Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects.
The effects of colony-stimulating factor 1 (CSF-1), the primary regulator of mononuclear phagocyte production, are thought to be mediated by the CSF-1 receptor (CSF-1R), encoded by the c-fms proto-oncogene. To investigate the in vivo specificity of CSF-1 for the CSF-1R, the mouse Csf1r gene was inactivated. The phenotype of Csf1(-)/Csf1r(-) mice closely resembled the phenotype of CSF-1-nullizygous (Csf1(op)/Csf1(op)) mice, including the osteopetrotic, hematopoietic, tissue macrophage, and reproductive phenotypes. Compared with their wild-type littermates, splenic erythroid burst-forming unit and high-proliferative potential colony-forming cell levels in both Csf1(op)/Csf1(op) and Csf1(-)/Csf1r(-) mice were significantly elevated, consistent with a negative regulatory role of CSF-1 in erythropoiesis and the maintenance of primitive hematopoietic progenitor cells. The circulating CSF-1 concentration in Csf1r(-)/Csf1r(-) mice was elevated 20-fold, in agreement with the previously reported clearance of circulating CSF-1 by CSF-1R-mediated endocytosis and intracellular destruction. Despite their overall similarity, several phenotypic characteristics of the Csf1r(-)/Csf1r(-) mice were more severe than those of the Csf1(op)/Csf1(op) mice. The results indicate that all of the effects of CSF-1 are mediated via the CSF-1R, but that subtle effects of the CSF-1R could result from its CSF-1-independent activation.


Determinants of Muscle and Bone Aging.
Loss of bone and muscle with advancing age represent a huge threat to loss of independence in later life. Osteoporosis represents a major public health problem through its association with fragility fractures, primarily of the hip, spine and distal forearm. Sarcopenia, the age related loss of muscle mass and function, may add to fracture risk by increasing falls risk. In the context of muscle aging, it is important to remember that it is not just a decline in muscle mass which contributes to the deterioration of muscle function. Other factors underpinning muscle quality come into play, including muscle composition, aerobic capacity and metabolism, fatty infiltration, insulin resistance, fibrosis and neural activation. Genetic, developmental, endocrine and lifestyle factors, such as physical activity, smoking and poor diet have dual effects on both muscle and bone mass in later life and these will be reviewed here. Recent work has highlighted a possible role for the early environment. Inflammaging is an exciting emerging research field that is likely to prove relevant to future work, including interventions designed to retard to reverse bone and muscle loss with age.


A Toxoplasma Prolyl Hydroxylase Mediates Oxygen Stress Responses by Regulating Translation Elongation.
As the protozoan parasite Toxoplasma gondii disseminates through its host, it responds to environmental changes by altering its gene expression, metabolism, and other processes. Oxygen is one variable environmental factor, and properly adapting to changes in oxygen levels is critical to prevent the accumulation of reactive oxygen species and other cytotoxic factors. Thus, oxygen-sensing proteins are important, and among these, 2-oxoglutarate-dependent prolyl hydroxylases are highly conserved throughout evolution. Toxoplasma expresses two such enzymes, TgPHYa, which regulates the SCF-ubiquitin ligase complex, and TgPHYb. To characterize TgPHYb, we created a Toxoplasma strain that conditionally expresses TgPHYb and report that TgPHYb is required for optimal parasite growth under normal growth conditions. However, exposing TgPHYb-depleted parasites to extracellular stress leads to severe decreases in parasite invasion, which is likely due to decreased abundance of parasite adhesins. Adhesin protein abundance is reduced in TgPHYb-depleted parasites as a result of inactivation of the protein synthesis elongation factor eEF2 that is accompanied by decreased rates of translational elongation. In contrast to most other oxygen-sensing proteins that mediate cellular responses to low O2, TgPHYb is specifically required for parasite growth and protein synthesis at high, but not low, O2 tensions as well as resistance to reactive oxygen species. In vivo, reduced TgPHYb expression leads to lower parasite burdens in oxygen-rich tissues. Taken together, these data identify TgPHYb as a sensor of high O2 levels, in contrast to TgPHYa, which supports the parasite at low O2IMPORTANCE Because oxygen plays a key role in the growth of many organisms, cells must know how much oxygen is available. O2-sensing proteins are therefore critical cellular factors, and prolyl hydroxylases are the best-studied type of O2-sensing proteins. In general, prolyl hydroxylases trigger cellular responses to decreased oxygen availability. But, how does a cell react to high levels of oxygen? Using the protozoan parasite Toxoplasma gondii, we discovered a prolyl hydroxylase that allows the parasite to grow at elevated oxygen levels and does so by regulating protein synthesis. Loss of this enzyme also reduces parasite burden in oxygen-rich tissues, indicating that sensing both high and low levels of oxygen impacts the growth and physiology of Toxoplasma.


Adaptive hidden Markov model with anomaly States for price manipulation detection.
Price manipulation refers to the activities of those traders who use carefully designed trading behaviors to manually push up or down the underlying equity prices for making profits. With increasing volumes and frequency of trading, price manipulation can be extremely damaging to the proper functioning and integrity of capital markets. The existing literature focuses on either empirical studies of market abuse cases or analysis of particular manipulation types based on certain assumptions. Effective approaches for analyzing and detecting price manipulation in real time are yet to be developed. This paper proposes a novel approach, called adaptive hidden Markov model with anomaly states (AHMMAS) for modeling and detecting price manipulation activities. Together with wavelet transformations and gradients as the feature extraction methods, the AHMMAS model caters to price manipulation detection and basic manipulation type recognition. The evaluation experiments conducted on seven stock tick data from NASDAQ and the London Stock Exchange and 10 simulated stock prices by stochastic differential equation show that the proposed AHMMAS model can effectively detect price manipulation patterns and outperforms the selected benchmark models.


Using costs in cost-effectiveness models for chronic diseases: lessons from diabetes.
Cost-effectiveness models for chronic diseases frequently require simulating the development of disease complications over a long period. Model development often focuses on disease progression, with less attention devoted to costs. To identify key challenges in incorporating costs in cost-effectiveness models for chronic diseases. We use our experience in developing and applying a diabetes cost-effectiveness model to illustrate the challenges in incorporating costs in cost-effectiveness models for chronic diseases. Costs used in cost-effectiveness analyses for chronic diseases are sometimes drawn from a variety of published sources with little concern about consistency between sources or the underlying functional form for costs. Identifying costs of complications in chronic disease modeling often receives inadequate attention compared to the time and effort devoted to modeling disease progression. Costs of averted complications typically cannot be estimated during a trial, because these complications begin to accrue years after the intervention. Complication costs may be estimated through gross-costing, using an additive cost function with individual complication costs derived from difference sources, or through cost regressions that apply a multiplicative functional form using a single data source. The choice between additive and multiplicative cost functions may affect the cost-effectiveness ratios generated by the model. Current guidelines do not provide much guidance on choosing between the costing approaches. Developing a set of standard cost estimates might streamline the modeling process for chronic diseases, but standardization will require careful attention to functional form and the selection of appropriate data sets.


Recombinant human secretory phospholipase A2 released thromboxane from guinea pig bronchoalveolar lavage cells: in vitro and ex vivo evaluation of a novel secretory phospholipase A2 inhibitor.
The primary objective of this study was to develop a functional assay that could provide rapid and reliable information on some pharmacologic characteristics of a novel inhibitor of human secretory phospholipase A2 (sPLA2). Guinea pig bronchoalveolar lavage (BAL) fluid, containing predominantly macrophages, eosinophils and epithelial cells, released thromboxane A2, as measured by thromboxane B2, in a concentration-dependent manner on exposure to recombinant human sPLA2 (rh-sPLA2). Similarly, n-formyl-L-methionyl-L-leucyl-L-phenylalanine (n-F-Met-Leu-Phe) or arachidonic acid also released this lipid mediator. Indomethacin, a cyclooxygenase inhibitor, blocked synthesis of thromboxane in response to these agents. p-Bromophenacylbromide-inactivated rh-sPLA2 was substantially less effective than the untreated enzyme in causing release of thromboxane. LY311727 is a potent indole-derived inhibitor of the isolated enzyme (IC50 = 23 nM). Incubation of this agent with BAL cells, just before addition of rh-sPLA2, reduced release of thromboxane with an IC50 = 1.8 x 10(-6) M. Specificity for sPLA2 was demonstrated in that LY311727, unlike indomethacin, did not reduce synthesis and subsequent release of thromboxane A2 in response to arachidonic acid. Using this technique as a basis, we determined whether LY311727 could sufficiently accumulate in lung after i.v. administration to inhibit rh-sPLA2-induced thromboxane A2 release from BAL cells. The compound, given i.v. to guinea pigs 5 min before collecting BAL fluid, produced a dose-dependent inhibition of rh-sPLA2 with an ED50 = 50 mg/kg. Thus, new in vitro and ex vivo assays were developed that permit functional evaluation of novel sPLA2 inhibitors. These techniques should serve as secondary assays for evaluation of human sPLA2 inhibitory activity from a chemical series and in addition provide initial data related to metabolic stability and distribution to the lung.


Progress of Induced Pluripotent Stem Cell Technologies to Understand Genetic Epilepsy.
The study of the pathomechanisms by which gene mutations lead to neurological diseases has benefit from several cellular and animal models. Recently, induced Pluripotent Stem Cell (iPSC) technologies have made possible the access to human neurons to study nervous system disease-related mechanisms, and are at the forefront of the research into neurological diseases. In this review, we will focalize upon genetic epilepsy, and summarize the most recent studies in which iPSC-based technologies were used to gain insight on the molecular bases of epilepsies. Moreover, we discuss the latest advancements in epilepsy cell modeling. At the two dimensional (2D) level, single-cell models of iPSC-derived neurons lead to a mature neuronal phenotype, and now allow a reliable investigation of synaptic transmission and plasticity. In addition, functional characterization of cerebral organoids enlightens neuronal network dynamics in a three-dimensional (3D) structure. Finally, we discuss the use of iPSCs as the cutting-edge technology for cell therapy in epilepsy.


Chirality transfer effects in proline-substituted coumarin compounds.
Conformations of proline-substituted chromophores are determined by using circular dichroism (CD) spectroscopy and quantum chemistry calculation method. Coumarin is chosen for the optical chromophore and proline amino acid is attached to its C7 position. The coumarin-proline conjugate considered contains both fluorophore and peptide linker where any polypeptides or biomolecules can be additionally connected to the free carboxyl group of the proline. Thus, the coumarin-proline is a potentially useful composite chirality-probe system for studies of protein dynamics in solution. However, detailed conformation of coumarin ring with respect to the proline ring has to be determined first. We found that there are two possible conformers, which differ from each other by the relative orientation of the coumarin ring. Comparing the measured CD spectra with the calculated ones, we directly show that only one of the two conformers is dominant in polar solvents except for water. The present study suggests that the local structure around an optical chromophore, when it is introduced to polypeptides or other biomolecules, can be studied by examining the electronic optical activity of the probe chromophore, as long as the chirality transfer from the attached amino acid to the chromophore is significantly large.


Secular Changes in the Postcranial Skeleton of American Whites.
Secular change in height has been extensively investigated, but size and shape of the postcranial skeleton much less so. The availability of large, documented collections of nineteenth- and twentieth-century skeletons makes it possible to examine changes in skeletal structure over the past 150 years. We examined secular changes in long bone lengths and proportions, their allometric relationship to stature, and crosssectional properties of long bone shafts. Bone measurements and stature were organized into 10-year birth cohorts, ranging from 1840 to 1989. Variation among cohorts was tested by one-way ANOVA, and secular trend was examined visually by plotting mean measurements by birth decade. Allometry was examined by regressing log bone lengths onto log stature, using least squares regression. Allometry was also examined using the geometric mean of log bone lengths as the size variable. All bone lengths and stature showed positive secular change. Stature and the distal long bones showed the most pronounced changes. Proportions also changed, as revealed by the brachial and crural indices. Both indices increased, but the brachial index change was the most pronounced. Allometric relationships suggest that brachial index changes result from positive allometry of the radius and negative allometry of the humerus. Similar but less marked allometric relationships were found in the tibia and femur. Long bone shaft properties changed in the following ways: femur midshafts and tibia shafts at the nutrient foramen became more mediolaterally narrowed, and the femur became more mediolaterally thickened at the subtrochanteric level, approaching platymeria. All major long bones became more gracile. These remarkable changes in the postcranial skeleton are a response to the unparalleled changes in the environment in which modern Americans now live. Changes in growth resulting from plentiful and secure nutrition, reduced disease load, and marked reduction in bone loading from reduced activity levels are mainly responsible.


Genetic prion disease: the EUROCJD experience.
A total of 10-15% of human transmissible spongiform encephalopathies (TSEs) or prion diseases are characterised by disease-specific mutations in the prion protein gene (PRNP). We examined the phenotype, distribution, and frequency of genetic TSEs (gTSEs) in different countries/geographical regions. We collected standardised data on gTSEs between 1993 and 2002 in the framework of the EUROCJD collaborative surveillance project. Our results show that clinicopathological phenotypes include genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Gerstmann-Sträussler-Scheinker disease (GSS). Genetic TSE patients with insert mutation in the PRNP represent a separate group. Point and insertional mutations in the PRNP gene varies significantly in frequency between countries. The commonest mutation is E200K. Absence of a positive family history is noted in a significant proportion of cases in all mutation types (12-88%). FFI and GSS patients develop disease earlier than gCJD. Base pair insertions associated with the Creutzfeldt-Jakob disease (CJD) phenotype, GSS, and FFI cases have a longer duration of illness compared to cases with point mutations and gCJD. Cerebrospinal fluid 14-3-3 immunoassay, EEG, and MRI brain scan are useful in the diagnosis of CJD with point mutations, but are less sensitive in the other forms. Given the low prevalence of family history, the term "gTSE" is preferable to "familial TSE". Application of genetic screening in clinical practice has the advantage of early diagnosis and may lead to the identification of a risk of a TSE.


The anti-proliferative function of the TGF-β1 signaling pathway involves the repression of the oncogenic TBX2 by its homologue TBX3.
A growing body of work has shown that the highly homologous T-box transcription factors TBX2 and TBX3 play critical but distinct roles in embryonic development and cancer progression. For example, TBX2 and TBX3 are up-regulated in several cancers and recent evidence suggests that whereas TBX2 functions as a pro-proliferative factor, TBX3 inhibits cell proliferation but promotes cancer cell migration and invasion. While the molecular mechanisms regulating these functions of TBX2 and TBX3 are poorly understood we recently reported that the TGF-β1 signaling pathway up-regulates TBX3 expression to mediate, in part, its well described anti-proliferative and pro-migratory roles. The TBX3 targets responsible for these functions were however not identified. Here we reveal for the first time that the TGF-β1 signaling pathway represses TBX2 transcriptionally and we provide a detailed mechanism to show that this is mediated by TBX3. Furthermore, we implicate the down-regulation of TBX2 in the anti-proliferative function of the TGF-β1-TBX3 axis. These findings have important implications for our understanding of the regulation of TBX2 and TBX3 and shed light on the mechanisms involved in the anti-proliferative and pro-migratory roles of TGF-β1.


Child malnutrition in Ifanadiana district, Madagascar: associated factors and timing of growth faltering ahead of a health system strengthening intervention.
Child malnutrition, a leading cause of death and disability worldwide, is particularly severe in Madagascar, where 47% of children under 5 years are stunted (low height-for-age) and 8% are wasted (low weight-for-height). Widespread poverty and a weak health system have hindered attempts to implement life-saving malnutrition interventions in Madagascar during critical periods for growth faltering. This study aimed to shed light on the most important factors associated with child malnutrition, both acute and chronic, and the timing of growth faltering, in Ifanadiana, a rural district of Madagascar. We analyzed data from a 2014 district-representative cluster household survey, which had information on 1175 children ages 6 months to 5 years. We studied the effect of child health, birth history, maternal and paternal health and education, and household wealth and sanitation on child nutritional status. Variables associated with stunting and wasting were modeled separately in multivariate logistic regressions. Growth faltering was modeled by age range. All analyses were survey-adjusted. Stunting was associated with increasing child age (OR = 1.03 (95%CI 1.02-1.04) for each additional month), very small birth size (OR = 2.32 (1.24-4.32)), low maternal weight (OR = 0.94 (0.91-0.97) for each kilogram, kg) and height (OR = 0.95 (0.92-0.99) for each centimeter), and low paternal height (OR = 0.95 (0.92-0.98)). Wasting was associated with younger child age (OR = 0.98 (0.97-0.99)), very small birth size (OR = 2.48 (1.23-4.99)), and low maternal BMI (OR = 0.84 (0.75-0.94) for each kg/m2). Height-for-age faltered rapidly before 24 months, then slowly until age 5 years, whereas weight-for-height faltered rapidly before 12 months, then recovered gradually until age 5 years but did not reach the median. Intergenerational transmission of growth faltering and early life exposures may be important determinants of malnutrition in Ifanadiana. Timing of growth faltering, in the first 1000 days, is similar to international populations; however, child growth does not recover to the median.


Epidemiologic and genetic aspects of spina bifida and other neural tube defects.
The worldwide incidence of neural tube defects (NTDs) ranges from 1.0 to 10.0 per 1,000 births with almost equal frequencies between two major categories: anencephaly and spina bifida (SB). Epidemiological studies have provided valuable insight for (a) researchers to identify nongenetic and genetic factors contributing to etiology, (b) public health officials to design and implement policies to prevent NTD pregnancies, and (c) individuals to take precautions to reduce the chance of having an NTD-affected pregnancy. Despite extensive research, our knowledge of the genetic etiology of human NTDs is limited. Although more than 200 small animal models with NTDs exist, most of these models do not replicate the human disease phenotype. Over a hundred candidate genes have been examined for risk association to human SB. The candidate genes studied include those important in folic acid metabolism, glucose metabolism, retinoid metabolism, and apoptosis. Many genes that regulate transcription in early embryogenesis and maintain planar cell polarity have also been tested as candidates. Additionally, genes identified through mouse models of NTDs have been explored as candidates. We do not know how many genes in the human genome may confer risk for NTDs in human. Less than 20% of the studied candidate genes have been determined to confer even a minor effect on risk association. Many studies have provided conflicting conclusions due to limitations in study design that potentially affect the power of statistical analysis. Future directions such as genomewide association studies (GWAS) and whole exome or even whole genome sequencing are discussed as possible avenues to identify genes that affect risk for human NTDs.


GeneMarker® HID: A reliable software tool for the analysis of forensic STR data.
GeneMarker(®) HID was assessed as a software tool for the analysis of forensic short tandem repeat (STR) data and as a resource for analysis of custom STR multiplexes. The software is easy to learn and use, and includes design features that have the potential to reduce user fatigue. To illustrate reliability and accuracy, STR data from both single-source and mixture profiles were analyzed and compared to profiles interpreted with another software package. A total of 1898 STR profiles representing 28,470 loci and more than 42,000 alleles were analyzed with 100% concordance. GeneMarker HID was also used to successfully analyze data generated from a custom STR multiplex, with simplified and rapid implementation. Finally, the impact of the user-friendly design features of the software was assessed through a time scale study. The results suggest that laboratories can reduce the time required for data analysis by at least 25% when using GeneMarker HID.


Extracellular Superoxide Dismutase Expression in Papillary Thyroid Cancer Mesenchymal Stem/Stromal Cells Modulates Cancer Cell Growth and Migration.
Tumor stroma-secreted growth factors, cytokines, and reactive oxygen species (ROS) influence tumor development from early stages to the metastasis phase. Previous studies have demonstrated downregulation of ROS-producing extracellular superoxide dismutase (SOD3) in thyroid cancer cell lines although according to recent data, the expression of SOD3 at physiological levels stimulates normal and cancer cell proliferation. Therefore, to analyze the expression of SOD3 in tumor stroma, we characterized stromal cells from the thyroid. We report mutually exclusive desmoplasia and inflammation in papillary and follicular thyroid cancers and the presence of multipotent mesenchymal stem/stromal cells (MSCs) in non-carcinogenic thyroids and papillary thyroid cancer (PTC). The phenotypic and differentiation characteristics of Thyroid MSCs and PTC MSCs were comparable with bone marrow MSCs. A molecular level analysis showed increased FIBROBLAST ACTIVATING PROTEIN, COLLAGEN 1 TYPE A1, TENASCIN, and SOD3 expression in PTC MSCs compared to Thyroid MSCs, suggesting the presence of MSCs with a fibrotic fingerprint in papillary thyroid cancer tumors and the autocrine-paracrine conversion of SOD3 expression, which was enhanced by cancer cells. Stromal SOD3 had a stimulatory effect on cancer cell growth and an inhibitory effect on cancer cell migration, thus indicating that SOD3 might be a novel player in thyroid tumor stroma.


Evaluation of in vitro Assays to Assess the Modulation of Dendritic Cells Functions by Therapeutic Antibodies and Aggregates.
Therapeutic antibodies have the potential to induce immunogenicity leading to the development of anti-drug antibodies (ADA) that consequently may result in reduced serum drug concentrations, a loss of efficacy or potential hypersensitivity reactions. Among other factors, aggregated antibodies have been suggested to promote immunogenicity, thus enhancing ADA production. Dendritic cells (DC) are the most efficient antigen-presenting cell population and are crucial for the initiation of T cell responses and the subsequent generation of an adaptive immune response. This work focuses on the development of predictive in vitro assays that can monitor DC maturation, in order to determine whether drug products have direct DC stimulatory capabilities. To this end, four independent laboratories aligned a common protocol to differentiate human monocyte-derived DC (moDC) that were treated with either native or aggregated preparations of infliximab, natalizumab, adalimumab, or rituximab. These drug products were subjected to different forms of physical stress, heat and shear, resulting in aggregation and the formation of subvisible particles. Each partner developed and optimized assays to monitor diverse end-points of moDC maturation: measuring the upregulation of DC activation markers via flow cytometry, analyzing cytokine, and chemokine production via mRNA and protein quantification and identifying cell signaling pathways via quantification of protein phosphorylation. These study results indicated that infliximab, with the highest propensity to form aggregates when heat-stressed, induced a marked activation of moDC as measured by an increase in CD83 and CD86 surface expression, IL-1β, IL-6, IL-8, IL-12, TNFα, CCL3, and CCL4 transcript upregulation and release of respective proteins, and phosphorylation of the intracellular signaling proteins Syk, ERK1/2, and Akt. In contrast, natalizumab, which does not aggregate under these stress conditions, induced no DC activation in any assay system, whereas adalimumab or rituximab aggregates induced only slight parameter variation. Importantly, the data generated in the different assay systems by each partner site correlated and supported the use of these assays to monitor drug-intrinsic propensities to drive maturation of DC. This moDC assay is also a valuable tool as an in vitro model to assess the intracellular mechanisms that drive DC activation by aggregated therapeutic proteins.


Attributions of Blame in a Hypothetical Child Sexual Abuse Case: Roles of Behavior Problems and Frequency of Abuse.
Youth who are blamed for their sexual abuse may experience increased negative outcomes, such as amplified self-blame. Similarly, blaming nonoffending parents can impede their ability to support their child following disclosure. Understanding the factors that influence how people perceive victim, caregiver, and perpetrator responsibility is imperative for the protection and treatment of families who have experienced sexual abuse. Little research has explored victim and abuse characteristics that influence the perception of sexual abuse. As such, the purpose of this study was to examine the roles of behavior problems and frequency of abuse in the attribution of blame in a hypothetical sexual abuse case. In addition, the relationship between several respondent characteristics and assignment of responsibility were explored as secondary aims. The study used a two (behavior problems: three suspensions in one school semester vs. no mention of behavior problems) by two (one abuse occurrence vs. five abuse occurrences) between-subjects design. Seven hundred forty-two participants read one of the four child sexual abuse (CSA) vignettes and completed measures related to responsibility. ANOVAs revealed those who read a vignette where the youth experienced multiple abuse incidents rated the victim as more responsible regardless of whether or not the youth was described as having behavior problems. Results indicate that respondents may have attributed more blame to the victim due to the belief that she could have done something to stop the abuse after the first incident. The abuse frequency manipulation when combined with the behavior manipulation appeared to relate to how respondents perceived the victim's parents. Males and younger respondents attributed more blame to the victim; however, sexual abuse or assault history did not associate with victim responsibility ratings. Clinical and research implications were discussed.


In vitro transcription of the Escherichia coli K-12 argA, argE, and argCBH operons.
Deoxyribonucleic acid isolated from argA and argECBH transducing phages was utilized to study the in vitro synthesis of argA, argE, and argCBH messenger ribonucleic acid. The specific regulation of these operons by the arginine holorepressor was demonstrated, providing evidence that the majority, if not all, of the control of these operons is exercised at the transcriptional level. Data are presented which indicate that the arginine holorepressor functions by binding to the operator region and concomitantly prevents the binding of ribonucleic acid polymerase to the corresponding promoter region.


Association of Serum T cell Immunoglobulin Domain and Mucin-3 and Interleukin-17 with Systemic Lupus Erythematosus.
BACKGROUND Previous studies have shown that T cell immunoglobulin domain and mucin-3 (Tim-3) and interleukin-17 (IL-17) are implicated in the development of several autoimmune diseases. However, it is unclear whether these proteins contribute to the pathogenesis of systemic lupus erythematosus (SLE). The purpose of this study was to evaluate SLE patient serum Tim-3 and IL-17 levels, and to assess correlations between these proteins and major clinical parameters of SLE. MATERIAL AND METHODS Overall, 55 SLE patients and 55 healthy controls were recruited in a case-control study. Serum Tim-3 and IL-17 levels were quantified using an enzyme-linked immunosorbent assay (ELISA) kit. RESULTS Serum Tim-3 and IL-17 levels in SLE patients were significantly elevated relative to healthy controls (all P<0.05). Serum Tim-3 levels were significantly lower in SLE patients with nephritis than in those SLE without nephritis (P<0.05), while no statistically significant correlation between serum IL-17 and nephritis was detected (P>0.05). Serum Tim-3 with IL-17 levels were positively correlated in SLE patients (rs=0.817, P<0.01); however, no statistically significant correlation was found between serum Tim-3 or IL-17 levels and systemic lupus erythematosus disease activity index (SLEDAI) scores in those with SLE (all P>0.05). In addition, serum Tim-3 was associated with central lesions in SLE patients, while there were no significant correlations between serum Tim-3 or IL-17 levels and other SLE clinical parameters. CONCLUSIONS Increased serum Tim-3 and IL-17 levels and their clinical associations in SLE patients suggest their possible role in this disease.


Identification of cells of the human mononuclear phagocyte system with rat monoclonal antibodies.
Five rat monoclonal antibodies (McAbs) to human macrophages are described: YTH 8.18, YTH 25.7, YTH 51.1, YTH 85.12.1, and YHB 65.5. These McAbs are divided into three groups, since YTH 8.18, YTH 51.1, and YHB 65.5 are thought to identify the same antigen. These McAbs react with some bone marrow blast cells, granulocytes, and different percentages of peripheral blood monocytes. When studied on different body tissues, they were found to identify all members of the mononuclear phagocyte system (MPS), except Langerhans cells of skin and epithelium and in the case of one group (YTH 8.18/YTH 51.1/YHB 65.5) osteoclasts. In nine reactive lymph nodes the anti macrophage McAbs identified germinal centre macrophages, sinus macrophages, and interdigitating cells, but not dendritic reticulum cells. They also identified epithelioid macrophages and Langhans-type multi-nucleated giant cells in lymph nodes involved in granulomatous lesions (sarcoidosis and toxoplasmosis). In 24 cases of non-Hodgkin's lymphoma, the antimacrophage McAbs identified reactive macrophages in cases of B- or T-lymphocyte origin, whereas in three selected cases of true histiocytic lymphoma all the McAbs were found to be reactive with the vast majority of neoplastic macrophages as they were with the cells of a neoplastic macrophage line (U937). The possible use of these McAbs in the identification of benign and malignant macrophages in different systems is discussed.


Oral intake of soy isoflavone aglycone improves the aged skin of adult women.
A double-blind, placebo-controlled trial was conducted to clinically evaluate the effect of soy isoflavone aglycone on the aged skin of middle-aged women. Twenty-six women volunteers in their late 30s and early 40s were randomly assigned to receive either a test food (13 women, the test food group) or a placebo food (13 women, the control group). These groups were given the test food (40 mg of soy isoflavone aglycone per day) and placebo, respectively, for 12 wk. The extent of linear and fine wrinkles at the lateral angle of the eyes was selected as the major evaluation criterion to assess the effects of foods, and the wrinkles' area ratio was used as the evaluation parameter. The extent of skin microrelief at the lateral angle of eyes and that of malar skin elasticity were used as secondary evaluation criteria, and the skin microrelief's area ratio and recovery of skin elasticity were used as the respective evaluation parameters. These parameters were assessed 4, 8, and 12 wk after the start of the test food or placebo intake. The test food group showed a statistically significant improvement of fine wrinkles at week 12 (p<0.05) and of malar skin elasticity at week 8 (p<0.05), compared with the control group. Although there was no significant difference between the test food group and the control group regarding effects on skin microrelief at lateral angle of the eyes, a significant intragroup improvement was observed at week 8 in the test food group (p<0.05). As for the test food safety, none of the subjects presented adverse symptoms during the study period or discontinued the intake of the test food. These data indicate that the oral intake of 40 mg soy isoflavone aglycones per day improves the aged skin of middle-aged women.


Manipulation of glycemic response with isomaltulose in a milk-based drink does not affect cognitive performance in healthy adults.
Previous research suggests that glucoregulation and nutrient interventions, which alter circulating glucose, impact cognitive function. To examine the effect of modulating glycemic response using isomaltulose on cognitive function 24 healthy male adult participants consumed energy and macronutrient-matched milk-based drinks containing 50 g isomaltulose, 50 g sucrose or a water control in a counterbalanced within-subject design. Interstitial glucose was measured continuously in 12 subjects and all provided 9 capillary measures on each test day. A 30-min cognitive test battery was administered before and twice (+35 and +115 min) after drink ingestion. Immediate, delayed, recognition, verbal and working memory, and psychomotor performance were assessed. Glycemic profiles induced by the drinks differed significantly during the first but not the second post-drink test battery. Neither administration of the sucrose nor isomaltulose drinks produced consistent effects on verbal or working memory, or psychomotor performance. This study used isomaltulose as an investigative tool to lower glycemic response. Importantly, it demonstrates a lack of effect of modulating glucose on cognitive performance based on reliable, continuously measured glycemia. It refutes the hypothesis that glycemia is associated with cognitive performance and questions the suggestion that isomaltulose has an effect on cognitive performance.


Psychometric evaluation of 'The 25-item Sex after MI Knowledge Test' in a Swedish context.
The patients' sexual life after a myocardial infarction is important for his/her quality of life. In spite of this, many patients are in doubt regarding their sex life after a myocardial infarction (MI) and the sexual information received, and counselling from health care providers has been seen to be insufficient. The purpose of this study was to evaluate the psychometric properties of 'The 25-item Sex after MI Knowledge Test' in a Swedish context. A convenience sample was recruited. The scale was translated into Swedish and completed by 79 former patients from The Heart and Lung Patients' National Association on two occasions, with an interval of 2 weeks. The scale was tested for face and content validity, internal consistency and test-retest reliability. The result in this study indicates that the instrument has good face and content validity and displayed a moderate internal consistency (alpha 0.61). The instrument showed some level of instability in test-retest reliability with 60% of the items presenting moderate or strong agreement between the test and retest. Further studies that use this instrument in larger and more diverse samples are thus needed.


Age-Related Neural Oscillation Patterns During the Processing of Temporally Manipulated Speech.
This EEG-study aims to investigate age-related differences in the neural oscillation patterns during the processing of temporally modulated speech. Viewing from a lifespan perspective, we recorded the electroencephalogram (EEG) data of three age samples: young adults, middle-aged adults and older adults. Stimuli consisted of temporally degraded sentences in Swedish-a language unfamiliar to all participants. We found age-related differences in phonetic pattern matching when participants were presented with envelope-degraded sentences, whereas no such age-effect was observed in the processing of fine-structure-degraded sentences. Irrespective of age, during speech processing the EEG data revealed a relationship between envelope information and the theta band (4-8 Hz) activity. Additionally, an association between fine-structure information and the gamma band (30-48 Hz) activity was found. No interaction, however, was found between acoustic manipulation of stimuli and age. Importantly, our main finding was paralleled by an overall enhanced power in older adults in high frequencies (gamma: 30-48 Hz). This occurred irrespective of condition. For the most part, this result is in line with the Asymmetric Sampling in Time framework (Poeppel in Speech Commun 41:245-255, 2003), which assumes an isomorphic correspondence between frequency modulations in neurophysiological patterns and acoustic oscillations in spoken language. We conclude that speech-specific neural networks show strong stability over adulthood, despite initial processes of cortical degeneration indicated by enhanced gamma power. The results of our study therefore confirm the concept that sensory and cognitive processes undergo multidirectional trajectories within the context of healthy aging.


Thermal transport in electrospun vinyl polymer nanofibers: effects of molecular weight and side groups.
Understanding and enhancing thermal transport in polymers is of great importance, and is necessary to enable next-generation flexible electronics, heat exchangers, and energy storage devices. Over the past several decades, significant enhancement of the thermal conductivity of polymeric materials has been achieved, but several key questions related to the effects of molecular structure on thermal transport still remain. By studying a series of electrospun vinyl polymer nanofibers, we investigate the relationship between thermal conductivity and both molecular chain length and side group composition. For polyethylene nanofibers with different molecular weights, the measured thermal conductivity increases monotonically with molecular chain length, as energy transport along molecular chains is more efficient than between chains. The observed trend is also consistent with structural characterization by Raman spectroscopy, which shows enhanced crystallinity as molecular weight increases. Further, by comparing the measured thermal conductivity of vinyl polymer nanofibers with different side groups, we found that phonons travel along polymer chains more effectively when the side groups are either lighter or more symmetric. These experimental results help reveal the underlying correlation between the molecular structure and thermal conductivity of polymer nanofibers, providing valuable insights into the design of polymeric materials with enhanced thermal conductivity.


Six-Year Follow-up of Slaughterhouse Surveillance (2008-2013): The Catalan Slaughterhouse Support Network (SESC).
Meat inspection has the ultimate objective of declaring the meat and offal obtained from carcasses of slaughtered animals fit or unfit for human consumption. This safeguards the health of consumers by ensuring that the food coming from these establishments poses no risk to public health. Concomitantly, it contributes to animal disease surveillance. The Catalan Public Health Protection Agency (Generalitat de Catalunya) identified the need to provide its meat inspectors with a support structure to improve diagnostic capacity: the Slaughterhouse Support Network (SESC). The main goal of the SESC was to offer continuing education to meat inspectors to improve the diagnostic capacity for lesions observed in slaughterhouses. With this aim, a web-based application was designed that allowed meat inspectors to submit their inquiries, images of the lesions, and samples for laboratory analysis. This commentary reviews the cases from the first 6 years of SESC operation (2008-2013). The program not only provides continuing education to inspectors but also contributes to the collection of useful information on animal health and welfare. Therefore, SESC complements animal disease surveillance programs, such as those for tuberculosis, bovine cysticercosis, and porcine trichinellosis, and is a powerful tool for early detection of emerging animal diseases and zoonoses.


Mutism and amnesia following high-voltage electrical injury: psychogenic symptomatology triggered by organic dysfunction?
Mutism and dense retrograde amnesia are found both in organic and dissociative contexts. Moreover, dissociative symptoms may be modulated by right prefrontal activity. A single case, M.R., developed left hemiparesis, mutism and retrograde amnesia after a high-voltage electric shock without evidence of lasting brain lesions. M.R. suddenly recovered from his mutism following a mild brain trauma 2 years later. M.R.'s neuropsychological pattern and anatomoclinical correlations were studied through (i) language and memory assessment to characterize his deficits, (ii) functional neuroimaging during a standard language paradigm, and (iii) assessment of frontal and left insular connectivity through diffusion tractography imaging and transcranial magnetic stimulation. A control evaluation was repeated after recovery. M.R. recovered from the left hemiparesis within 90 days of the accident, which indicated a transient right brain impairment. One year later, neurobehavioral, language and memory evaluations strongly suggested a dissociative component in the mutism and retrograde amnesia. Investigations (including MRI, fMRI, diffusion tensor imaging, EEG and r-TMS) were normal. Twenty-seven months after the electrical injury, M.R. had a very mild head injury which was followed by a rapid recovery of speech. However, the retrograde amnesia persisted. This case indicates an interaction of both organic and dissociative mechanisms in order to explain the patient's symptoms. The study also illustrates dissociation in the time course of the two different dissociative symptoms in the same patient.


Body temperature differentially affects ethanol sensitivity in both inbred strains and selected lines of mice.
Offsetting ethanol-induced hypothermia in five inbred strains of mice changed ethanol sensitivity within strains and markedly reduced differences between strains in brain sensitivity to hypnotic ethanol doses. The present study extended this work to mice selectively bred for sensitivity and resistance to ethanol-induced loss of righting reflex (LORR) and hypothermia. In all experiments LORR duration and ethanol concentrations at return of righting reflex were measured after i.p. hypnotic ethanol doses and exposure to 22 or 34 degrees C. In experiment 1, C57BL/6J, A/HeJ, 129/J, LS/lbg and SS/lbg mice were given 4.2 g/kg ethanol. In experiment 2, the same mouse genotypes were tested with different ethanol doses (2.5-4.9 g/kg) selected to produce an equivalent degree of impairment (60 min LORR duration). In experiment 3, HOT and COLD lines of mice were given 4.0 g/kg ethanol. In agreement with previous work, offsetting hypothermia reduced differences between genotypes in ethanol sensitivity. Comparisons within genotypes indicated that ethanol sensitivity in C57, A/He, SS, HOT and COLD mice increased as body temperature increased. In contrast, ethanol sensitivity in 129 and LS mice decreased as body temperature increased. These results extend previous findings indicating that body temperature during intoxication contributes to differences between genotypes in ethanol sensitivity. The present findings also suggest that there are qualitative differences in the effects of temperature on ethanol sensitivity within genotypes.


Effects of external beam radiation on in vitro formation of Abeta1-42 fibrils and preformed fibrils.
Plaques containing fibrillar amyloid-beta (Abeta) are a characteristic finding in Alzheimer's disease. Although plaque counts correlate poorly with the extent of cognitive deficits in this disorder, fibrillar Abeta can promote neuronal damage through a variety of mechanisms. External beam radiotherapy has been reported to be an effective treatment for tracheobronchial amyloidosis, in which amyloid is deposited as submucosal plaques and tumor-like masses in the trachea and/or bronchi. Radiotherapy's effectiveness in this disorder is thought to be due to its toxicity to plasma cells, but direct effects of radiotherapy on amyloid may also be involved. On this basis, whole-brain radiotherapy has been suggested as a treatment for Alzheimer's disease. The objective of this study was to determine the effects of external beam radiation on preformed Abeta1-42 fibrils and on the formation of these fibrils. Using the Thioflavin-T assay, no effects of radiation were found on either of these parameters. Our results in this in vitro study suggest that whole-brain irradiation is unlikely to directly reduce plaque counts in the Alzheimer's disease brain. This treatment might still lower plaque counts indirectly, but any potential benefits would need to be weighed against its possible neurotoxic effects, which could induce further cognitive deficits.


Studies on the molecular mechanism of bioactivation of the selective nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
Detailed studies have been carried out on the monoamine oxidase B-catalyzed bioactivation of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by rat brain mitochondrial preparations. Isolates of incubation mixtures run in H2O and D2O displayed chemical ionization mass spectral characteristics expected for the 1-methyl-4-phenyl-2,3-dihydropyridinium species MPDP+, a proposed intermediate in the biotransformation of MPTP to the 1-methyl-4-phenylpyridinium metabolite (MPP+) previously characterized in both in vitro and in vivo experiments. Further characterization of MPDP+ was achieved by comparison of the diode array UV spectral tracings of the metabolite with synthetic MPDP+ perchlorate (CIO4-) and by the isolation of a cyano adduct from mitochondrial coincubation mixtures of MPTP and sodium cyanide. MPDP+ CIO4- was shown to undergo disproportionation to MPP+ and MPTP, a reaction which suggests that this molecule may participate in redox reactions with dopamine that could lead to neurotoxic oxidation products.


Further Stabilization of Alcalase Immobilized on Glyoxyl Supports: Amination Plus Modification with Glutaraldehyde.
Alcalase was immobilized on glyoxyl 4% CL agarose beads. This permitted to have Alcalase preparations with 50% activity retention versus Boc-l-alanine 4-nitrophenyl ester. However, the recovered activity versus casein was under 20% at 50 °C, as it may be expected from the most likely area of the protein involved in the immobilization. The situation was different at 60 °C, where the activities of immobilized and free enzyme became similar. The chemical amination of the immobilized enzyme or the treatment of the enzyme with glutaraldehyde did not produce any significant stabilization (a factor of 2) with high costs in terms of activity. However, the modification with glutaraldehyde of the previously aminated enzyme permitted to give a jump in Alcalase stability (e.g., with most than 80% of enzyme activity retention for the modified enzyme and less than 30% for the just immobilized enzyme in stress inactivation at pH 7 or 9). This preparation could be used in the hydrolysis of casein at pH 9 even at 67 °C, retaining around 50% of the activity after 5 hydrolytic cycles when the just immobilized preparation was almost inactive after 3 cycles. The modified enzyme can be reused in hydrolysis of casein at 45 °C and pH 9 for 6 cycles (6 h) without any decrease in enzyme activity.


Uncomplicated Plasmodium vivax malaria in pregnancy associated with mortality from acute respiratory distress syndrome.
The association between severe malaria and Plasmodium vivax species is contentious. On the Thai-Myanmar border, all pregnant women are followed systematically with active weekly malaria screening. Over a 27-year period of providing antenatal care, 48,983 have been prospectively followed until pregnancy outcome (miscarriage or delivery) and 4,298 women have had P. vivax detected at least once. Reported here is the first known P. vivax-associated death amongst these women. The initial patient presentation was of uncomplicated P. vivax (0.5% parasitaemia) in a term, multigravida woman who responded rapidly to oral artesunate and mefloquine treatment, clearing her blood stage parasites within 48 hours. The patient appeared well, was ambulatory and due to be discharged but became unwell with acute respiratory distress syndrome (ARDS) requiring ventilation three days (67 hours) into treatment. Despite induction and delivery of a stillborn foetus, ventilatory requirements increased and the patient died on day 7. The patient had a low body mass index. Sensitive detection with nested PCR confirmed only the presence of P. vivax species and concomitant infections such as tuberculosis and human immunodeficiency virus (HIV) were also ruled out. The contemporaneous treatment of acute uncomplicated P. vivax and the onset of ARDS on day 3 in this patient implies a possible but unconfirmed association with death in this patient. Assuming this death was caused by P. vivax, the risk of ARDS-related maternal mortality in this setting did not differ significantly between Plasmodium falciparum and P. vivax (0.24 per 1,000 (1/4,158) versus 0.23 per 1,000 (1/4,298), contrary to the increased risk of maternal mortality from P. falciparum compared to P. vivax, 2.89 per 1,000 (12/4,158) versus 0.23 per 1,000 (1/4,298), P = 0.003.


Low energy diet and intracranial pressure in women with idiopathic intracranial hypertension: prospective cohort study.
To observe intracranial pressure in women with idiopathic intracranial hypertension who follow a low energy diet. Prospective cohort study. Outpatient department and the clinical research facility based at two separate hospitals within the United Kingdom. 25 women with body mass index (BMI) >25, with active (papilloedema and intracranial pressure >25 cm H(2)O), chronic (over three months) idiopathic intracranial hypertension. Women who had undergone surgery to treat idiopathic intracranial hypertension were excluded. Stage 1: no new intervention; stage 2: nutritionally complete low energy (calorie) diet (1777 kJ/day (425 kcal/day)); stage 3: follow-up period after the diet. Each stage lasted three months. The primary outcome was reduction in intracranial pressure after the diet. Secondary measures included score on headache impact test-6, papilloedema (as measured by ultrasonography of the elevation of the optic disc and diameter of the nerve sheath, together with thickness of the peripapillary retina measured by optical coherence tomography), mean deviation of Humphrey visual field, LogMAR visual acuity, and symptoms. Outcome measures were assessed at baseline and three, six, and nine months. Lumbar puncture, to quantify intracranial pressure, was measured at baseline and three and six months. All variables remained stable over stage 1. During stage 2, there were significant reductions in weight (mean 15.7 (SD 8.0) kg, P<0.001), intracranial pressure (mean 8.0 (SD 4.2) cm H(2)O, P<0.001), score on headache impact test (7.6 (SD 10.1), P=0.004), and papilloedema (optic disc elevation (mean 0.15 (SD 0.23) mm, P=0.002), diameter of the nerve sheath (mean 0.7 (SD 0.8) mm, P=0.004), and thickness of the peripapillary retina (mean 25.7 (SD 36.1) micro, P=0.001)). Mean deviation of the Humphrey visual field remained stable, and in only five patients, the LogMAR visual acuity improved by one line. Fewer women reported symptoms including tinnitus, diplopia, and obscurations (10 v 4, P=0.004; 7 v 0, P=0.008; and 4 v 0, P=0.025, respectively). Re-evaluation at three months after the diet showed no significant change in weight (0.21 (SD 6.8) kg), and all outcome measures were maintained. Women with idiopathic intracranial hypertension who followed a low energy diet for three months had significantly reduced intracranial pressure compared with pressure measured in the three months before the diet, as well as improved symptoms and reduced papilloedema. These reductions persisted for three months after they stopped the diet.


Oxford meniscal bearing knee versus the Marmor knee in unicompartmental arthroplasty for arthrosis. A Swedish multicenter survival study.
In the Swedish Knee Arthroplasty Study, all 699 Oxford meniscal bearing cemented unicompartmental prostheses (Biomet, Bridgend, UK) were identified and analyzed regarding failure pattern and compared with all Marmor prostheses (Smith & Nephew Richards, Orthez, France) and with a time-, age-, and sex-matched subset of Marmor prostheses using survival statistics expressed as cumulative revision rates. After 1 year there was already a higher rate, and after 6 years the rate of the Oxford group was more than twice that of the Marmor group. There were 50 revisions in the Oxford group: dislocating meniscus in 16, loosening of the femoral component in 6, tibial component in 4, both components in 4, contralateral arthrosis in 10, infection in 4, and technical failure with instability, pain, and/or impingement of the meniscal bearing anterior in the femoral condyle in 6. It is still unclear if the design with the sliding menisci will, in the long turn, reduce wear and loosening, thereby compensating for the initially inferior results. It is recommended that until this question is clarified, the Oxford knee should be used on a limited scale for long-term comparative studies only.


Association of ABO blood groups with diabetes mellitus.
So far no studies have been performed in Malaysia to look at association of diabetes mellitus (DM) with blood groups. We studied the association of ABO blood groups with DM type 2. It was a case control study conducted at Kepala Batas Hospital Batas, Penang, Malaysia in the year 2009, involving 70 patients with DM type 2 and 140 healthy controls. Ethical approval was obtained from Universiti Sains Malaysia. Blood samples were collected from the patients after consent. Samples were tested for ABO blood groups using ID-Card gel method. Chi-square test results showed that there was an association between the ABO blood groups and DM type 2. It was found that A and O blood groups were negatively associated with DM type 2 (P<0.05) with higher percentage of A and O groups individuals were non-diabetic. No significant association was noted between DM type 2 and blood groups B (P=0.423) and AB (P=0.095). It was also noted that B blood group was distributed with highest percentage among patients with DM type 2 (53.71%) compared to controls (22.52%), but no statistical significance achieved. The results obtained suggest that there was a negative association between ABO blood groups A and O with DM type 2, with A and O group having less chances of diabetes. Large studies in other ethnic groups are needed to confirm these results.


First-line antiretroviral therapy with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor and switch at higher versus low viral load in HIV-infected children: an open-label, randomised phase 2/3 trial.
Children with HIV will be on antiretroviral therapy (ART) longer than adults, and therefore the durability of first-line ART and timing of switch to second-line are key questions. We assess the long-term outcome of protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) first-line ART and viral load switch criteria in children. In a randomised open-label factorial trial, we compared effectiveness of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor versus two NRTIs plus an NNRTI and of switch to second-line ART at a viral load of 1000 copies per mL versus 30,000 copies per mL in previously untreated children infected with HIV from Europe and North and South America. Random assignment was by computer-generated sequentially numbered lists stratified by age, region, and by exposure to perinatal ART. Primary outcome was change in viral load between baseline and 4 years. Analysis was by intention to treat, which we defined as all patients that started treatment. This study is registered with ISRCTN, number ISRCTN73318385. Between Sept 25, 2002, and Sept 7, 2005, 266 children (median age 6.5 years; IQR 2.8-12.9) were randomly assigned treatment regimens: 66 to receive protease inhibitor and switch to second-line at 1000 copies per mL (PI-low), 65 protease inhibitor and switch at 30,000 copies per mL (PI-higher), 68 NNRTI and switch at 1000 copies per mL (NNRTI-low), and 67 NNRTI and switch at 30,000 copies per mL (NNRTI-higher). Median follow-up was 5.0 years (IQR 4.2-6.0) and 188 (71%) children were on first-line ART at trial end. At 4 years, mean reductions in viral load were -3.16 log(10) copies per mL for protease inhibitors versus -3.31 log(10) copies per mL for NNRTIs (difference -0.15 log(10) copies per mL, 95% CI -0.41 to 0.11; p=0.26), and -3.26 log(10) copies per mL for switching at the low versus -3.20 log(10) copies per mL for switching at the higher threshold (difference 0.06 log(10) copies per mL, 95% CI -0.20 to 0.32; p=0.56). Protease inhibitor resistance was uncommon and there was no increase in NRTI resistance in the PI-higher compared with the PI-low group. NNRTI resistance was selected early, and about 10% more children accumulated NRTI mutations in the NNRTI-higher than the NNRTI-low group. Nine children had new CDC stage-C events and 60 had grade 3/4 adverse events; both were balanced across randomised groups. Good long-term outcomes were achieved with all treatments strategies. Delayed switching of protease-inhibitor-based ART might be reasonable where future drug options are limited, because the risk of selecting for NRTI and protease-inhibitor resistance is low. Paediatric European Network for Treatment of AIDS (PENTA) and Pediatric AIDS Clinical Trials Group (PACTG/IMPAACT).


Higher-order Kerr terms allow ionization-free filamentation in gases.
We show that higher-order nonlinear indices (n(4), n(6), n(8), n(10)) provide the main defocusing contribution to self-channeling of ultrashort laser pulses in air and argon at 800 nm, in contrast with the previously accepted mechanism of filamentation where plasma was considered as the dominant defocusing process. Their consideration allows us to reproduce experimentally observed intensities and plasma densities in self-guided filaments.


Alcoholic beverage consumption and associated factors in Porto Alegre, a southern Brazilian city: a population-based survey.
To describe the pattern of alcoholic beverage consumption and the prevalence of at risk drinking behaviors, as well as their association with demographic and socioeconomic factors in the adult population of Porto Alegre, a southern Brazilian city. In a cross-sectional, population-based, multistage random sampling study, 1,091 (600 female) individuals (92% of those eligible) were selected and interviewed at home. Exposure to alcohol was measured by the CAGE questionnaire and by inquiring about the type, quantity and frequency of alcoholic beverage consumption. An average consumption of 30 g per day or more, a level of exposure associated with health risks, was considered as heavy drinking. Two positive answers to the GAGE questionnaire represented the cutoff for indicating dependence. The prevalences were: 9.3% (95% CI: 7.6 to 11.0) for dependence, 15.5% (13.4 to 17.7) for heavy drinking and 12.3% (10.4 to 14.2) for daily drinking; 24.1% (21.7 to 26.6) were abstinent. Women consumed alcoholic beverages in lower frequency and amounts than men. The most widely consumed beverages were beer, wine and "cachaça," a Brazilian sugarcane spirit. In a logistic regression model, increasing age, lower education and income, and nonwhite race were associated with heavy drinking and dependence. Households with 3-4 persons were associated with the lowest risk of heavy drinking, but the prevalence of dependence was higher in crowded households. The presence of another heavy drinker or dependent in the household was associated with heavy drinking but not with dependence. The study characterized a detailed pattern of alcoholic beverage use and indicated that at risk drinking is an important public health problem in a developing country. The risk factors for heavy drinking and dependence were the same, with the exception of age at starting to drink, heavy drinking or dependence-positive household members.


Reliability of transvaginal ultrasonography at 7-9 weeks' gestation in the determination of chorionicity and amnionicity in twin pregnancies.
To assess the agreement in the diagnosis of chorionicity and amnionicity between transvaginal ultrasound examination at 7-9 weeks' gestation and at the 11-14-week transabdominal scan. This was a retrospective analysis of prospectively collected data of twin pregnancies over a 3-year period. Chorionicity and amnionicity were assessed in women with viable twin pregnancies who underwent a transvaginal ultrasound scan at between 7 and 9 weeks' gestation. These findings were compared with the diagnoses of chorionicity and amnionicity at the subsequent 11-14-week scan in these women. Chorionicity and amnionicity were documented in 67 viable twin pregnancies at both 7-9 and 11-14 weeks' gestation. There was agreement in the chorionicity and amnionicity reported at each of the two scans in 65 out of 67 (97%) cases. Of the dichorionic-diamniotic (DCDA) pregnancies reported at 7-9 weeks, 53 out of 54 (98%) were confirmed at the 11-14-week scan and one (2%) was found to be monochorionic-diamniotic (MCDA). However, at birth these twins were of different sex, confirming DCDA twins as initially diagnosed at 7-9 weeks. Of the 12 pregnancies diagnosed as MCDA at 7-9 weeks, all were found to be MCDA at the 11-14-week scan. There was one monochorionic-monoamniotic (MCMA) pregnancy diagnosed at 7-9 weeks that was subsequently found to be MCDA at the 11-14-week scan. Transvaginal ultrasound examination at 7-9 weeks' gestation shows very high agreement with the 11-14-week scan in the diagnosis of chorionicity and amnionicity in twin pregnancies, suggesting that it provides a similar level of accuracy. Accuracy may be higher for DC twins than MC twins, which may relate to the gestational age at which the sonographic appearance of the amniotic sac develops.


Glutamine-enriched parenteral nutrition after autologous peripheral blood stem cell transplantation: effects on immune reconstitution and mucositis.
Glutamine (gln), a non-essential amino acid, has recently received increasing attention because it becomes essential during stress and catabolic states: glutamine seems to modulate immune function and to promote faster intestinal healing after chemotherapy. We designed two consecutive randomized clinical trials to evaluate the role of glutamine-enriched parenteral nutrition (GEPN) in patients with hematologic malignancies submitted to high dose chemotherapy and autologous peripheral blood stem cell transplantation (aPBSCT) or immunoselected CD34+ aPBSCT. In study1, the Gln group (12 patients) received total parenteral nutrition (TPN) enriched with glutamine 20 g from day +1 after aPBSCT, while the placebo group (15 patients) received TPN lacking in glutamine (placebo). In study2, the Gln group (10 patients) received TPN enriched with glutamine 13.46 g from day +1, while the placebo group (11 patients) received a placebo. In the first study, a lymphocyte count >0.5 109/L was achieved on day 16.5 in the Gln group and on day 29 in the placebo group (p=0.005); in the second study, the lymphocyte count >0.5 109/L was achieved on day 18 in the Gln group and on day 29 in the placebo group (p=0.009). Lymphocyte subset analysis showed an increase of CD3+ and CD4+ and normalization of the CD16+CD56+ subset. Furthermore patients receiving GEPN showed a decrease in the mucositis severity peak calculated by the DMS (daily mucositis score: sum of the daily score of signs and symptoms) (p=0.047). GEPN is safe and effective and improves lymphocyte recovery after aPBSCT; further studies are needed to assess the clinical benefits of such an approach in order to justify its economic impact.


The computation of finite-time Lyapunov exponents on unstructured meshes and for non-Euclidean manifolds.
We generalize the concepts of finite-time Lyapunov exponent (FTLE) and Lagrangian coherent structures to arbitrary Riemannian manifolds. The methods are illustrated for convection cells on cylinders and Mobius strips, as well as for the splitting of the Antarctic polar vortex in the spherical stratosphere and a related point vortex model. We modify the FTLE computational method and accommodate unstructured meshes of triangles and tetrahedra to fit manifolds of arbitrary shape, as well as to facilitate dynamic refinement of the FTLE mesh.


Facile preparation of hybrid thin films composed of spin-crossover nanoparticles and carbon nanotubes for electrical memory devices.
In this study, organic solvent-dispersible nanoparticles of an FeII-1,2,4-triazole spin-crossover complex were synthesized. On mixing the suspension of the spin-crossover nanoparticles with a solution of single-walled carbon nanotubes (SWCNTs), the nanoparticles were strongly adsorbed on the hydrophobic SWCNT bundles, resulting in hybrid network structures. Variable temperature DC electrical conductivity measurements of the hybrid network thin films demonstrated that the conductivities of the composite films were switched by the spin transition of the nanoparticles.


Fire and herbivory drive fungal and bacterial communities through distinct above- and belowground mechanisms.
Fire and herbivory are important natural disturbances in grassy biomes. Both drivers are likely to influence belowground microbial communities but no studies have unravelled the long-term impact of both fire and herbivory on bacterial and fungal communities. We hypothesized that soil bacterial communities change through disturbance-induced shifts in soil properties (e.g. pH, nutrients) while soil fungal communities change through vegetation modification (biomass and species composition). To test these ideas, we characterised soil physico-chemical properties (pH, acidity, C, N, P and exchangeable cations content, texture, bulk density, moisture), plant species richness and biomass, microbial biomass and bacterial and fungal community composition and diversity (using 16S and ITS rRNA amplicon sequencing, respectively) in six long-term (18 to 70 years) ecological research sites in South African savanna and grassland ecosystems. We found that fire and herbivory regimes profoundly modified soil physico-chemical properties, plant species richness and standing biomass. In all sites, an increase in woody biomass (ranging from 12 to 50%) was observed when natural disturbances were excluded. The intensity and direction of changes in soil properties were highly dependent on the topo-pedo-climatic context. Overall, fire and herbivory shaped bacterial and fungal communities through distinct driving forces: edaphic properties (including Mg, pH, Ca) for bacteria, and vegetation (herbaceous biomass and woody cover) for fungi. Fire and herbivory explained on average 7.5 and 9.8% of the fungal community variability, respectively, compared to 6.0 and 5.6% for bacteria. The relatively small changes in microbial communities due to natural disturbance is in stark contrast to dramatic vegetation and edaphic changes and suggests that soil microbial communities, having evolved with disturbance, are resistant to change. This represents both a buffer to short-term anthropogenic-induced changes and a restoration challenge in the face of long-term changes.


Longitudinal course of self-labeling, stigma stress and well-being among young people at risk of psychosis.
Stigma may undermine the well-being of young people at risk of psychosis. We therefore measured self-labeling, stigma variables and well-being at baseline and again one year later among 77 at-risk participants. An increase in self-labeling during this period predicted heightened stigma stress after one year and a decrease in stigma stress predicted better well-being at follow-up, controlling for symptoms, psychiatric comorbidity and sociodemographic variables. Besides early intervention programmes, strategies are needed to reduce the public stigma associated with at-risk status and to support young people at risk to better cope with self-labeling and stigma stress.


Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin.
Genomic studies have linked mTORC1 pathway-activating mutations with exceptional response to treatment with allosteric inhibitors of mTORC1 called rapalogs. Rapalogs are approved for selected cancer types, including kidney and breast cancers. Here, we used sequencing data from 22 human kidney cancer cases to identify the activating mechanisms conferred by mTOR mutations observed in human cancers and advance precision therapeutics. mTOR mutations that clustered in focal adhesion kinase targeting domain (FAT) and kinase domains enhanced mTORC1 kinase activity, decreased nutrient reliance, and increased cell size. We identified 3 distinct mechanisms of hyperactivation, including reduced binding to DEP domain-containing MTOR-interacting protein (DEPTOR), resistance to regulatory associated protein of mTOR-mediated (RAPTOR-mediated) suppression, and altered kinase kinetics. Of the 28 mTOR double mutants, activating mutations could be divided into 6 complementation groups, resulting in synergistic Rag- and Ras homolog enriched in brain-independent (RHEB-independent) mTORC1 activation. mTOR mutants were resistant to DNA damage-inducible transcript 1-mediated (REDD1-mediated) inhibition, confirming that activating mutations can bypass the negative feedback pathway formed between HIF1 and mTORC1 in the absence of von Hippel-Lindau (VHL) tumor suppressor expression. Moreover, VHL-deficient cells that expressed activating mTOR mutants grew tumors that were sensitive to rapamycin treatment. These data may explain the high incidence of mTOR mutations observed in clear cell kidney cancer, where VHL loss and HIF activation is pathognomonic. Our study provides mechanistic and therapeutic insights concerning mTOR mutations in human diseases.


Transitions to substance use and sexual intercourse among South african high school students.
This study examined longitudinal patterns of initiating substance use and sexual intercourse among a sample of 1,143 high school students from a low-income township in Cape Town, South Africa. Longitudinal data on lifetime incidence of sexual intercourse and alcohol and marijuana use were collected semiannually from 2004 to 2006. Latent transition analysis (LTA) was used to test competing models of transitions to these behaviors. Participants were more likely to move from no risk behavior to substance use, rather than from no risk behavior to sexual intercourse. At all time points, the proportion of youth who had engaged in sexual intercourse but not substance use was very small. The study's limitations and directions for future research are discussed.


Seizure forecasting and cyclic control of seizures.
Epilepsy is a unique neurologic condition characterized by recurrent seizures, where causes, underlying biomarkers, triggers, and patterns differ across individuals. The unpredictability of seizures can heighten fear and anxiety in people with epilepsy, making it difficult to take part in day-to-day activities. Epilepsy researchers have prioritized developing seizure prediction algorithms to combat episodic seizures for decades, but the utility and effectiveness of prediction algorithms has not been investigated thoroughly in clinical settings. In contrast, seizure forecasts, which theoretically provide the probability of a seizure at any time (as opposed to predicting the next seizure occurrence), may be more feasible. Many advances have been made over the past decade in the field of seizure forecasting, including improvements in algorithms as a result of machine learning and exploration of non-EEG-based measures of seizure susceptibility, such as physiological biomarkers, behavioral changes, environmental drivers, and cyclic seizure patterns. For example, recent work investigating periodicities in individual seizure patterns has determined that more than 90% of people have circadian rhythms in their seizures, and many also experience multiday, weekly, or longer cycles. Other potential indicators of seizure susceptibility include stress levels, heart rate, and sleep quality, all of which have the potential to be captured noninvasively over long time scales. There are many possible applications of a seizure-forecasting device, including improving quality of life for people with epilepsy, guiding treatment plans and medication titration, optimizing presurgical monitoring, and focusing scientific research. To realize this potential, it is vital to better understand the user requirements of a seizure-forecasting device, continue to advance forecasting algorithms, and design clear guidelines for prospective clinical trials of seizure forecasting.


DNA2 and EXO1 in replication-coupled, homology-directed repair and in the interplay between HDR and the FA/BRCA network.
During DNA replication, stalled replication forks and DSBs arise when the replication fork encounters ICLs (interstrand crosslinks), covalent protein/DNA intermediates or other discontinuities in the template. Recently, homologous recombination proteins have been shown to function in replication-coupled repair of ICLs in conjunction with the Fanconi anemia (FA) regulatory factors FANCD2-FANCI, and, conversely, the FA gene products have been shown to play roles in stalled replication fork rescue even in the absence of ICLs, suggesting a broader role for the FA network than previously appreciated. Here we show that DNA2 helicase/nuclease participates in resection during replication-coupled repair of ICLs and other replication fork stresses. DNA2 knockdowns are deficient in HDR (homology-directed repair) and the S phase checkpoint and exhibit genome instability and sensitivity to agents that cause replication stress. DNA2 is partially redundant with EXO1 in these roles. DNA2 interacts with FANCD2, and cisplatin induces FANCD2 ubiquitylation even in the absence of DNA2. DNA2 and EXO1 deficiency leads to ICL sensitivity but does not increase ICL sensitivity in the absence of FANCD2. This is the first demonstration of the redundancy of human resection nucleases in the HDR step in replication-coupled repair, and suggests that DNA2 may represent a new mediator of the interplay between HDR and the FA/BRCA pathway.


Hamaker constants in integrated circuit metalization.
A new method for determining Hamaker constants was examined for materials of interest in integrated circuit manufacture. An ultra-high vacuum atomic force microscope and an atomic force microscope operated in a nitrogen environment were used to measure the interaction forces between metals, dielectrics, and barriers used during the metalization portion of integrated circuit manufacturing. The materials studied included copper, silver, titanium nitride, silicon dioxide, poly(tetrafluoroethylene), and parylene-N. Spheres coated with a material of interest were mounted on AFM cantilevers and brought into contact with substrates of interest. The interaction force was measured as the cantilever approached the substrate but before the two surfaces came into contact, and also when the particle was pulled out of contact with the substrate. The Hamaker constant calculation from the contact measurement is based on an adhesion model that quantifies the contribution of geometrical, morphological and mechanical properties of materials to the measured adhesion force. Hamaker constants determined with this new approach were compared with values found by using the Derjaguin approximation for a sphere to describe the interaction force as the cantilever approaches the surface. Both approaches produced similar values for most of the systems studied, with variations of less than 10%.


Improved hand hygiene technique and compliance in healthcare workers using gaming technology.
In 2009, the World Health Organization recommended the use of a 'multi-faceted, multi-modal hand hygiene strategy' (Five Moments for Hand Hygiene) to improve hand hygiene compliance among healthcare workers. As part of this initiative, a training programme was implemented using an automated gaming technology training and audit tool to educate staff on hand hygiene technique in an acute healthcare setting. To determine whether using this automated training programme and audit tool as part of a multi-modal strategy would improve hand hygiene compliance and technique in an acute healthcare setting. A time-series quasi-experimental design was chosen to measure compliance with the Five Moments for Hand Hygiene and handwashing technique. The study was performed from November 2009 to April 2012. An adenosine triphosphate monitoring system was used to measure handwashing technique, and SureWash (Glanta Ltd, Dublin, Ireland), an automated auditing and training unit, was used to provide assistance with staff training and education. Hand hygiene technique and compliance improved significantly over the study period (P < 0.0001). Incorporation of new automated teaching technology into a hand hygiene programme can encourage staff participation in learning, and ultimately improve hand hygiene compliance and technique in the acute healthcare setting.


CRIPTO and miR-371a-3p Are Serum Biomarkers of Testicular Germ Cell Tumors and Are Detected in Seminal Plasma from Azoospermic Males.
miR-371a-3p is currently the most informative reported biomarker for germ cell tumors (GCTs). Another developmental-related biomarker, CRIPTO, is involved in the regulation of pluripotency and germ cell fate commitment. We aimed to assess the value of CRIPTO as a diagnostic and prognostic biomarker of testicular GCTs (TGCTs) and also to assess its presence in seminal plasma samples, compared with miR-371a-3p. In total, 217 and 94 serum/seminal plasma samples were analyzed. CRIPTO was quantified using ELISA and miR-371a-3p using bead-based isolation followed by RT-qPCR. Methylation profiling (EPIC array) for the CRIPTO promoter region was undertaken in 35 TGCT tissues plus four (T)GCT cell lines. Significantly higher CRIPTO concentration was found in sera of non-seminomas compared to controls (p = 0.0297), and in stage II/III disease compared to stage I (p = 0.0052, p = 0.0097). CRIPTO concentration was significantly positively correlated with miR-371a-3p levels in serum (r = 0.16) and seminal plasma (r = 0.40). CRIPTO/miR-371a-3p levels were significantly higher in seminal plasma controls when compared to serum controls (p = 0.0001, p < 0.0001). CRIPTO/miR-371a-3p were detected both in normospermic and azoospermic males, and levels were higher in TGCTs compared to GCNIS-only. We have provided the largest dataset of evaluation of CRIPTO in serum and seminal plasma of GCTs, showing its potential value as a biomarker of the disease.


Relative Contribution of Magnetic Resonance Imaging, Microelectrode Recordings, and Awake Test Stimulation in Final Lead Placement during Deep Brain Stimulation Surgery of the Subthalamic Nucleus in Parkinson's Disease.
For deep brain stimulation (DBS) surgery of the subthalamic nucleus (STN) in Parkinson's disease (PD), many centers employ visualization of the nucleus on magnetic resonance imaging (MRI), intraoperative microelectrode recordings (MER), and test stimulation in awake patients. The value of these steps is a subject for ongoing debate. In the current study, we determined the relative contribution of MRI targeting, multitrack MER, and awake test stimulation in final lead placement during STN DBS surgery for PD. Data on PD patients undergoing MRI-targeted STN DBS surgery with three-channel MER and awake test stimulation between February 2010 and January 2014 were analyzed to determine in which MER trajectory final leads were implanted and why this tract was chosen. Seventy-six patients underwent implantation of 146 DBS leads. In 92% of the STN, the final leads were implanted in one of the three planned channels. In 6%, additional channels were needed. In 2%, surgery was aborted before final lead implantation due to anxiety or fatigue. The final leads were implanted in the channels with the longest STN MER signal trajectory in 60% of the STN (38% of the bilaterally implanted patients). This was the central channel containing the MRI target in 39% of the STN (18% bilaterally). The most frequently noted reasons why another channel than the central channel was chosen for final lead placement were (1) a lower threshold for side effects (54%) and (2) no or a too short trajectory of the STN MER signal (40%) in the central channel. The latter reason correlated with larger 2D (x and y) errors in our stereotactic method. STN DBS leads were often not implanted in the MRI-planned trajectory or in the trajectory with the longest STN MER signal. Thresholds for side effects during awake test stimulation were decisive for final target selection in the majority of patients.


Abnormal visual phenomena in posterior cortical atrophy.
Individuals with posterior cortical atrophy (PCA) report a host of unusual and poorly explained visual disturbances. This preliminary report describes a single patient (CRO), and documents and investigates abnormally prolonged colour afterimages (concurrent and prolonged perception of colours complimentary to the colour of an observed stimulus), perceived motion of static stimuli, and better reading of small than large letters. We also evaluate CRO's visual and vestibular functions in an effort to understand the origin of her experience of room tilt illusion, a disturbing phenomenon not previously observed in individuals with cortical degenerative disease. These visual symptoms are set in the context of a 4-year longitudinal neuropsychological and neuroimaging investigation of CRO's visual and other cognitive skills. We hypothesise that prolonged colour after-images are attributable to relative sparing of V1 inhibitory interneurons; perceived motion of static stimuli reflects weak magnocellular function; better reading of small than large letters indicates a reduced effective field of vision; and room tilt illusion effects are caused by disordered integration of visual and vestibular information. This study contributes to the growing characterisation of PCA whose atypical early visual symptoms are often heterogeneous and frequently under-recognised.


Hand hygiene and aseptic techniques during routine anesthetic care - observations in the operating room.
More knowledge is needed about task intensity in relation to hand hygiene in the operating room during anesthetic care in order to choose effective improvement strategies. The aim of this study was to explore the indications and occurrence of hand hygiene opportunities and the adherence to hand hygiene guidelines during routine anesthetic care in the operating room. Structured observational data on hand hygiene during anesthetic care during 94 surgical procedures was collected using the World Health Organization's observational tool in a surgical department consisting of 16 operating rooms serving different surgical specialties such as orthopedic, gynecological, urological and general surgery. A total of 2,393 opportunities for hand hygiene was recorded. The number of hand hygiene opportunities when measured during full-length surgeries was mean = 10.9/hour, SD 6.1 with an overall adherence of 8.1%. The corresponding numbers for the induction phase were, mean =77.5/h, SD 27.4 with an associated 3.1% adherence to hand hygiene guidelines. Lowest adherence was observed during the induction phase before an aseptic task (2.2%) and highest during full-length surgeries after body fluid exposure (15.9%). There is compelling evidence for low adherence to hand hygiene guidelines in the operating room and thus an urgent need for effective improvement strategies. The conclusion of this study is that any such strategy should include education and practical training in terms of how to carry out hand hygiene and aseptic techniques and how to use gloves correctly. Moreover it appears to be essential to optimize the work processes in order to reduce the number of avoidable hand hygiene opportunities thereby enhancing the possibilities for adequate use of HH during anesthetic care.


Spatial variations in STIs among women enrolled in HIV prevention clinical trials in Durban, KwaZulu-Natal, South Africa.
South Africa is faced with a high HIV and STI prevalence and incidence, respectively, with pockets of high burden areas driving these diseases. Localised monitoring of the HIV epidemic and STI endemic would enable more effective targeted prevention strategies. We assessed spatial variations in curable STI incidence among a cohort of women enrolled in HIV prevention clinical trials between 2002 and 2012. STI incidence rates from 7557 South African women enrolled in five HIV prevention trials were geo-mapped using participant household GPS coordinates. Age and period standardised incidence rates were calculated for 43 recruitment areas and Bayesian conditional autoregressive areal spatial regression (CAR) was used to identify significant patterns and spatial patterns of STI infections in recruitment communities. Overall age and period standardised STI incidence rate were estimated as 15 per 100 PY and ranged from 6 to 24 per 100 PY. We identified five significant STI high risk areas with higher-than-expected incidence of STIs located centrally (three-locations) and southern neighbouring areas of Durban (two-locations). Younger age (<25), not married/cohabitating, parity <3 and poor education were all significant correlates of high STI communities. Findings demonstrate sustained STI incidence rates across the greater Durban area. The role of STI incidence in HIV acquisition in high HIV endemic areas need to be revisited as current highly effective PrEP interventions do not protect from STI acquisition. In these settings there is an urgent need for integrative HIV and STI prevention and treatment services.


Acupuncture for the Treatment of Cardiovascular Diseases: A Systematic Review.
Acupuncture, for the westerns countries, is an innovative and low-cost therapy for treatment and prevention of cardiovascular diseases (CVDs). However, most of its effects and mechanisms are poorly understood. Thus, the objective of this work was to systematically review the literature regarding the clinical effects of acupuncture for the treatment and prevention of CVDs. A search for papers published in English or Portuguese in the past 20 years was conducted at PubMed, SciELO, and PEDro databases. Clinical trials conducted on the effects of acupuncture were included in this review. Two reviewers extracted the data independently from the remaining 17 articles after screening. The most used acupoint was PC6 (10 studies, 64.7%), followed by ST36 (6 studies, 35.3%) and auricular acupoints (4 studies, 23.5%). Among the clinical applications, hypertension was the most studied CVD, with acupuncture being the most reported method among the studies (70.6%). Only three articles reported no benefit in the treatment of CVDs for the methodology used. We conclude that although several studies indicated an improvement in the response of the cardiovascular system in CVDs by acupuncture, electroacupuncture, or electrostimulation treatment, the heterogeneity of the studies does not allow a standardization of its application for each specific disease, making further studies necessary for its use to become a reality.


A systematic review of dietary protein during caloric restriction in resistance trained lean athletes: a case for higher intakes.
Caloric restriction occurs when athletes attempt to reduce body fat or make weight. There is evidence that protein needs increase when athletes restrict calories or have low body fat. The aims of this review were to evaluate the effects of dietary protein on body composition in energy-restricted resistance-trained athletes and to provide protein recommendations for these athletes. Database searches were performed from earliest record to July 2013 using the terms protein, and intake, or diet, and weight, or train, or restrict, or energy, or strength, and athlete. Studies (N = 6) needed to use adult (≥ 18 yrs), energy-restricted, resistance-trained (> 6 months) humans of lower body fat (males ≤ 23% and females ≤ 35%) performing resistance training. Protein intake, fat free mass (FFM) and body fat had to be reported. Body fat percentage decreased (0.5-6.6%) in all study groups (N = 13) and FFM decreased (0.3-2.7kg) in nine of 13. Six groups gained, did not lose, or lost nonsignificant amounts of FFM. Five out of these six groups were among the highest in body fat, lowest in caloric restriction, or underwent novel resistance training stimuli. However, the one group that was not high in body fat that underwent substantial caloric restriction, without novel training stimuli, consumed the highest protein intake out of all the groups in this review (2.5-2.6g/kg). Protein needs for energy-restricted resistance-trained athletes are likely 2.3-3.1g/kg of FFM scaled upwards with severity of caloric restriction and leanness.


Effect of phenylephrine on the compartmentation of inorganic phosphate in perfused rat liver during gluconeogenesis and urea synthesis: a 31P-n.m.r.-spectroscopic study.
The transport of Pi between the cytosol and the mitochondria was investigated in perfused rat liver stimulated with phenylephrine and metabolic precursors of glucose and urea: pyruvate, lactate, NH4+ and ornithine. The relative concentrations of phosphorus metabolites in the liver were measured by 31P-n.m.r. spectroscopy. When added simultaneously, phenylephrine and the precursors induced a decrease in the Pi level which in 4-5 min reached a new steady state at 73% of the control level. After 5 min or more of stimulation the ATP level had also decreased. When the stimulation ended, Pi and ATP returned to their initial levels within 15 min. In mitochondria isolated after 5 min of stimulation, Pi was increased more than 2-fold as compared with control mitochondria and, in addition, an accumulation of Pi from the perfusion buffer into the liver was observed. Phenylephrine by itself did not cause any significant changes in the ATP or Pi levels, whereas the glucose and urea precursors in the absence of phenylephrine induced a 9% decrease in Pi, while ATP remained constant. The Pi content of mitochondria isolated under these conditions was not significantly increased as compared with control mitochondria. These results showed that Pi accumulated into the mitochondria by a mechanism possibly involving exchange for malate, and that a major part of the intramitochondrial Pi was invisible by n.m.r.


The validity of self-reported cancer diagnoses and factors associated with accurate reporting in a cohort of older Australian women.
Epidemiological research often ascertains cancer history via self-reported questionnaires. We assessed the validity of self-reported cancer diagnoses in women born 1921-1926 recruited to the Australian Longitudinal Study in Women's Health (ALSWH) and determined the factors associated with false positive (FP) and false negative (FN) reporting. 4234 ALSWH cohort members were asked at baseline (1996) and in subsequent three-yearly surveys whether they had been diagnosed with specific cancers, including breast, cervical, lung and colorectal. We linked the cohort to the population-based New South Wales Central Cancer Registry (CCR) from 1972 to 2005 to identify registered invasive cancers. We calculated sensitivity, specificity and positive predictive value (PPV) of self-reported cancer diagnoses overall, at baseline (prevalent cancers) and follow-up (incident cancers) using the CCR diagnosis as the 'gold standard'. We used adjusted logistic regression to examine the determinants of FP and FN reports. Overall sensitivity was 89.2% (95% CI 86.0-91.7%) and exceeded 90% for breast, lung and colorectal cancer at baseline. Overall specificity was 96.9% (95% CI 96.3-97.5%), however, PPV was lower at 66.5% (95% CI 62.7-70.1%). FN reporting of any cancer at baseline was associated with being born overseas. Sensitivity and specificity of self-reported cancer diagnoses in this cohort of older women (aged 70-75 years at baseline) is high but PPV is comparatively lower. Hence, the use of linked data from population-based cancer registries is recommended for studies of cancer epidemiology. Particular attention must also be paid to country of birth in self-reported cancer data, as these findings suggest cancer will be under-reported by this group of women.


Tyrosine phosphorylation and association with phospholipase C gamma-1 of the GAP-associated 62-kD protein after CD2 stimulation of Jurkat T cell.
Numerous substrates are tyrosine phosphorylated upon CD2 stimulation of human Jurkat T cells using a mitogenic pair of CD2 monoclonal antibodies, including the phospholipase C (PLC)gamma-1-p35/36 complex. Most of these substrates are identically tyrosine phosphorylated after CD3 ligation, suggesting that both stimuli share the same biochemical pathway. We show, however, in this report that a 63-kD protein is specifically phosphorylated on tyrosine residues after ligation of the CD2 molecule. The tyrosine phosphorylation of p63 can be induced independently of other substrates when using a single CD2 mAb recognizing the D66 epitope of the molecule. Importantly, this CD2-induced tyrosine phosphorylation of p63 can also occur in the absence of the CD3 zeta chain membrane expression, and is also distinct from the protein tyrosine kinases p56lck and p59fyn. We demonstrate, moreover, that p63 is physically linked with PLC gamma-1 and p35/36 upon CD2 stimulation. Finally, we also show that a 62-kD protein coimmunoprecipitating with the p21ras GTPase activating protein (GAP) is heavily tyrosine phosphorylated only after CD2 stimulation. This ultimately suggests that p63 may represent in fact the 62-kD protein that associates with GAP after tyrosine phosphorylation. Taken together, these results demonstrate the occurrence in Jurkat cells of a tyrosine kinase pathway specifically coupled to the CD2 molecule. They also suggest a function of the p62-GAP-associated protein as a link between PLC gamma-1 and p21ras activation pathways after CD2 activation.


Patterned radial GaAs nanopillar solar cells.
Photovoltaic devices using GaAs nanopillar radial p-n junctions are demonstrated by means of catalyst-free selective-area metal-organic chemical vapor deposition. Dense, large-area, lithographically defined vertical arrays of nanowires with uniform spacing and dimensions allow for power conversion efficiencies for this material system of 2.54% (AM 1.5 G) and high rectification ratio of 213 (at ±1 V). The absence of metal catalyst contamination results in leakage currents of ∼236 nA at -1 V. High-resolution scanning photocurrent microscopy measurements reveal the independent functioning of each nanowire in the array with an individual peak photocurrent of ∼1 nA at 544 nm. External quantum efficiency shows that the photocarrier extraction highly depends on the degenerately doped transparent contact oxide. Two different top electrode schemes are adopted and characterized in terms of Hall, sheet resistance, and optical transmittance measurements.