The experimental group in the study showed greater decrease in uncertainty and anxiety in premeasurements and postmeasurements than the control group did. However, no statistically significant differences in the implantation rate between groups were observed. This study is meaningful as the first intervention program for alleviating uncertainty and anxiety provided during the IVF treatment process. The positive effects of the mind-body therapeutic program in alleviating both uncertainty and anxiety have direct meaning for clinical applications.


ATP-sensitive K+ channels mediate dilatation of cerebral arterioles during hypoxia.
We tested the hypothesis that dilatation of cerebral arterioles during hypoxia is mediated by activation of ATP-sensitive K+ channels. The diameter of pial arterioles was measured through a closed cranial window in anesthetized rabbits. Topical application of aprikalim (10(-6) mol/L), a direct activator of ATP-sensitive K+ channels, dilated pial arterioles by 18 +/- 3% (mean +/- SEM). Glibenclamide (10(-6) mol/L), an inhibitor of ATP-sensitive K+ channels, virtually abolished aprikalim-induced vasodilatation. When arterial PO2 was reduced from 129 +/- 3 to 25 +/- 1 mm Hg, the diameter of cerebral arterioles increased by 66 +/- 9% (P < .05). Glibenclamide inhibited dilatation of pial arterioles during hypoxia by 46 +/- 5% (P < .05). In contrast, vasodilatation in response to sodium nitroprusside was not altered by glibenclamide. Topical application of adenosine (10(-4) mol/L) increased arteriolar diameter by 21 +/- 4%. Glibenclamide did not affect adenosine-induced vasodilatation. These findings suggest that dilatation of cerebral arterioles in response to hypoxia is mediated, in part, by activation of ATP-sensitive K+ channels.


The effect of intracellular protein delivery on the anti-tumor activity of recombinant human endostatin.
Endostatin (ES), a 20 kDa protein derived from the carboxy-terminus of collagen XVIII is a potent angiogenesis inhibitor, but clinical development has been hindered by poor clinical efficacy and insufficient functional information from which to design agents with improved activity. The present study investigated protein uptake by cells as a determinant of ES activity. We developed a cell-permeable ES protein (HM73ES) with enhanced capacity to enter cells by adding a macromolecule transduction domain (MTD). HM73ES inhibited angiogenesis-associated phenotypes in cultured endothelial cells [as assessed by tube formation, wound-healing, cell proliferation and survival assays]. These effects were accompanied by reductions in MAPK signaling (ERK phosphorylation), and in β-Catenin, c-Myc, STAT3, and VEGF protein expression. The cell-permeable ES displayed greater tissue penetration in mice and suppressed the growth of human tumor xenografts to a significantly greater extent than ES protein without the MTD sequence. Our results suggest that anti-angiogenic activities of native ES are limited at the level of protein uptake and/or subcellular localization, and that much of the activity of ES against tumors depends on one or more intracellular functions. This study will inform future efforts to understand ES function(s) and suggest strategies for improving ES-based cancer therapeutics.


Clinical impact of antimicrobial resistance in humans.
The dramatic rise in the number and spread of resistant bacterial species continues. This involves not only bacteria that cause infections in the healthcare sector but also those that originate in the community. Antibiotic resistance rates are rising in almost all bacterial species, including those that are the most common bacterial pathogens in people (Escherichia coli and Staphylococcus aureus). Serious infections caused by resistant bacteria do not respond well to therapy and these infections are often associated with worse outcomes, including increased rates of complications, additional expense, higher associated mortality rates and prolonged hospital stays.


ABT1 modifies SMARD1 pathology via interactions with IGHMBP2 and stimulation of ATPase and helicase activity.
SMA with respiratory distress type 1 (SMARD1) and Charcot-Marie-Tooth type 2S (CMT2S) are results of mutations in immunoglobulin mu DNA binding protein 2 (IGHMBP2). IGHMBP2 is a UPF1-like helicase with proposed roles in several cellular processes, including translation. This study examines activator of basal transcription 1 (ABT1), a modifier of SMARD1-nmd disease pathology. Microscale thermophoresis and dynamic light scattering demonstrate that IGHMBP2 and ABT1 proteins directly interact with high affinity. The association of ABT1 with IGHMBP2 significantly increases the ATPase and helicase activity as well as the processivity of IGHMBP2. The IGHMBP2/ABT1 complex interacts with the 47S pre-rRNA 5' external transcribed spacer and U3 small nucleolar RNA (snoRNA), suggesting that the IGHMBP2/ABT1 complex is important for pre-rRNA processing. Intracerebroventricular injection of scAAV9-Abt1 decreases FVB-Ighmbp2nmd/nmd disease pathology, significantly increases lifespan, and substantially decreases neuromuscular junction denervation. To our knowledge, ABT1 is the first disease-modifying gene identified for SMARD1. We provide a mechanism proposing that ABT1 decreases disease pathology in FVB-Ighmbp2nmd/nmd mutants by optimizing IGHMBP2 biochemical activity (ATPase and helicase activity). Our studies provide insight into SMARD1 pathogenesis, suggesting that ABT1 modifies IGHMBP2 activity as a means to regulate pre-rRNA processing.


Quantitative analysis of chromium in potatoes by laser-induced breakdown spectroscopy coupled with linear multivariate calibration.
Laser-induced breakdown spectroscopy (LIBS) coupled with the linear multivariate regression method was utilized to analyze chromium (Cr) quantitatively in potatoes. The plasma was generated using a Nd:YAG laser, and the spectra were acquired by an Andor spectrometer integrated with an ICCD detector. The models between intensity of LIBS characteristic line(s) and concentration of Cr were constructed to predict quantitatively the content of target. The unary, binary, ternary, and quaternary variables were chosen for verifying the accuracy of linear regression calibration curves. The intensity of characteristic lines Cr (CrI: 425.43, 427.48, 428.97 nm) and Ca (CaI: 422.67, 428.30, 430.25, 430.77, 431.86 nm) were used as input data for the multivariate calculations. According to the results of linear regression, the model of quaternary linear regression was established better in comparing with the other three models. A good agreement was observed between the actual content provided by atomic absorption spectrometry and the predicted value obtained by the quaternary linear regression model. And the relative error was below 5.5% for validation samples S1 and S2. The result showed that the multivariate approach can obtain better predicted accuracy than the univariate ones. The result also suggested that the LIBS technique coupled with the linear multivariate calibration method could be a great tool to predict heavy metals in farm products in a rapid manner even though samples have similar elemental compositions.


Phylogenetics of Bonamia parasites based on small subunit and internal transcribed spacer region ribosomal DNA sequence data.
The genus Bonamia (Haplosporidia) includes economically significant oyster parasites. Described species were thought to have fairly circumscribed host and geographic ranges: B. ostreae infecting Ostrea edulis in Europe and North America, B. exitiosa infecting O. chilensis in New Zealand, and B. roughleyi infecting Saccostrea glomerata in Australia. The discovery of B. exitiosa-like parasites in new locations and the observation of a novel species, B. perspora, in non-commercial O. stentina altered this perception and prompted our wider evaluation of the global diversity of Bonamia parasites. Samples of 13 oyster species from 21 locations were screened for Bonamia spp. by PCR, and small subunit and internal transcribed spacer regions of Bonamia sp. ribosomal DNA were sequenced from PCR-positive individuals. Infections were confirmed histologically. Phylogenetic analyses using parsimony and Bayesian methods revealed one species, B. exitiosa, to be widely distributed, infecting 7 oyster species from Australia, New Zealand, Argentina, eastern and western USA, and Tunisia. More limited host and geographic distributions of B. ostreae and B. perspora were confirmed, but nothing genetically identifiable as B. roughleyi was found in Australia or elsewhere. Newly discovered diversity included a Bonamia sp. in Dendostrea sandvicensis from Hawaii, USA, that is basal to the other Bonamia species and a Bonamia sp. in O. edulis from Tomales Bay, California, USA, that is closely related to both B. exitiosa and the previously observed Bonamia sp. from O. chilensis in Chile.


Interplay between arginine methylation and ubiquitylation regulates KLF4-mediated genome stability and carcinogenesis.
KLF4 is an important regulator of cell-fate decision, including DNA damage response and apoptosis. We identify a novel interplay between protein modifications in regulating KLF4 function. Here we show that arginine methylation of KLF4 by PRMT5 inhibits KLF4 ubiquitylation by VHL and thereby reduces KLF4 turnover, resulting in the elevation of KLF4 protein levels concomitant with increased transcription of KLF4-dependent p21 and reduced expression of KLF4-repressed Bax. Structure-based modelling and simulations provide insight into the molecular mechanisms of KLF4 recognition and catalysis by PRMT5. Following genotoxic stress, disruption of PRMT5-mediated KLF4 methylation leads to abrogation of KLF4 accumulation, which, in turn, attenuates cell cycle arrest. Mutating KLF4 methylation sites suppresses breast tumour initiation and progression, and immunohistochemical stain shows increased levels of both KLF4 and PRMT5 in breast cancer tissues. Taken together, our results point to a critical role for aberrant KLF4 regulation by PRMT5 in genome stability and breast carcinogenesis.


Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys.
The proliferation of mural epithelial cells is a major cause of progressive cyst enlargement in autosomal-dominant polycystic kidney disease (ADPKD). Adenosine 3', 5' cyclic monophosphate (cAMP) stimulates the proliferation of cells from ADPKD cysts, but not cells from normal human kidney cortex (HKC), through the activation of protein kinase A (PKA), mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (ERK/MAPK). In the current study, we examined the signaling pathway between PKA and MEK in ADPKD and HKC cells. Primary cultures of human ADPKD and HKC cells were prepared from nephrectomy specimens. We determined the effects of cAMP and epidermal growth factor (EGF) on the activation of ERK, B-Raf and Raf-1 in ADPKD and HKC cells by immune kinase assay and Western blot. 8-Br-cAMP increased phosphorylated ERK (2.7- +/- 0.6-fold, N = 7), and B-Raf kinase activity (3.6- +/- 1.1-fold, N = 5) in cells from ADPKD kidneys; levels of phosphorylated Raf-1 were not changed. Inhibition of PKA by H89 strikingly decreased cAMP-stimulated phosphorylation of ERK and B-Raf, and MAPK inhibition by PD98059 blocked the effect of the nucleotide to activate ERK. By contrast, in HKC cells 8-Br-cAMP did not activate B-Raf and ERK. EGF stimulated the phosphorylation of ERK and Raf-1 in both ADPKD and HKC cells, but had no effect on B-Raf. 8-Br-cAMP and EGF conjointly increased ERK activation above that of either agonist alone in ADPKD cells, and this combined effect was abolished by PD98059, indicating that ERK was activated by EGF- and cAMP-responsive cascades that converge at MAPK. cAMP activates ERK and increases proliferation of ADPKD epithelial cells, but not cells from normal human kidney cortex, through the sequential phosphorylation of PKA, B-Raf and MAPK in a pathway separate from, but complementary to, the classical receptor tyrosine kinase cascade. Consequently, cAMP and EGF have great potential to accelerate the progressive enlargement of renal cysts.


Influence of Coca-Cola on orthodontic materials. A systematic review.
This analysis was conducted to assess the impact of Coca-Cola on orthodontic materials compared to that of other fluids. Electronical searches were carried out in PubMed, Livivo, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov, supplemented by manual searches in the reference lists of the articles selected for full text evaluation. The risk of bias was assessed on the basis of a "risk of bias summary." A total of 216 bibliographic summaries of articles were obtained, eleven of which were relevant. Nine of these papers showed a low risk, while two publications from one in vivo study exhibited a high risk of bias. The continuing influence of Coca-Cola caused significant discoloration of elastomeric materials and resulted in significantly lower shear bond strength of the brackets and higher corrosion. With regard to orthodontic appliances, additional in situ and in vivo studies are desirable. Special attention should be paid to an appropriate number of samples or patients, as most investigations lacked a sufficient number of test subjects. In addition, investigations with long observation periods and documented beverage consumption should be preferred. The intake of cola-containing beverages during orthodontic therapy and the exposure duration of these beverages to orthodontic material should be reduced to a minimum, as this can impair the adhesive strength and lead to corrosion of orthodontic brackets. The interval between orthodontic appointments should be short to avoid discoloration of orthodontic elastomeric ligatures.


Critical role of P1-Runx1 in mouse basophil development.
Runx1(P1N/P1N) mice are deficient in the transcription factor distal promoter-derived Runt-related transcription factor 1 (P1-Runx1) and have a > 90% reduction in the numbers of basophils in the BM, spleen, and blood. In contrast, Runx1(P1N/P1N) mice have normal numbers of the other granulocytes (neutrophils and eosinophils). Although basophils and mast cells share some common features, Runx1(P1N/P1N) mice have normal numbers of mast cells in multiple tissues. Runx1(P1N/P1N) mice fail to develop a basophil-dependent reaction, IgE-mediated chronic allergic inflammation of the skin, but respond normally when tested for IgE- and mast cell-dependent passive cutaneous anaphylaxis in vivo or IgE-dependent mast cell degranulation in vitro. These results demonstrate that Runx1(P1N/P1N) mice exhibit markedly impaired function of basophils, but not mast cells. Infection with the parasite Strongyloides venezuelensis and injections of IL-3, each of which induces marked basophilia in wild-type mice, also induce modest expansions of the very small populations of basophils in Runx1(P1N/P1N) mice. Finally, Runx1(P1N/P1N) mice have normal numbers of the granulocyte progenitor cells, SN-Flk2(+/-), which can give rise to all granulocytes, but exhibit a > 95% reduction in basophil progenitors. The results of the present study suggest that P1-Runx1 is critical for a stage of basophil development between SN-Flk2(+/-) cells and basophil progenitors.


Alterations in the pulsatile mode of growth hormone release in men and women with insulin-dependent diabetes mellitus.
The mechanisms responsible for the elevated levels of circulating GH observed in diabetes mellitus (DM) remain incompletely defined. To assess the episodic fluctuations in serum GH as a reflection of hypothalamic-pituitary activity, we accumulated GH concentration-time series in a total of 48 adult men and women with and without insulin-dependent DM by obtaining serum samples at 10-min intervals over 24 h. Significant pulses of GH release were subsequently identified and characterized by an objective, statistically based pulse detection algorithm (Cluster) and fixed circadian (24-h) periodicities of secretory activity, resolved using Fourier expansion time-series analysis. Compared to those in age-matched controls, integrated 24-h concentrations of GH were 2- to 3.5-fold higher in diabetic men (P = 0.002) and women (P = 0.0005). Both men and women with DM had over 50% more GH pulses per 24 h than their non-DM counterparts. In addition, maximal GH pulse amplitude was markedly elevated in the men and women with DM (P = 0.0019 and 0.0189, respectively). That the increase in maximal pulse amplitude was accounted for by greater baseline levels was documented by a higher interpulse valley mean GH concentration in the diabetics compared to the controls (P = 0.0437 and 0.0056, men and women, respectively) and the absence of any difference in incremental pulse amplitude for either sex (P greater than 0.05). DM men had larger GH pulse areas (P = 0.039) than control men, apparently accounted for by greater pulse width (P = 0.0037). Pulse areas in DM and non-DM women were indistinguishable. Time-series analysis revealed that the 24-h (circadian) rhythms of serum GH concentrations exhibited significantly increased amplitudes in the diabetic group as a whole (compared to the controls, P = 0.011). However, the times of maximal GH concentrations (acrophases) were not significantly different. As a group, serum insulin-like growth factor-I was lower in DM vs. non-DM individuals (P = 0.0014), although when separated by sex this difference did not reach statistical significance in women (P = 0.317). The present data confirm the higher circulating levels of GH previously reported to occur in individuals with poorly controlled DM. The altered frequency of GH pulses together with enhanced interpulse GH concentrations and an amplified circadian GH rhythm are compatible with hypothalamic dysfunction associated with dysregulation of somatostatin and/or GHRH secretion.(ABSTRACT TRUNCATED AT 400 WORDS)


An occupational perspective of the lived experience of familial dementia caregivers: A thematic review of qualitative literature.
Dementia caregiving is thought to have a negative impact on health and wellbeing. This critical review of qualitative literature explored the lived experience of familial dementia caregivers from an occupational therapy perspective. The method was informed by systematic review and qualitative research methodologies and was structured within the occupational dimensions framework of doing-being-becoming-belonging. A comprehensive search of major databases was undertaken which identified 484 studies on the topic; 14 met the inclusion criteria and were included in the review. Ten themes emerged within the doing-being-becoming-belonging framework from the analysis of the studies. The occupational participation of caregivers is conveyed within the 'doing' domain. Ways in which caregiving impacts upon opportunities for self-nurture are presented within the 'being' domain. The 'becoming' domain elucidates ways in which caregivers redefine themselves, their values and their priorities through their caregiving role. The 'belonging' domain depicts ways in which caregivers' connections with their care recipient and others are shaped over time. Practice implications for health and social care practitioners who work with familial dementia caregivers are presented in light of the findings.


Antimicrobial Stewardship Activities in Public Healthcare Facilities in South Africa: A Baseline for Future Direction.
Antimicrobial resistance (AMR) is a growing problem worldwide, including South Africa, where an AMR National Strategy Framework was implemented to instigate antimicrobial stewardship programmes (ASPs) and improve antimicrobial prescribing across sectors. To address the need to assess progress, a sequential mixed methodology with an explanatory research design was employed. In Phase 1, a self-administered questionnaire was completed by healthcare professionals (HCPs) from 26 public sector healthcare facilities across South Africa to assess compliance with the Framework. The results were explored in Phase 2 through 10 focus group discussions and two in-depth interviews, including 83 participants. Emerging themes indicated that public healthcare facilities across South Africa are facing many challenges, especially at entry level primary healthcare (PHC) facilities, where antimicrobial stewardship activities and ASPs are not yet fully implemented. Improved diagnostics and surveillance data are a major shortcoming at these facilities. Continuous education for HCPs is deficient, especially for the majority of prescribers at PHC level and health campaigns are nearly non-existent. Involvement and visibility of management at certain facilities is a serious shortfall. Consequently, it is important to call attention to the challenges faced with improving antimicrobial prescribing across countries and address these to reduce AMR, especially in PHC facilities, being the first point of access to healthcare for the vast majority of patients in developing countries.


N-acetyl cysteine reduces oxidative toxicity, apoptosis, and calcium entry through TRPV1 channels in the neutrophils of patients with polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is a common inflammatory and oxidant disease with an uncertain pathogenesis. N-acetyl cysteine (NAC) decreases oxidative stress, intracellular free calcium ion [Ca(2+)]i, and apoptosis levels in human neutrophil. We aimed to investigate the effects of NAC on apoptosis, oxidative stress, and Ca(2+) entry through transient receptor potential vanilloid 1 (TRPV1) and TRP melastatin 2 (TRPM2) channels in neutrophils from patients with PCOS. Neutrophils isolated from PCOS group were investigated in three settings: (1) after incubation with TRPV1 channel blocker capsazepine or TRPM2 channel blocker 2-aminoethyl diphenylborinate (2-APB), (2) after supplementation with NAC (for 6 weeks), and (3) with combination (capsazepine + 2-APB + NAC) exposure. The neutrophils in TRPM2 and TRPV1 experiments were stimulated by N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP; 1 μM) and capsaicin (10 μM) as concentration agonists, respectively. Neutrophil lipid peroxidation and capsaicin-induced increase in [Ca(2+)]i concentrations were reduced by capsazepine and NAC treatments. However, the [Ca(2+)]i concentration did not change by fMLP stimulation. Neutrophil lipid peroxidation, apoptosis, caspase-3, caspase-9, cytosolic reactive oxygen species production, and mitochondrial membrane depolarization values were decreased by NAC treatment although neutrophil glutathione peroxidase and reduced glutathione levels were increased by the NAC treatment. Serum lipid peroxidation, luteinizing hormone, testosterone, insulin, interleukin-1 beta, and homocysteine levels were decreased by NAC treatment although serum vitamin A, beta-carotene, vitamin E, and total antioxidant status were increased by the NAC treatment. In conclusion, NAC reduced oxidative stress, apoptosis, cytokine levels, and Ca(2+) entry through TRPV1 channel, which provide supportive evidence that oxidative stress and TRPV1 channel plays a key role in etiology of PCOS.


Segmental duplications arise from Pol32-dependent repair of broken forks through two alternative replication-based mechanisms.
The propensity of segmental duplications (SDs) to promote genomic instability is of increasing interest since their involvement in numerous human genomic diseases and cancers was revealed. However, the mechanism(s) responsible for their appearance remain mostly speculative. Here, we show that in budding yeast, replication accidents, which are most likely transformed into broken forks, play a causal role in the formation of SDs. The Pol32 subunit of the major replicative polymerase Poldelta is required for all SD formation, demonstrating that SDs result from untimely DNA synthesis rather than from unequal crossing-over. Although Pol32 is known to be required for classical (Rad52-dependant) break-induced replication, only half of the SDs can be attributed to this mechanism. The remaining SDs are generated through a Rad52-independent mechanism of template switching between microsatellites or microhomologous sequences. This new mechanism, named microhomology/microsatellite-induced replication (MMIR), differs from all known DNA double-strand break repair pathways, as MMIR-mediated duplications still occur in the combined absence of homologous recombination, microhomology-mediated, and nonhomologous end joining machineries. The interplay between these two replication-based pathways explains important features of higher eukaryotic genomes, such as the strong, but not strict, association between SDs and transposable elements, as well as the frequent formation of oncogenic fusion genes generating protein innovations at SD junctions.


Economic reforms and the acute inpatient care of patients with schizophrenia: the Chinese experience.
This study compared insured and uninsured schizophrenic inpatients in China and examined changes in the acute inpatient care of schizophrenic patients during China's economic reform era. Detailed chart reviews of 50 randomly selected inpatients discharged from a hospital in central China each year from 1984 through 1993 identified 321 patients with schizophrenia. Demographic, insurance, treatment, and cost data of these patients were collected from the charts. With logistic regression models to control for confounding variables, the analyses showed that the 129 insured patients were significantly more likely than the 192 uninsured patients to be urban residents, to be older, to have had 7 or more years of schooling, and to have had more psychiatric hospitalizations; moreover, their index admissions were longer and were more likely to include use of traditional Chinese medications. The estimated 19% of schizophrenic individuals in the community with health insurance receive inpatient treatment 2.8 times more frequently than the 81% without insurance. Compared to admissions in 1984-1988, admissions in 1989-1993 were significantly shorter and involved longer periods of polypharmacy with multiple antipsychotic medications but included lower mean chlorpromazine-equivalent doses of medication. The relative cost of inpatient care for an acute episode of schizophrenia increased 3.5-fold over the 10-year period, from 11% of mean annual household income in 1984 to 37% in 1993. Changes in the incentive system for care providers and rapid increases in the cost of care during the economic reform era have resulted in increasingly restricted availability of services for the many schizophrenic patients without health insurance.


Increased type II collagen cleavage by cathepsin K and collagenase activities with aging and osteoarthritis in human articular cartilage.
The intra-helical cleavage of type II collagen by proteases, including collagenases and cathepsin K, is increased with aging and osteoarthritis (OA) in cartilage as determined by immunochemical assays. The distinct sites of collagen cleavage generated by collagenases and cathepsin K in healthy and OA human femoral condylar cartilages were identified and compared. Fixed frozen cartilage sections were examined immunohistochemically, using antibodies that react with the collagenase-generated cleavage neoepitopes, C2C and C1,2C, and the primary cleavage neoepitope (C2K) generated in type II collagen by the action of cathepsin K and possibly by other proteases, but not by any collagenases studied to date. In most cases, the staining patterns for collagen cleavage were similar for all three epitopes: weak to moderate mainly pericellular staining in non-OA cartilage from younger individuals and stronger, more widespread staining in aging and OA cartilages that often extended from the superficial to the mid/deep zone of the tissue. In very degenerate OA specimens, with significant disruption of the articular surface, staining was distributed throughout most of the cartilage matrix. Cleavage of collagen by proteases usually arises pericellularly around chondrocytes at and near the articular surface, subsequently becoming more intense and extending progressively deeper into the cartilage with aging and OA. The close correspondence between the distributions of these products suggests that both collagenases and cathepsin K, and other proteases that may generate this distinct cathepsin K cleavage site, are usually active in the same sites in the degradation of type II collagen.


In vivo chemosensitization by misonidazole in sensitive and resistant tumor lines.
In an attempt to evaluate whether the radiation sensitizer misonidazole (MISO) could enhance the responsiveness of chemoresistant tumors, MISO was combined with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and/or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) for the treatment of BALB/c X DBA/2 F1 (hereafter called CD2F1) and C3H/HeJ mice bearing nitrosourea-resistant L1210/BCNU or KHT/CCR tumors, respectively. To determine whether comparable degrees of enhancement could be achieved in sensitive and resistant tumor lines, the magnitude of chemosensitization produced by treating the resistant tumors with the MISO-nitrosourea combinations was compared to the chemopotentiation produced in similarly treated nitrosourea-sensitive tumor lines from which the resistant lines had been derived. As evidenced by increased cure probabilities, the addition of MISO [5.0 mmol/kg (1.0 mg/g)] significantly potentiated the response of the parental nitrosourea-sensitive L1210/0 tumor to a 20-mg/kg dose of CCNU. When combined with doses of CCNU lower than 20 mg/kg or with BCNU, MISO failed to significantly modify the response of the L1210/0 tumor. Significant chemosensitization also was evident when 2.5- and 1.25-mmol/kg doses of MISO were used in combination with CCNU at 20 mg/kg. The effectiveness of BCNU and CCNU against the nitrosourea-resistant L1210/BCNU tumor was not significantly improved by MISO (5.0 mmol/kg), even when the sensitizer was combined with doses of nitrosoureas approaching 10% lethal dose (60 days) concentrations. In contrast, the effectiveness of CCNU against the parental KHT and resistant KHT/CCR tumors, assessed using a tumor regrowth assay, was equally enhanced by simultaneous MISO treatment. Therefore, one cannot safely predict the extent of enhancement which might result from the addition of MISO to a chemotherapeutic regimen based solely on the responsiveness of the tumor to the chemotherapy drug(s) alone.