Introduction and elimination of Bovine Viral Diarrhoea Virus in a commercial beef herd: a case study.
Routine Bovine Viral Diarrhoea Virus (BVDV) monitoring of a commercial beef herd in southern New South Wales over a 10-year period provided an opportunity to assess the impact of the introduction of BVDV on that herd. BVDV antibody testing provided strong evidence that the herd was initially free of BVDV (2009-2011). Testing from 2012 suggested BVDV had been introduced into the herd and this was confirmed in 2015 with the identification of persistently infected (PI) animals. Having become established in the herd, the owners then set out to eliminate BVDV from the herd. Antigen testing aimed at identifying PI animals revealed BVDV was already absent from the herd. Subsequent antibody testing confirmed that the herd was now free from BVDV. Despite the incursion of BVDV in this herd, there was little measurable impact on reproductive performance (pregnancy rates), although suspected increased calf losses from birth to calf marking were reported. This is the first time such self-clearance has been documented as part of a longitudinal study under Australian conditions.


Early Childhood Household Smoke Exposure Predicts Less Task-Oriented Classroom Behavior at Age 10.
Secondhand tobacco smoke is considered a developmental neurotoxicant especially given underdeveloped vital systems in young children. An ecological test of its negative influence on brain development can be made by examining the prospective association between early childhood household smoke exposure and later classroom behavior. Using a longitudinal birth cohort, we examined the unique contribution of household tobacco smoke exposure to children's subsequent classroom engagement at age 10. From child ages 1.5 to 7 years, parents of 2,055 participants from the Quebec Longitudinal Study of Child Development reported on household smoking by themselves and other home occupants. At age 10, fourth-grade teachers reported on the child's classroom engagement. In terms of prevalence, 58% of parents reported that their children were never exposed to smoke in the home, while 34% and 8% of children were exposed to transient and continuous household smoke, respectively. Compared with never exposed children, those who were exposed to transient and continuous household smoke scored 13% and 9% of a standard deviation lower on classroom engagement in fourth grade, standardized B = -.128 (95% confidence interval = -.186, -.069) and standardized B = -.093 (95% confidence interval = -.144, -.043), respectively. Compared with their never exposed peers, children exposed to transient and continuous early childhood household smoke showed proportionately less classroom engagement, which reflects task-orientation, following directions, and working well autonomously and with others. This predisposition poses risks for high school dropout, which from a population health perspective is closely linked with at-risk lifestyle habits and unhealthy outcomes.


Inferring network connectivity by delayed feedback control.
We suggest a control based approach to topology estimation of networks with N elements. This method first drives the network to steady states by a delayed feedback control; then performs structural perturbations for shifting the steady states M times; and finally infers the connection topology from the steady states' shifts by matrix inverse algorithm (M = N) or l(1)-norm convex optimization strategy applicable to estimate the topology of sparse networks from M << N perturbations. We discuss as well some aspects important for applications, such as the topology reconstruction quality and error sources, advantages and disadvantages of the suggested method, and the influence of (control) perturbations, inhomegenity, sparsity, coupling functions, and measurement noise. Some examples of networks with Chua's oscillators are presented to illustrate the reliability of the suggested technique.


A population-based gene signature is predictive of breast cancer survival and chemoresponse.
It remains a critical issue to improve the survival rate in patients with recurrent or metastatic breast cancer. This study sought to develop a prognostic scheme based on a 28-gene signature in a broad patient population, including those with advanced disease. Clinically annotated transcriptional profiles of 1,734 breast cancer patients were obtained to validate the 28-gene signature in prognostic categorization. The 28-gene signature generated significant patient stratification with regard to breast cancer disease-free survival (log-rank P<0.0001; n=1,337) and overall survival (log-rank P<0.0001; n=806) in Kaplan-Meier analyses. The gene expression signature provides refined prognosis of disease-free survival (log-rank P<0.006; Kaplan-Meier analysis) within each classic clinicopathologic factor-defined subgroup, including LN-, LN+, ER-, ER+ and tumor grade II. Furthermore, it was investigated whether this gene signature predicts chemoresponse to drugs commonly used to treat breast cancer. The mRNA expression levels of this gene signature in NCI-60 cell lines were used to predict chemoresponse to CMF, tamoxifen, paclitaxel, docetaxel, and doxorubicin (adriamycin). The 28-gene prognostic signature accurately (P<0.02) predicted chemotherapeutic response to the studied drugs. This study confirmed the prognostic applicability of the breast cancer gene signature in a broad clinical setting. This prognostic signature is also predictive of drug response in cancer cell lines.


Triclosan causes spontaneous abortion accompanied by decline of estrogen sulfotransferase activity in humans and mice.
Triclosan (TCS), an antibacterial agent, is identified in serum and urine of humans. Here, we show that the level of urinary TCS in 28.3% patients who had spontaneous abortion in mid-gestation were increased by 11.3-fold (high-TCS) compared with normal pregnancies. Oral administration of TCS (10 mg/kg/day) in mice (TCS mice) caused an equivalent urinary TCS level as those in the high-TCS abortion patients. The TCS-exposure from gestation day (GD) 5.5 caused dose-dependently fetal death during GD12.5-16.5 with decline of live fetal weight. GD15.5 TCS mice appeared placental thrombus and tissue necrosis with enhancement of platelet aggregation. The levels of placenta and plasma estrogen sulfotransferase (EST) mRNA and protein in TCS mice or high-TCS abortion patients were not altered, but their EST activities were significantly reduced compared to controls. Although the levels of serum estrogen (E2) in TCS mice and high-TCS abortion patients had no difference from controls, their ratio of sulfo-conjugated E2 and unconjugated E2 was reduced. The estrogen receptor antagonist ICI-182,780 prevented the enhanced platelet aggregation and placental thrombosis and attenuated the fetal death in TCS mice. The findings indicate that TCS-exposure might cause spontaneous abortion probably through inhibition of EST activity to produce placental thrombosis.


[Toward establishment of an economical basis for neurological care in Japan: appropriate assessment of techniques for diagnosis and treatments].
Appropriate assessments for medical techniques of clinical diagnostic examination have been one of long-standing issues in social insurance system in Japan. Assessments of those in the surgical fields in which the most of assessments are evaluated by surgical operations including related materials as well as surgeons' techniques, is rather easy to evaluate quantitatively. Comparing with this, medical fields including neurology, quantitative assessments of medical techniques either diagnostic or treatment is not so easy. In order to evaluate the burden in each technique in the medical fields, several research and surveillance have been performed. In terms of 'duration' of the medical techniques, there have been several date in favor of long duration techniques are evaluated as to be worth to cost higher. However, these data were criticized for the reasons of ignorance of patients' opinion such as satisfaction to the diagnosis and treatments. However, in neurological fields, "the neurological examination techniques" which has a consensus of taking long duration in each patient, was able to be evaluated as an independent item in medical social insurance system in 2008, albeit it is not as technique but as laboratory examination. Towards establishment of the economical basis for medical care, Japanese Neurological Association should have another identity of artisans' union as well as academic union.


Influence of long-range dipolar interactions on the phase stability and hysteresis shapes of ferroelectric and antiferroelectric multilayers.
Phase transition and field driven hysteresis evolution of a two-dimensional Ising grid consisting of ferroelectric-antiferroelectric multilayers that take into account the long range dipolar interactions were simulated by a Monte-Carlo method. Simulations were carried out for a 1 + 1 bilayer and a 5 + 5 superlattice. Phase stabilities of components comprising the structures with an electrostatic-like coupling term were also studied. An electrostatic-like coupling, in the absence of an applied field, can drive the ferroelectric layers toward 180° domains with very flat domain interfaces mainly due to the competition between this term and the dipole-dipole interaction. The antiferroelectric layers do not undergo an antiferroelectric-to-ferroelectric transition under the influence of an electrostatic-like coupling between layers as the ferroelectric layer splits into periodic domains at the expense of the domain wall energy. The long-range interactions become significant near the interfaces. For high periodicity structures with several interfaces, the interlayer long-range interactions substantially impact the configuration of the ferroelectric layers while the antiferroelectric layers remain quite stable unless these layers are near the Neel temperature. In systems investigated with several interfaces, the hysteresis loops do not exhibit a clear presence of antiferroelectricity that could be expected in the presence of anti-parallel dipoles, i.e., the switching takes place abruptly. Some recent experimental observations in ferroelectric-antiferroelectric multilayers are discussed where we conclude that the different electrical properties of bilayers and superlattices are not only due to strain effects alone but also due to long-range interactions. The latter manifests itself particularly in superlattices where layers are periodically exposed to each other at the interfaces.


Spatiotemporal Patterns of Infection for Emerging Larval Liver Fluke ( Dicrocoelium dendriticum) in Three Species of Land Snail in Southern Alberta, Canada.
The control of emerging parasites requires a fundamental knowledge of where and when rates of transmission are high. Data on spatiotemporal patterns of infection are challenging to obtain, particularly for complex life cycle parasites that involve transmission into multiple obligate hosts. The lancet liver fluke, Dicrocoelium dendriticum, has a long history of colonization outside its native host and geographical range in continental Europe. Infection patterns involving adult and metacercarial stages have been characterized for this trematode in a region of emergence in western Canada within co-grazing herbivores and ants, but infection patterns in snail intermediate hosts in this region are unknown. We combined spatiotemporal prevalence surveys with sequence analyses of the cytochrome c oxidase subunit 1 ( COI) barcoding gene from samples of sporocyst tissue in infected snails to confirm that D. dendriticum utilizes 3 sympatric species of Oreohelid land snail ( Oreohelix subrudis, Oreohelix sp., and Oreohelix cooperi) as first intermediate host. Mean prevalence within a total sample of 900 adult snails collected over 1 field season from 6 sites was 9.9 ± 2.4%. For each species of snail, prevalence ranged between 5-30% within monthly samples, with peaks in mid-summer followed by declines in fall. Between-site variation in prevalence was low and non-significant, implying that rates of transmission of D. dendriticum miracidia from domestic stock and wildlife into snails are similar within localized sites, despite high variation in local habitat characteristics and in the structure of the definitive host community.


Different features are stored independently in visual working memory but mediated by object-based representations.
The question of whether visual working memory (VWM) stores individual features or bound objects as basic units is actively debated. Evidence exists for both feature-based and object-based storages, as well as hierarchically organized representations maintaining both types of information at different levels. One argument for feature-based storage is that features belonging to different dimensions (e.g., color and orientations) can be stored without interference suggesting independent capacities for every dimension. Here, we studied whether the lack of cross-dimensional interference reflects genuinely independent feature storages or mediated by common objects. In three experiments, participants remembered and recalled the colors and orientations of sets of objects. We independently manipulated set sizes within each feature dimension (making colors and orientations either identical or differing across objects). Critically, we assigned to-be-remembered colors and orientations either to same spatially integrated or to different spatially separated objects. We found that the precision and recall probability within each dimension was not affected by set size manipulations in a different dimension when the features belonged to integrated objects. However, manipulations with color set sizes did affect orientation memory when the features were separated. We conclude therefore that different feature dimensions can be encoded and stored independently but the advantage of the independent storages are mediated at the object-based level. This conclusion is consistent with the idea of hierarchically organized VWM.


Levodopa-induced dyskinesias in Parkinson's disease: clinical and pharmacological classification.
Levodopa-induced dyskinesias (LID) in Parkinson's disease (PD) may be classified into three main categories: "On" dyskinesias, diphasic dyskinesias (DD), and "off" periods. The study of 168 parkinsonian patients showed that about half (n = 84) showed one pattern of LID only. A combination of two was present in 68, and 16 had the three presentation patterns. A fairly good correlation between type of dyskinesia and presentation pattern was established. Chorea, myoclonus, and dystonic movements occurred during the "on" period. Dystonic postures, particularly affecting the feet, were mainly present in the "off" period, but a few patients had a diphasic presentation. Repetitive stereotyped movements of the lower limbs always corresponded to DD. Acute pharmacological tests using dopamine agonists (subcutaneous apomorphine 3-8 mg; intravenous lisuride 0.1-0.15 mg) and dopamine antagonists (intravenous sulpiride 200-400 mg and intravenous chlorpromazine 25 mg) were performed in 40 patients. Dopamine agonists enhanced "on" dyskinesias and markedly reduced or abolished "off" period dystonia and DD. Dopamine antagonists reduced all types of LID but usually aggravated parkinsonism. These clinical and pharmacological results indicate that LID in PD are a heterogeneous phenomenon difficult to explain on the basis of a single pathophysiological mechanism.


Assignment of the vibrations of the S0, S1, and D0 (+) states of perhydrogenated and perdeuterated isotopologues of chlorobenzene.
We report vibrationally resolved spectra of the S1←S0 transition of chlorobenzene using resonance-enhanced multiphoton ionization spectroscopy. We study chlorobenzene-h5 as well as its perdeuterated isotopologue, chlorobenzene-d5. Changes in the form of the vibrational modes between the isotopologues and also between the S0 and S1 electronic states are discussed for each species. Vibrational bands are assigned utilizing quantum chemical calculations, previous experimental results, and isotopic shifts, including those between the (35)Cl and (37)Cl isotopologues. Previous work and assignments of the S1 spectra are discussed. Additionally, the vibrations in the ground state cation, D0 (+), are considered, since these have also been used by previous workers in assigning the excited neutral state spectra.


AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ANDROGEN EXCESS AND PCOS SOCIETY DISEASE STATE CLINICAL REVIEW: GUIDE TO THE BEST PRACTICES IN THE EVALUATION AND TREATMENT OF POLYCYSTIC OVARY SYNDROME - PART 2.
Polycystic ovary syndrome (PCOS) is recognized as the most common endocrine disorder of reproductive-aged women around the world. This document, produced by the collaboration of the American Association of Clinical Endocrinologists and the Androgen Excess Society aims to highlight the most important clinical issues confronting physicians and their patients with PCOS. It is a summary of current best practices in 2014. Insulin resistance is believed to play an intrinsic role in the pathogenesis of PCOS. The mechanism by which insulin resistance or insulin give rise to oligomenorrhea and hyperandrogenemia, however, is unclear. Hyperinsulinemic-euglycemic clamp studies have shown that both obese and lean women with PCOS have some degree of insulin resistance. Insulin resistance is implicated in the ovulatory dysfunction of PCOS by disrupting the hypothalamic-pituitary-ovarian axis. Given the association with insulin resistance, all women with PCOS require evaluation for the risk of metabolic syndrome (MetS) and its components, including type 2 diabetes, hypertension, hyperlipidemia, and the possible risk of clinical events, including acute myocardial infarction and stroke. Obese women with PCOS are at increased risk for MetS with impaired glucose tolerance (IGT; 31 to 35%) and type 2 diabetes mellitus (T2DM; 7.5 to 10%). Rates of progression from normal glucose tolerance to IGT, and in turn to T2DM, may be as high as 5 to 15% within 3 years. Data suggest the need for baseline oral glucose tolerance test every 1 to 2 years based on family history of T2DM as well as body mass index (BMI) and yearly in women with IGT. Compared with BMI- and age-matched controls, young, lean PCOS women have lower high-density lipoprotein (HDL) size, higher very-low-density lipoprotein particle number, higher low-density lipoprotein (LDL) particle number, and borderline lower LDL size. Statins have been shown to lower testosterone levels either alone or in combination with oral contraceptives (OCPs) but have not shown improvement in menses, spontaneous ovulation, hirsutism, or acne. Statins reduce total and LDL cholesterol but have no effect on HDL, C-reactive protein, fasting insulin, or homeostasis model assessment of insulin resistance in PCOS women, in contrast to the general population. There have been no long-term studies of statins on clinical cardiac outcomes in women with PCOS. Coronary calcification is more prevalent and more severe in PCOS than in controls. In women under 60 years of age undergoing coronary angiography, the presence of polycystic ovaries on sonography has been associated with more arterial segments with >50% stenosis, but the relationship between PCOS and actual cardiovascular events remains unclear. Therapies for PCOS are varied in their effects and targets and include both nonpharmacologic as well as pharmacologic approaches. Weight loss is the primary therapy in PCOS--reduction in weight of as little as 5% can restore regular menses and improve response to ovulation- inducing and fertility medications. Metformin in premenopausal PCOS women has been associated with a reduction in features of MetS. Clamp studies using ethinyl estradiol/drosperinone combination failed to reveal evidence of an increase in either peripheral or hepatic insulin resistance. Subjects with PCOS have a 1.5-times higher baseline risk of venous thromboembolic disease and a 3.7-fold greater effect with OCP use compared with non-PCOS subjects. There is currently no genetic test to screen for or diagnose PCOS, and there is no test to assist in the choice of treatment strategies. Persistent bleeding should always be investigated for pregnancy and/or uterine pathology--including transvaginal ultrasound exam and endometrial biopsy--in women with PCOS. PCOS women can have difficulty conceiving. Those who become pregnant are at risk for gestational diabetes (which should be evaluated and managed appropriately) and the microvascular complications of diabetes. Assessment of a woman with PCOS for infertility involves evaluating for preconceptional issues that may affect response to therapy or lead to adverse pregnancy outcomes and evaluating the couple for other common infertility issues that may affect the choice of therapy, such as a semen analysis. Women with PCOS have multiple factors that may lead to an elevated risk of pregnancy, including a high prevalence of IGT--a clear risk factor for gestational diabetes--and MetS with hypertension, which increases the risk for pre-eclampsia and placental abruption. Women should be screened and treated for hypertension and diabetes prior to attempting conception. Women should be counseled about weight loss prior to attempting conception, although there are limited clinical trial data demonstrating a benefit to this recommendation. Treatment for women with PCOS and anovulatory infertility should begin with an oral agent such as clomiphene citrate or letrozole, an aromatase inhibitor.


Big Data Analytics in Healthcare.
The rapidly expanding field of big data analytics has started to play a pivotal role in the evolution of healthcare practices and research. It has provided tools to accumulate, manage, analyze, and assimilate large volumes of disparate, structured, and unstructured data produced by current healthcare systems. Big data analytics has been recently applied towards aiding the process of care delivery and disease exploration. However, the adoption rate and research development in this space is still hindered by some fundamental problems inherent within the big data paradigm. In this paper, we discuss some of these major challenges with a focus on three upcoming and promising areas of medical research: image, signal, and genomics based analytics. Recent research which targets utilization of large volumes of medical data while combining multimodal data from disparate sources is discussed. Potential areas of research within this field which have the ability to provide meaningful impact on healthcare delivery are also examined.


Deconstructing the conveyor belt.
For the past several decades, oceanographers have embraced the dominant paradigm that the ocean's meridional overturning circulation operates like a conveyor belt, transporting cold waters equatorward at depth and warm waters poleward at the surface. Within this paradigm, the conveyor, driven by changes in deepwater production at high latitudes, moves deep waters and their attendant properties continuously along western boundary currents and returns surface waters unimpeded to deepwater formation sites. A number of studies conducted over the past few years have challenged this paradigm by revealing the vital role of the ocean's eddy and wind fields in establishing the structure and variability of the ocean's overturning. Here, we review those studies and discuss how they have collectively changed our view of the simple conveyor-belt model.


Effect of Crohn's Disease on Villous Length and CYP3A4 Expression in the Pediatric Small Intestine.
Changes in absorptive capacity and first-pass metabolism in the small intestine affect oral drug bioavailability. Characterization of such changes as a consequence of inflammation is important for developing physiologically-based pharmacokinetic (PBPK) models for inflammatory bowel disease. We sought to elucidate the impact of small intestinal Crohn's disease (CD) on villous length and CYP3A4 expression in children. Freshly frozen duodenal and terminal ileum (TI) biopsies from 107 children (1-19 years) with and without CD were evaluated for active inflammation. Villous length and CYP3A4 mRNA/protein expression were compared among regions of active and inactive inflammation in CD and controls. A twofold reduction in villous length was observed in inflamed duodena and ilia of children with CD, but in the absence of regional inflammation, villi in CD were comparable in length to controls. Expression of CYP3A4 mRNA correlated significantly with villous length in the TI (P = 0.0003), with a trend observed in the duodenum that did not reach statistical significance. In the presence of active inflammation, a significant decrease in CYP3A protein expression was confirmed in the duodenum, where protein expression also correlated significantly with villous length across diagnoses (P < 0.0001). Our findings suggest that previous observations of decreased CYP3A4 expression and function in inflamed intestine may not be due solely to downregulation by inflammatory cytokines, but also to villous blunting and subsequent loss of surface area for protein expression. This information is relevant for PBPK model development and could aid with dose adjustment decisions for oral CYP3A4 substrates administered during CD flare (e.g., budesonide).


Determinants and mechanisms of enamel fluorosis.
Enamel fluorosis occurs when fluoride concentrations in or in the vicinity of the forming enamel are excessive during its pre-eruptive development. Fluoride concentrations in plasma, enamel and other tissues reflect the difference between intake and excretion, i.e. fluoride balance. In addition to the diet, modern sources of ingested fluoride include a variety of dental products, some of which have been identified as risk factors for fluorosis. Fluoride absorption is inversely related to dietary calcium which, at high concentrations, may cause net fluoride secretion into the gastrointestinal tract. The excretion of absorbed fluoride occurs almost exclusively via the kidneys, a process which is directly related to urinary pH. Thus, fluoride balance and tissue concentrations and the risk of fluorosis are increased by factors such as high protein diets, residence at high altitude, and certain metabolic and respiratory disorders that decrease pH. Factors that increase urinary pH and decrease the balance of fluoride include vegetarian diets, certain drugs and some other medical conditions. Although several other fluoride-induced effects might be involved in the aetiology of fluorosis, it now appears that inhibition of enzymatic degradation of amelogenins, which may delay their removal from the developing enamel and impair crystal growth, may be of critical importance. In addition to the effects of fluoride, disturbances in enamel formation that can be confused with fluorosis are caused by chronic acidosis and hypoxia independently of the level of fluoride exposure.


Molecular epidemiology of malaria.
Malaria persists as an undiminished global problem, but the resources available to address it have increased. Many tools for understanding its biology and epidemiology are well developed, with a particular richness of comparative genome sequences. Targeted genetic manipulation is now effectively combined with in vitro culture assays on the most important human parasite, Plasmodium falciparum, and with in vivo analysis of rodent and monkey malaria parasites in their laboratory hosts. Studies of the epidemiology, prevention, and treatment of human malaria have already been influenced by the availability of molecular methods, and analyses of parasite polymorphisms have long had useful and highly informative applications. However, the molecular epidemiology of malaria is currently undergoing its most substantial revolution as a result of the genomic information and technologies that are available in well-resourced centers. It is a challenge for research agendas to face the real needs presented by a disease that largely exists in extremely resource-poor settings, but it is one that there appears to be an increased willingness to undertake. To this end, developments in the molecular epidemiology of malaria are reviewed here, emphasizing aspects that may be current and future priorities.


Biomedical psychiatry and its concealed metaphors: an anthropological perspective.
The idea that power relations structure social life is self-evident to most anthropologists. Western medical knowledge or biomedicine, and by extension science or scientific knowledge, however, has until relatively recently been exempt from anthropological scrutiny in political terms. An understanding of biomedicine as a system of knowledge that is not a copy of facts but a representation of them has entailed a break with the traditional separation of folk knowledge and scientific knowledge in anthropology, making it possible to include biomedicine in the repertoire of ethnographic objects. The peculiarity of biomedicine as a cultural system, seen from this perspective, lies in a paradox: its self-characterization as a set of non-ideological discourses and practices is a representation that conceals its ideological and power-saturated nature. Through an analysis of DSM-IV-TR, this article explores some of the representational strategies through which this concealment takes place in biomedical psychiatry: the asocial and universal character of mental illness categories; the neutrality of clinical practice; and the non-moral nature of clinical criteria and judgment. These are concealed metaphors in the true sense, for not only do they speak of something without naming it but they also deny their own existence as metaphors.


Raynaud's phenomenon: primary and secondary causes.
The terms "Raynaud's disease" and "Raynaud's phenomenon" are often used interchangeably, as if they were a single problem. Because prognosis and therapy are different with each of these entities, 86 patients with episodic digit ischemia were evaluated over the past five years. All patients were evaluated similarly with plethysmography, angiography, and other studies for underlying causes of the digital ischemia. From the study, it was concluded that the majority of the patients had an underlying cause for the problem even though they satisfied the commonly accepted criteria for the diagnosis of Raynaud's disease. It is clear that the diagnosis of Raynaud's disease must be one of exclusion, because it is more uncommon than is generally appreciated by the medical community.


Rare disease registries classification and characterization: a data mining approach.
The European Commission and Patients Organizations identify rare disease registries (RDRs) as strategic instruments to develop research and improve knowledge in the field of rare diseases. Interoperability between RDRs is needed for research activities, validation of therapeutic treatments, and public health actions. Sharing and comparing information requires a uniform and standardized way of data collection, so levels of interconnection between RDRs with similar aims and/or nature of data should be identified. The objective of this study is to define a classification and characterization of RDRs in order to identify different profiles and informative needs. Exploratory statistical analyses (cluster analysis and random forest) were applied to data derived from the EPIRARE project ('Building Consensus and Synergies for the EU Rare Disease Patient Registration') survey on the activities and needs of RDRs. The cluster analysis identified 3 main typologies of RDRs: public health, clinical and genetic research, and treatment registries. The analysis of the most informative variables, identified by the random forest method, led to the characterization of 3 types of RDRs and the definition of different profiles and informative needs. These results represent a useful source of information to facilitate the harmonization and interconnection of RDRs in accordance with the different profiles identified. It could help sharing the information between RDRs with similar profiles and, whenever possible, interconnections between registries with different profiles.


Decreased Expression of KIFC1 in Human Testes with Globozoospermic Defects.
Globozoospermia is a rare (prevalence of <0.1%) but severe male infertility condition. In our previous study, we found that robust KIFC1 immunostaining was detected in the human elongating/elongated spermatids during human acrosomogenesis. However, the relationship between the decreased expression of KIFC1 and human globozoospermia remains largely unknown. Testicular biopsies of 30 globozoospermia and 30 obstructive azoospermia patients who underwent infertility evaluation and treatment were utilized in this study. Reverse transcriptase polymerase chain reaction (RT-PCR), Western blots, immunohistochemistry, an in vivo model, and intratesticular injection of small inhibitory RNA (siRNA) against the Kifc1 gene were employed, and sperm abnormalities were evaluated by hematoxylin and eosin (H&E) staining and immunocytochemistry. We revealed that the testicular level of KIFC1 mRNA in globozoospermia was significantly reduced compared with that in obstructive azoospermia, and the KIFC1 protein was barely detectable in testicular specimens in 30% (9 of 30) of patients with globozoospermia. Furthermore, knockdown of the Kifc1 gene in mice increased the percentage of sperm with globozoospermic defects (26.5%). Decreased KIFC1 expression was mainly observed in the testes of patients with globozoospermia at the spermatid stage, which may be useful for counseling and management of such patients.


Newtonian flow inside carbon nanotube with permeable boundary taking into account van der Waals forces.
Here, water flow inside large radii semi-infinite carbon nanotubes is investigated. Permeable wall taking into account the molecular interactions between water and a nanotube, and the slip boundary condition will be considered. Furthermore, interactions among molecules are approximated by the continuum approximation. Incompressible and Newtonian fluid is assumed, and the Navier-Stokes equations, after certain assumptions, transformations and derivations, can be reduced into two first integral equations. In conjunction with the asymptotic expansion technique, we are able to derive the radial and axial velocities analytically, capturing the effect of the water leakage, where both mild and exceptionally large leakages will be considered. The radial velocity obeys the prescribed boundary condition at the (im)permeable wall. Through the mean of the radial forces, the sufficiently large leakages will enhance the radial velocity at the center of the tube. On the other hand, unlike the classical laminar flow, the axial velocity attains its maximum at the wall due to the coupling effect with the radial forces as water is being pushed into the proximity of the inner wall. In addition, the axial velocity and the flux with the consideration of the suck-in forces, induced by the tubes' entry turn out to be one order higher than that without the suck-in forces. All the aforementioned considerations might partially resolve the mysteriously high water penetration through nanotubes. Axial velocity also drops with the tube's length when the water leakage is permitted and the suck-in forces will ease the decline rate of the axial velocity. The present mathematical framework can be directly employed into the water flow inside other porous nano-materials, where large water leakage is permitted and therefore are of huge practical impact on ultra-filtration and environmental protection.


Wearable Sensing Devices: Towards the Development of a Personalized System for Construction Safety and Health Risk Mitigation.
Wearable sensing devices (WSDs) are increasingly helping workers stay safe and healthy in several industries. However, workers, especially in the construction industry, have shown some aversion towards the use of WSDs due to their ability to capture specific information that may be considered personal and private. However, this revered information may provide some critical insight needed by management to plan and optimize worksite safety and support technology adoption in decision making. Therefore, there is a need to develop personalized WSD systems that are mutually beneficial to workers and management to ensure successful WSD integration. The present study aims to contribute to knowledge and practice by filling this critical gap using insight from 330 construction workers with experience using WSDs. The results from this study indicate that all 11 WSD functions identified through this study play a vital role in improving worker safety and health and that approximately two out of three workers are open to sharing the physiological and environmental information captured using these WSDs with their management. However, functions for detecting workers' proximity to workplace hazards, specifically energized electrical materials, toxic gas, and fire/smoke, were the most critical functions that had mutual value to workers and management. Finally, the present study proposed and evaluated a phased personalized WSD system that should encourage successful WSD integration.


Mutation of the casein kinase II phosphorylation site abolishes the anti-proliferative activity of p53.
The p53 tumour suppressor protein is phosphorylated by several protein kinases, including casein kinase II. In order to understand the functional significance of phosphorylation by casein kinase II, we have introduced mutations at serine 386 in mouse p53, the residue phosphorylated by this kinase, and investigated their effects on the ability of p53 to arrest cell growth. Replacement of serine 386 by alanine led to loss of growth suppressor activity, while aspartic acid at this position partially retained suppressor function. These data suggest that the anti-proliferative activity of p53 is activated by phosphorylation at serine 386, and establish a direct link between the covalent modification of a growth suppressor protein and regulation of its activity in mammalian cells.


Targeting tacrolimus to deeper layers of skin with improved safety for treatment of atopic dermatitis.
Atopic dermatitis (AD) is chronically relapsing eczematous skin disorder having significant impact worldwide. Tacrolimus is the drug-of-choice which inhibits T-cell activation resulting in suppression of inflammation. However, despite being effective, most common adverse events of tacrolimus are low-and-variable bioavailability, burning sensation and pruritus at application site, which prompt for development of novel carrier that could effectively target tacrolimus to site-of-action without producing undesirable side-effects. Tacrolimus-loaded lipid-nanoparticles (T-LN) were prepared and optimized. DSC and FT-IR have been employed to study drug-excipient incompatibility and encapsulation of drug in lipid which was further confirmed by (1)H NMR. In vitro studies revealed much higher drug release, skin penetration and enhanced skin accumulation as compared to reference Protopic. In vitro and in vivo occlusion studies demonstrated similar occlusiveness for T-LN and reference however; T-LN showed significantly higher drug levels penetrating into deeper skin layers where dendritic cells responsible for immunopathogenesis of AD mainly reside. In-vivo skin retention demonstrated 3.36, 30.81 and 28.68-times higher stratum corneum, epidermal and dermal levels respectively compared to reference. Visualization of cutaneous uptake in-vivo using CLSM confirmed targeting to deeper skin layers and Draize test showed no skin irritation with PII 0.00. Thus T-LN displayed superior performance, effective skin targeting and improved safety as compared to reference.


SOLiD sequencing of four Vibrio vulnificus genomes enables comparative genomic analysis and identification of candidate clade-specific virulence genes.
Vibrio vulnificus is the leading cause of reported death from consumption of seafood in the United States. Despite several decades of research on molecular pathogenesis, much remains to be learned about the mechanisms of virulence of this opportunistic bacterial pathogen. The two complete and annotated genomic DNA sequences of V. vulnificus belong to strains of clade 2, which is the predominant clade among clinical strains. Clade 2 strains generally possess higher virulence potential in animal models of disease compared with clade 1, which predominates among environmental strains. SOLiD sequencing of four V. vulnificus strains representing different clades (1 and 2) and biotypes (1 and 2) was used for comparative genomic analysis. Greater than 4,100,000 bases were sequenced of each strain, yielding approximately 100-fold coverage for each of the four genomes. Although the read lengths of SOLiD genomic sequencing were only 35 nt, we were able to make significant conclusions about the unique and shared sequences among the genomes, including identification of single nucleotide polymorphisms. Comparative analysis of the newly sequenced genomes to the existing reference genomes enabled the identification of 3,459 core V. vulnificus genes shared among all six strains and 80 clade 2-specific genes. We identified 523,161 SNPs among the six genomes. We were able to glean much information about the genomic content of each strain using next generation sequencing. Flp pili, GGDEF proteins, and genomic island XII were identified as possible virulence factors because of their presence in virulent sequenced strains. Genomic comparisons also point toward the involvement of sialic acid catabolism in pathogenesis.


The sex-selective impact of the Black Death and recurring plagues in the Southern Netherlands, 1349-1450.
Although recent work has begun to establish that early modern plagues had selective mortality effects, it was generally accepted that the initial outbreak of Black Death in 1347-52 was a "universal killer." Recent bioarchaeological work, however, has argued that the Black Death was also selective with regard to age and pre-plague health status. The issue of the Black Death's potential sex selectivity is less clear. Bioarchaeological research hypothesizes that sex-selection in mortality was possible during the initial Black Death outbreak, and we present evidence from historical sources to test this notion. To determine whether the Black Death and recurring plagues in the period 1349-1450 had a sex-selective mortality effect. We present a newly compiled database of mortality information taken from mortmain records in Hainaut, Belgium, in the period 1349-1450, which not only is an important new source of information on medieval mortality, but also allows for sex-disaggregation. We find that the Black Death period of 1349-51, as well as recurring plagues in the 100 years up to 1450, often had a sex-selective effect-killing more women than in "non-plague years." Although much research tends to suggest that men are more susceptible to a variety of diseases caused by bacteria, viruses and parasites, we cannot assume that the same direction of sex-selection in mortality applied to diseases in the distant past such as Second Pandemic plagues. While the exact reasons for the sex-selective effect of late-medieval plague are unclear in the absence of further data, we suggest that simple inequities between the sexes in exposure to the disease may not have been a key driver.


Endothelium-dependent responses in carotid and renal arteries of normotensive and hypertensive rats.
Endothelium-dependent relaxations are impaired in the aorta of various models of hypertension, but no data are available regarding the cerebral or renal circulation. Endothelium-dependent relaxations were studied in the carotid and renal artery of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Rings with and without endothelium were suspended in organ chambers for isometric tension recording. Acetylcholine and adenosine 5'-diphosphate (ADP) caused endothelium-dependent relaxations in both arteries that were impaired in the carotid, but not in the renal artery, of the SHR, similar to those to the endothelium-independent vasodilator sodium nitroprusside. Indomethacin did not affect relaxations to acetylcholine in the carotid artery, but it significantly augmented them in the renal artery. This finding suggests that an impaired vascular responsiveness to endothelium-derived relaxing factor is responsible for the decreased relaxations in the carotid artery of the SHR. In the renal artery, acetylcholine appears to release both endothelium-derived relaxing factor and a vasoconstrictor prostanoid. Carotid arteries of SHR were more sensitive to the constrictor effects of serotonin than were those of WKY. Endothelium removal caused a twofold to eightfold increase in sensitivity to serotonin in both strains. Thus, endothelium-dependent relaxations to acetylcholine and ADP are reduced and constrictions to serotonin are enhanced in the carotid, but not in the renal, artery of the SHR.


p202, an interferon-inducible protein, mediates multiple antitumor activities in human pancreatic cancer xenograft models.
p202, an IFN-inducible protein, interacts with certain transcriptional activators leading to transcriptional repression. p202 expression has been associated with inhibition of cancer cell growth in vitro and in vivo. To examine a potential p202-mediated antitumor activity in pancreatic cancer, we used both ectopic and orthotopic xenograft models and demonstrated that p202 expression is associated with multiple antitumor activities that include inhibition of tumor growth, reduced tumorigenicity, prolonged survival, and remarkably, suppression of metastasis and angiogenesis. In vitro invasion assay also showed that p202-expressing pancreatic cancer cells are less invasive than those without p202 expression. That observation was supported by the findings that p202-expressing tumors showed reduced expression of angiogenic markers, such as interleukin 8 and vascular endothelial growth factor, and p202-expressing pancreatic cancer cells have reduced level of matrix metalloproteinase-2 activity, a secreted protease activity important for metastasis. Importantly, we demonstrated a treatment efficacy by using p202/SN2 liposome complex in a nude mice xenograft model, suggesting a feasibility of using the p202/SN2 liposome in future preclinical gene therapy experiments. Together, our results strongly suggest that p202 expression mediates multiple antitumor activities against pancreatic cancer and may provide a scientific basis for developing a p202-based gene therapy in pancreatic cancer treatment.


Estimated GFR and Mortality in Older Men: Are All eGFR Formulae Equal.
Recently, the first estimated glomerular filtration rate (eGFR) formula specifically developed for community-dwelling older adults, the Berlin Initiative Study Equation 2 (BIS2), was reported. To date, however, no study has examined the performance of the BIS2 to predict death in older adults as compared to equations used clinically and in research. We prospectively followed 2,994 community-dwelling men (age 76.4 ± 5.6) enrolled in the MrOS Sleep Study. We calculated baseline eGFR from serum creatinine and cystatin-C using the BIS2, Chronic Kidney Disease Epidemiology (CKD-EPIcr,cysc), CKD-EPIcysc and CKD-EPIcr equations. Analyses included Cox-proportional hazards regression and net reclassification improvement (NRI) for the outcomes of all-cause and cardiovascular death. Follow-up time was 7.3 ± 1.9 years. By BIS2, 42 and 11% had eGFR <60 and <45, respectively, compared to CKD-EPIcr (23 and 6%), CKD-EPIcysc (36 and 13%) and CKD-EPIcr,cysc (28 and 8%). BIS2 eGFR <45 was associated with twofold higher rate of all-cause mortality when compared to eGFR ≥75 after multivariate adjustment (HR 2.1, 95% CI 1.5-2.8). Results were similar for CKD-EPIcr,cysc <45 (HR 2.1, 95% CI 1.6-2.7) and CKD-EPIcysc <45 (HR 2.1, 95% CI 1.7-2.7) and weaker for CKD-EPIcr <45 (HR 1.5, 95% CI 1.2-2.0). In NRI analyses, when compared to CKD-EPIcr,cysc, both BIS2 and CKD-EPIcr equations more often misclassified participants with respect to mortality. We found similar results for cardiovascular death. The BIS2 did not outperform and the CKD-EPIcr was inferior to the cystatin C-based CKD-EPI equations to predict death in this cohort of older men. Thus, the cystatin C-based CKD-EPI equations are the formulae of choice to predict death in community-dwelling older men.


Diabetes care policies and practices in Michigan nursing homes, 1991.
To describe local standards of care for nursing home patients with diabetes, to characterize the care that nursing home patients with diabetes receive in Michigan, and to determine if the care provided meets local and national standards. In March 1991, a questionnaire was administered and chart reviews were conducted as part of the Medical Review and Nursing Evaluation conducted by the Michigan Department of Public Health. The questionnaire was completed by the head nurses at 17 skilled nursing homes to learn about local institutional standards of care. Chart reviews were conducted on a sample of five patients with diabetes from each nursing home to describe the care provided and to compare it with local and national standards. Almost all nursing homes had some diabetes care orders or protocols. Standing orders were most often present to guide nutritional and nursing care (e.g., diet, blood glucose monitoring, foot care). Standing orders were less often present to guide medical care (e.g., blood glucose parameters to contact physician) and surveillance of complications (e.g., eye exams). In general, the care provided did not meet local or national standards for diabetes care. Care practices were closer to national standards when registered dietitians (RDs) participated in meal planning and written institutional policies existed. In this sample of Michigan nursing homes, those with RDs and standing orders provided care more in keeping with guidelines. There is room for improvement in diabetes care practices in nursing homes. It may be time for diabetes-related organizations to re-examine standards for diabetes care in nursing homes.


Recurrent ovarian cancer: use of contrast-enhanced CT and PET/CT to accurately localize tumor recurrence and to predict patients' survival.
To compare accuracy and interobserver variability in the detection and localization of recurrent ovarian cancer with contrast material-enhanced (CE) computed tomography (CT) and positron emission tomography (PET)/CT and determine whether imaging findings can be used to predict survival. Waiving informed consent, the institutional review board approved this HIPAA-compliant, retrospective study of 35 women (median age, 54.4 years) with histopathologically proven recurrent ovarian carcinoma who underwent CE CT and PET/CT before exploratory surgery. All CE CT and PET/CT scans were independently analyzed. Tumor presence, number of lesions, and the size and maximum standardized uptake value (SUV(max)) of the largest lesion were recorded for patient and region. Surgical histopathologic findings constituted the reference standard. Areas under the receiver operating characteristic curves (AUCs), κ statistics, and hazard ratios were calculated. Readers' AUCs in detection of recurrence for region were 0.85 (95% confidence interval [CI]: 0.81, 0.90) and 0.78 (95% CI: 0.72, 0.83) for CE CT and 0.84 (95% CI: 0.79, 0.89) and 0.74 (95% CI: 0.67, 0.81) for PET/CT (P = .76); 12 patients died. At PET/CT, size, number, and SUV(max) of peritoneal deposits were significantly associated with poor survival for readers 1 and 2 (P ≤ .01and ≤ .05, respectively), as were long- and short-axis diameters, number, and SUV(max) of distant lymph nodes for reader 1 (P ≤ .001). With CE CT, size (reader 1) and number (readers 1 and 3) of peritoneal deposits were significantly associated with poor survival (P ≤ .01), as were long- and short-axis diameters and number of distant lymph nodes for reader 1 (P ≤ .01). Interobserver agreement ranged from fair (patient, κ = 0.30) to moderate (region, κ = 0.55) for CE CT and fair (patient, κ = 0.24) to substantial (region, κ = 0.63) for PET/CT. Preliminary data suggest that CE CT and PET/CT may have similar accuracy in detection of recurrent ovarian cancer. Tumor size, number, and SUV(max) may have potential as prognostic biomarkers for patients with recurrent ovarian cancer.


Primary coronary angioplasty for ST-Elevation Myocardial Infarction in Qatar: First nationwide program.
In this article, we outline the plans, protocols and strategies to set up the first nationwide primary Percutaneous Coronary Intervention (PCI) program for ST-elevation myocardial Infarction (STEMI) in Qatar, as well as the difficulties and the multi-disciplinary solutions that we adopted in preparation. We will also report some of the landmark literature that guided our plans. The guidelines underscore the need for adequate number of procedures to justify establishing a primary-PCI service and maintain competency. The number of both diagnostic and interventional procedures in our centre has increased substantially over the years. The number of diagnostic procedures has increased from 1470 in 2007, to 2200 in 2009 and is projected to exceed 3000 by the end of 2012. The total number of PCIs has also increased from 443 in 2007, to 646 in 2009 and 1176 in 2011 and is expected to exceed 1400 by the end of 2012. These figures qualify our centre to be classified as 'high volume', both for the institution and for the individual interventional operators. The initial number of expected primary PCI procedures will be in excess of 600 procedures per year. Guidelines also emphasize the door to balloon time (DBT), which should not exceed 90 minutes. This interval mainly represents in-hospital delay and reflects the efficiency of the hospital system in the rapid recognition and transfer of the STEMI patient to the catheterization laboratory for primary-PCI. Although DBT is clearly important and is in the forefront of planning for the wide primary PCI program, it is not the only important time interval. Myocardial necrosis begins before the patient arrives to the hospital and even before first medical contact, so time is of the essence. Therefore, our primary PCI program includes a nationwide awareness program for both the population and health care professionals to reduce the pre-hospital delay. We have also taken steps to improve the pre-hospital diagnosis of STEMI. In addition to equipping all ambulances to perform 12-lead electrocardiograms (ECGs) we will establish advanced wireless transmission of the ECG to our Heart Centre and to the smart phone of the consultant on-call for the primary-PCI service. This will ensure that the patient is transferred directly to the cath lab without unnecessary delay in the emergency rooms. A single phone-call system will allow the first medic making the diagnosis to activate the primary PCI team. The emergency medical system is acquiring capability to track the exact position of each ambulance using GPS technology to give an accurate estimate of the time needed to arrive to the patient and/or to the hospital. We also plan for medical helicopter evacuation from remote or inaccessible areas. A comprehensive research database is being established to enable specific pioneering research projects and clinical trials, either as a single centre or in collaboration with other regional or international centers. The primary-PCI program is a collaborative effort between the Heart Hospital, Hamada Medical Corporation and the Qatar Cardiovascular Research Centre, a member of Qatar Foundation. Qatar will be first country to have a unified nationwide primary-PCI program. This clinical and research program could be a model that may be adopted in other countries to improve outcomes of patients with STEMI.


Stem cells in human breast cancer.
Increasing data support cancer as a stem cell-based disease. Cancer stem cells (CSCs) have been found in different human cancers, and recent evidence indicates that breast cancer originates from and is maintained by its own CSCs, as well as the normal mammary gland. Mammary stem cells and breast CSCs have been identified and purified in in vitro culture systems, transplantation assays and/or by cell surface antigen identification. Cell surface markers enable the functional isolation of stem cells that can initiate and propagate tumorigenesis in mammary gland. These observations have dramatic biological and clinical significance due to increasing evidence suggesting that the recurrence of human cancer and treatment failure may reflect the intrinsic quiescence and drug resistance of CSCs. Thus, the CSC hypothesis provides fundamental implications for understanding breast carcinogenesis and for developing new strategies for breast cancer prevention and therapy for advanced disease. Further strategies to isolate breast CSCs, to find additional trustworthy surface markers, and to compare gene expression pathways profiles with their normal stem cells counterparts are necessary to more accurately define putative breast cell-lineage markers for the different cell types present in the mature mammary gland and to identify potential therapeutical targets in breast cancer. This review discusses the current knowledge about stem cells and CSCs, focusing on mammary stem cells and breast CSCs, and their consequences for breast tumorigenesis and implications for breast cancer susceptibility, prognosis, and treatment.


Characterization and distribution of P2-purinoceptor subtypes in rat pulmonary vessels.
To characterize P2-purinoceptors in pulmonary vessels we have examined the effects of ATP analogs on rat isolated pulmonary artery and vein in vitro. The rank order of potency for causing vasoconstriction was: alpha,beta-methylene-ATP (alpha,beta-meATP) greater than beta,gamma-methylene-ATP (beta,gamma-meATP) greater than 2-methylthio-ATP (2m.S.ATP) greater than ATP for arteries; and alpha,beta-meATP much greater than beta,gamma-meATP = 2m.S.ATP greater than ATP for veins, indicating that a P2x receptor was involved. The contractile response to these analogs was virtually abolished after desensitization of P2x-receptors by alpha,beta-meATP. Removal of the endothelial cells enhanced the contractile responses to all of the ATP analogs in both arteries and veins. The rank order of potency for vasodilatation was 2m.S.ATP much greater than ATP = beta,gamma-meATP much greater than alpha,beta-meATP for arteries and 2m.S.ATP much greater than ATP = beta-gamma-meATP, with alpha,beta-meATP being no effect for veins, indicating a P2y receptor. Pretreatment of the pulmonary arteries with the P2y-antagonist reactive blue 2 caused a rightward shift of the dose-response curves to 2m.S.ATP, ATP and beta,gamma-meATP. Reactive blue 2 was only used with the pulmonary arteries. Removal of the endothelium converted the relaxant responses to all the ATP analogs (except to ATP in pulmonary artery) to further contraction. In the pulmonary artery, the small endothelium-independent relaxation induced by ATP was abolished completely by pretreating the vessels with 100 microM theophylline (a P1-purinoceptor antagonist), suggesting that it was due to conversion of ATP to adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)


Treatment of chronic hepatitis C virus infection via antioxidants: results of a phase I clinical trial.
The pathogenesis of chronic hepatitis C virus (HCV) infection is associated with a defective host antiviral immune response and intrahepatic oxidative stress. Oxidative stress and lipid peroxidation play major roles in the fatty liver accumulation (steatosis) that leads to necro-inflammation and necrosis of hepatic cells. Previous trials suggested that antioxidative therapy may have a beneficial effect on patients with chronic HCV infection. To determine the safety and efficacy of treatment of chronic HCV patients via a combination of antioxidants. Fifty chronic HCV patients were treated orally on a daily basis for 20 weeks with seven antioxidative oral preparations (glycyrrhizin, schisandra, silymarin, ascorbic acid, lipoic acid, L-glutathione, and alpha-tocopherol), along with four different intravenous preparations (glycyrrhizin, ascorbic acid, L-glutathione, B-complex) twice weekly for the first 10 weeks, and followed up for an additional 20 weeks. Patients were monitored for HCV-RNA levels, liver enzymes, and liver histology. Assessment of quality of life was performed using the SF-36 questionnaire. In one of the tested parameters (eg, liver enzymes, HCV RNA levels, or liver biopsy score), a combination of antioxidants induced a favorable response in 48% of the patients (24). Normalization of liver enzymes occurred in 44% of patients who had elevated pretreatment ALT levels (15 of 34). ALT levels remained normal throughout follow-up period in 72.7% (8 of 11). A decrease in viral load (one log or more) was observed in 25% of the patients (12). Histologic improvement (2-point reduction in the HAI score) was noted in 36.1% of the patients. The SF-36 score improved in 26 of 45 patients throughout the course of the trial (58% of the patients). Treatment was well tolerated by all patients. No major adverse reactions were noted. These data suggest that multi antioxidative treatment in chronic HCV patients is well tolerated and may have a beneficial effect on necro-inflammatory variables. A combination of antiviral and antioxidative therapies may enhance the overall response rate of these patients.


Targeting delivery of drugs in the vascular system.
Delivery and effects of therapeutics remain suboptimal. Most drugs do not have affinity to their targets. Biotherapeutics including enzymes and genetic materials require specific sub-cellular addressing not attainable naturally. Endothelium, lining the luminal surface of blood vessels, represents a key therapeutic target in many diseases. Studies in cell culture and animal models revealed that targeted delivery of therapeutics to, into and across endothelium can be achieved using carriers targeted to specific molecules expressed on the surface of the endothelial cells. For example, cell adhesion molecules represent attractive targets for drug delivery. Rational design of the drug delivery systems (e.g., selection of optimal geometry and affinity to specific epitopes) provides an unprecedented level of control of such parameters of drug delivery as pharmacokinetics, circulation in blood, binding to selected endothelial cell phenotypes, anchoring on cell surface or internalization into the endothelium, subsequent intracellular addressing and duration of the effects. We discusse here key aspects of design of endothelium-targeted drug delivery systems with potential for translation into the clinical domain.


Interventions for preventing and treating pelvic and back pain in pregnancy.
More than two-thirds of pregnant women experience low-back pain (LBP) and almost one-fifth experience pelvic pain. Pain increases with advancing pregnancy and interferes with work, daily activities and sleep. To assess the effects of interventions for preventing and treating pelvic and back pain in pregnancy. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (18 July 2012), identified related studies and reviews from the Cochrane Back Review Group search strategy to July 2012, and checked reference lists from identified reviews and studies. Randomised controlled trials (RCTs) of any treatment to prevent or reduce the incidence or severity of pelvic or back pain in pregnancy. Two review authors independently assessed risk of bias and extracted data. Quality of the evidence for outcomes was assessed using the five criteria outlined by the GRADE Working Group. We included 26 randomised trials examining 4093 pregnant women in this updated review. Eleven trials examined LBP (N = 1312), four examined pelvic pain (N = 661), and 11 trials examined lumbo-pelvic (LBP and pelvic) pain (N = 2120). Diagnoses ranged from self-reported symptoms to the results of specific tests. All interventions were added to usual prenatal care and unless noted, were compared to usual prenatal care. For LBP, there was low-quality evidence that in general, the addition of exercise significantly reduced pain (standardised mean difference (SMD) -0.80; 95% confidence interval (CI) -1.07 to -0.53; six RCTs, N = 543), and disability (SMD -0.56; 95% CI -0.89 to -0.23; two RCTs, N = 146); and water-based exercise significantly reduced LBP-related sick leave (risk ratio (RR) 0.40; 95% CI 0.17 to 0.92; one RCT, N = 241). Low-quality evidence from single trials suggested no significant difference in pain or function between two types of pelvic support belt, between osteopathic manipulation (OMT) and usual care or sham ultrasound (sham US). Very low-quality evidence suggested that a specially-designed pillow may relieve night pain better than a regular pillow. For pelvic pain, there was moderate-quality evidence that acupuncture significantly reduced evening pain better than exercise; both were better than usual care. Low-quality evidence from single trials suggested that adding a rigid belt to exercise improved average pain but not function; acupuncture was significantly better than sham acupuncture for improving evening pain and function, but not average pain; and evening pain relief was the same following either deep or superficial acupuncture. For lumbo-pelvic pain, there was moderate-quality evidence that an eight- to 20-week exercise program reduced the risk of women reporting lumbo-pelvic pain (RR 0.85; 95% CI 0.73 to 1.00; four RCTs, N = 1344); but a 16- to 20-week training program was no more successful than usual care at preventing pelvic pain (one RCT, N = 257). Low-quality evidence suggested that exercise significantly reduced lumbo-pelvic-related sick leave (RR 0.76; 95% CI 0.62 to 0.94, two RCTs, N = 1062), and improved function. Low-quality evidence from single trials suggested that OMT significantly reduced pain and improved function; either a multi-modal intervention that included manual therapy, exercise and education (MOM) or usual care significantly reduced disability, but only MOM improved pain and physical function; acupuncture improved pain and function more than usual care or physiotherapy; pain and function improved more when acupuncture was started at 26- rather than 20- weeks' gestation; and auricular (ear) acupuncture significantly improved these outcomes more than sham acupuncture.When reported, adverse events were minor and transient. Moderate-quality evidence suggested that acupuncture or exercise, tailored to the stage of pregnancy, significantly reduced evening pelvic pain or lumbo-pelvic pain more than usual care alone, acupuncture was significantly more effective than exercise for reducing evening pelvic pain, and a 16- to 20-week training program was no more successful than usual prenatal care at preventing pelvic or LBP. Low-quality evidence suggested that exercise significantly reduced pain and disability from LBP.There was low-quality evidence from single trials for other outcomes because of high risk of bias and sparse data; clinical heterogeneity precluded pooling. Publication bias and selective reporting cannot be ruled out.Physiotherapy, OMT, acupuncture, a multi-modal intervention, or the addition of a rigid pelvic belt to exercise seemed to relieve pelvic or back pain more than usual care alone. Acupuncture was more effective than physiotherapy at relieving evening lumbo-pelvic pain and disability and improving pain and function when it was started at 26- rather than 20-weeks' gestation, although the effects were small.There was no significant difference in LBP and function for different support belts, exercise, neuro emotional technique or spinal manipulation (SMT), or in evening pelvic pain between deep and superficial acupuncture.Very low-quality evidence suggested a specially-designed pillow may reduce night-time LBP.Further research is very likely to have an important impact on our confidence in the estimates of effect and is likely to change the estimates. Future research would benefit from the introduction of an agreed classification system that can be used to categorise women according to presenting symptoms.


Current aspects of spontaneous pneumothorax.
Although spontaneous pneumothoraces have been recognized and treated for almost 180 yrs, new aspects have emerged concerning pathogenesis, diagnostic procedures and treatment modalities. In spite of the fact that blebs and bullae are frequently found in patients with primary spontaneous pneumothorax, they seldom seem to be the actual cause of the pneumothorax. Inflammatory changes in the distal airways play an important role in the occurrence of the pneumothorax during transpulmonary pressure changes. The value of the routine use of additional expiratory chest radiographs in diagnosing pneumothoraces has been doubted in previous studies. In this review, the diagnostic yield from additional expiratory chest radiographs is analysed. The role of previous pneumothoraces at presentation and the presence of blebs and bullae are discussed in predicting future recurrences and choosing appropriate treatment for optimal cost-effectiveness. Recommendations are made regarding treatment of primary and secondary spontaneous pneumothorax.


Dynamics of the exponential integrate-and-fire model with slow currents and adaptation.
In order to properly capture spike-frequency adaptation with a simplified point-neuron model, we study approximations of Hodgkin-Huxley (HH) models including slow currents by exponential integrate-and-fire (EIF) models that incorporate the same types of currents. We optimize the parameters of the EIF models under the external drive consisting of AMPA-type conductance pulses using the current-voltage curves and the van Rossum metric to best capture the subthreshold membrane potential, firing rate, and jump size of the slow current at the neuron's spike times. Our numerical simulations demonstrate that, in addition to these quantities, the approximate EIF-type models faithfully reproduce bifurcation properties of the HH neurons with slow currents, which include spike-frequency adaptation, phase-response curves, critical exponents at the transition between a finite and infinite number of spikes with increasing constant external drive, and bifurcation diagrams of interspike intervals in time-periodically forced models. Dynamics of networks of HH neurons with slow currents can also be approximated by corresponding EIF-type networks, with the approximation being at least statistically accurate over a broad range of Poisson rates of the external drive. For the form of external drive resembling realistic, AMPA-like synaptic conductance response to incoming action potentials, the EIF model affords great savings of computation time as compared with the corresponding HH-type model. Our work shows that the EIF model with additional slow currents is well suited for use in large-scale, point-neuron models in which spike-frequency adaptation is important.


Endodontic infection caused by localized aggressive periodontitis: a case report and bacteriologic evaluation.
A rare case of a periodontally induced endodontic lesion in a systemically healthy subject of 28 years is described. The patient, having presented with severe attachment loss on the palatal and distal aspects of his maxillary right second premolar, was diagnosed with localized aggressive periodontitis. He had never received periodontal treatment. The tooth was nonvital and showed all signs of symptomatic apical periodontitis. It was also free of any restoration. All clinical findings clearly suggested that the endodontic problem was caused by the aggressive periodontal disease. Bacteriologic screening of the pocket and the root canal, by using "checkerboard" DNA-DNA hybridization analysis, revealed diverse flora in the periodontal lesion. The sample obtained from the root canal exhibited DNA from a limited number of species, including black-pigmented anaerobic rods. No bacterial DNA was found in the root canal that was not also recovered from the periodontal pocket.


The UK Pharmacy Care Plan service: Description, recruitment and initial views on a new community pharmacy intervention.
The UK government advocates person-centred healthcare which is ideal for supporting patients to make appropriate lifestyle choices and to address non-adherence. The Community Pharmacy Future group, a collaboration between community pharmacy companies and independents in the UK, introduced a person-centred service for patients with multiple long-term conditions in 50 pharmacies in Northern England. Describe the initial findings from the set up and delivery of a novel community pharmacy-based person-centred service. Patients over fifty years of age prescribed more than one medicine including at least one for cardiovascular disease or diabetes were enrolled. Medication review and person-centred consultation resulted in agreed health goals and steps towards achieving them. Data were collated and analysed to determine appropriateness of patient recruitment process and quality of outcome data collection. A focus group of seven pharmacists was used to ascertain initial views on the service. Within 3 months of service initiation, 683 patients had baseline clinical data recorded, of which 86.9% were overweight or obese, 53.7% had hypertension and 80.8% had high cardiovascular risk. 544 (77.2%) patients set at least one goal during the first consultation with 120 (22.1%) setting multiple goals. A majority of patients identified their goals as improvement in condition, activity or quality of life. Pharmacists could see the potential patient benefit and the extended role opportunities the service provided. Allowing patients to set their own goals occasionally identified gaps to be addressed in pharmacist knowledge. Pharmacists successfully recruited a large number of patients who were appropriate for such a service. Patients were willing to identify goals with the pharmacist, the majority of which, if met, may result in improvements in quality of life. While challenges in delivery were acknowledged, allowing patients to identify their own personalised goals was seen as a positive approach to providing patient services.


Clinical, histologic, and immunohistochemical characterization of wart-like lesions on the paw pads of dogs: 24 cases (2000-2007).
OBJECTIVE- To determine clinical, histologic, and immunohistochemical findings for dogs with wart-like lesions involving the paw pads. DESIGN- Retrospective case series. ANIMALS- 24 dogs (18 Greyhounds and 6 dogs of other breeds). PROCEDURES- Medical records were reviewed for information on signalment, physical examination findings, concurrent disease processes, location of all lesions, and, when available, results of histologic examination of biopsy specimens. Available biopsy specimens (n = 11) were submitted for immunohistochemical staining and a PCR assay to identify viral inclusion bodies. RESULTS- In Greyhounds, most lesions involved the pads of the third and fourth digits, had a consistent histologic appearance without evidence of inflammation, were negative for papillomavirus, and had an unsatisfactory response to treatment. In other breeds, lesions often involved the pads of non-weight-bearing digits, had histologic evidence of inflammation, were positive for papillomavirus, and responded to surgical treatment. CONCLUSIONS AND CLINICAL RELEVANCE- Results suggested that wart-like lesions involving the paw pads of Greyhounds were a distinct clinical entity with features resembling porokeratosis plantaris discreta in humans. In Greyhounds, these lesions were not associated with an underlying viral etiology and, therefore, should not be considered plantar warts. Alternative treatments should be investigated because current treatments were generally unsuccessful in Greyhounds. Wart-like lesions of the paw pads in other breeds were often associated with papillomavirus, and surgical excision appeared curative.


Two viable three-dimensional carbon semiconductors with an entirely sp2 configuration.
Using the first-principles method, we investigate the energetic stability, dynamic stability and electronic properties of two viable three-dimensional (3D) carbon semiconductors with an entirely sp(2) configuration, sp(2)-diamond and cubic-graphite. Both allotropes are more stable than the previously proposed K4-carbon and T-carbon and were confirmed to be dynamically stable. Interestingly, sp(2)-diamond and cubic-graphite behave as semiconductors, which is contrary to previously proposed all-sp(2) metallic carbons. sp(2)-Diamond is a semiconductor with a direct band gap of 1.66 eV and cubic-graphite is an indirect semiconductor with a band gap of 2.89 eV. Further studies show that both sp(2)-diamond and cubic-graphite possess structural all-sp(2) configurations but not electronic sp(2) hybridizations. The very low densities and entirely sp(2) configurations of sp(2)-diamond and cubic-graphite can be potentially applied in hydrogen-storage, photocatalysts and molecular sieves.


Trophoblast transferrin and transferrin receptors in the host--parasite relationship of human pregnancy.
Transferrin and specific transferrin receptors are demonstrated on the microvillous surface of syncytiotrophoblast in human immature and term placentae by immuno histological techniques with the use of light and electron microscopy. That the distribution of transferrin is limited to the materno-foetal interface supports the hypothesis that binding of maternal transferrin to trophoblast receptors is involved in the process of iron transport to the foetus. Parallel studies with baboon placentae demonstrate the presence of trophoblast receptors which bind both baboon and human transferrin, thereby putting forward an experimental model which might be used to test the biological significance of placental transferrin receptors in primates. In addition, investigation of a large number of human cell lines shows that many transformed cells, but no normal cells (such as blood lymphocytes) or cells from primary culture (such as neonatal foreskin fibroblasts), possess the ability to bind transferrin to their membranes. These findings suggest that transferrin receptors may play important biological roles in addition to that of iron transport from mother to foetus. One such role could be the limitation of iron in intervillous spaces, thus depriving iron-requiring microorganisms of iron, hence serving as a non-specific factor of resistance for placentae. Another role for foetal transferrin receptors on trophoblasts could be to bind maternal transferrin at the materno-foetal interface, thus frustrating maternal immunosurveillance. This is similar to a mechahism used by schistosomes in the host-parasite relation where host proteins are bound by the parasite to escape immunological recognition. The presence of transferrin receptors on transformed cells suggests that this mechanism might also be employed by tumour cells. Finally, in view of previous studies which show that transferrin is required by stimulated lymphocytes to pass from the G1 to the S phase of cellular replication, it is proposed that trophoblast transferrin receptors could limit the amount of transferrin in intervillous spaces and thus impede the proliferation and possible cytotoxicity of maternal activated lymphocytes at the materno-foetal interface.


Hox genes, digit identities and the theropod/bird transition.
Vargas and Fallon (2005. J Exp Zool (Mol Dev Evol) 304B:86-90) propose that Hox gene expression patterns indicate that the most anterior digit in bird wings is homologous to digit 1 rather than to digit 2 in other amniotes. This interpretation is based on the presence of Hoxd13 expression in combination with the absence of Hoxd12 expression in the second digit condensation from which this digit develops (the first condensation is transiently present). This is a pattern that is similar to that in the developing digit 1 of the chicken foot and the mouse hand and foot. They have tested this new hypothesis by analysing Hoxd12 and Hoxd13 expression patterns in two polydactylous chicken mutants, Silkie and talpid2. They conclude that the data support the notion that the most anterior remaining digit of the bird wing is homologous to digit 1 in other amniotes either in a standard phylogenetic sense, or alternatively in a (limited) developmental sense in agreement with the Frameshift Hypothesis of Wagner and Gautier (1999, i.e., that the developmental pathway is homologous to the one that leads to a digit 1 identity in other amniotes, although it occurs in the second instead of the first digit condensation). We argue that the Hoxd12 and Hoxd13 expression patterns found for these and other limb mutants do not allow distinguishing between the hypothesis of Vargas and Fallon (2005. J Exp Zool (Mol Dev Evol) 304B:86-90) and the alternative one, i.e., the most anterior digit in bird wings is homologous to digit 2 in other amniotes, in a phylogenetic or developmental sense. Therefore, at the moment the data on limb mutants does not present a challenge to the hypothesis, based on other developmental data (Holmgren, 1955. Acta Zool 36:243-328; Hinchliffe, 1984. In: Hecht M, Ostrom JH, Viohl G, Wellnhofer P, editors. The beginnings of birds. Eichstätt: Freunde des Jura-Museum. p 141-147; Burke and Feduccia, 1997. Science 278:666-668; Kundrát et al., 2002. J Exp Zool (Mol Dev Evol) 294B:151-159; Larsson and Wagner, 2002. J Exp Zool (Mol Dev Evol) 294B:146-151; Feduccia and Nowicki, 2002. Naturwissenschaften 89:391-393), that the digits of bird wings are homologous to digits 2,3,4 in amniotes. We recommend further testing of the hypothesis by comparing Hoxd expression patterns in different taxa.


Changes in Rubisco kinetics during the evolution of C4 photosynthesis in Flaveria (Asteraceae) are associated with positive selection on genes encoding the enzyme.
Rubisco, the primary photosynthetic carboxylase, evolved 3-4 billion years ago in an anaerobic, high CO(2) atmosphere. The combined effect of low CO(2) and high O(2) levels in the modern atmosphere, and the inability of Rubisco to distinguish completely between CO(2) and O(2), leads to the occurrence of an oxygenation reaction that reduces the efficiency of photosynthesis. Among land plants, C(4) photosynthesis largely solves this problem by facilitating a high CO(2)/O(2) ratio at the site of Rubisco that resembles the atmosphere in which the ancestral enzyme evolved. The prediction that such conditions favor Rubiscos with higher kcat(CO2) and lower CO(2)/O(2) specificity (S(C/O)) is well supported, but the structural basis for the differences between C(3) and C(4) Rubiscos is not clear. Flaveria (Asteraceae) includes C(3), C(3)-C(4) intermediate, and C(4) species with kinetically distinct Rubiscos, providing a powerful system in which to study the biochemical transition of Rubisco during the evolution from C(3) to C(4) photosynthesis. We analyzed the molecular evolution of chloroplast rbcL and nuclear rbcS genes encoding the large subunit (LSu) and small subunit (SSu) of Rubisco from 15 Flaveria species. We demonstrate positive selection on both subunits, although selection is much stronger on the LSu. In Flaveria, two positively selected LSu amino acid substitutions, M309I and D149A, distinguish C(4) Rubiscos from the ancestral C(3) species and statistically account for much of the kinetic difference between the two groups. However, although Flaveria lacks a characteristic "C(4)" SSu, our data suggest that specific residue substitutions in the SSu are correlated with the kinetic properties of Rubisco in this genus.


Risk of pancreatic cancer associated with family history of cancer and other medical conditions by accounting for smoking among relatives.
Family history (FH) of pancreatic cancer (PC) has been associated with an increased risk of PC, but little is known regarding the role of inherited/environmental factors or that of FH of other comorbidities in PC risk. We aimed to address these issues using multiple methodological approaches. Case-control study including 1431 PC cases and 1090 controls and a reconstructed-cohort study (N = 16 747) made up of their first-degree relatives (FDR). Logistic regression was used to evaluate PC risk associated with FH of cancer, diabetes, allergies, asthma, cystic fibrosis and chronic pancreatitis by relative type and number of affected relatives, by smoking status and other potential effect modifiers, and by tumour stage and location. Familial aggregation of cancer was assessed within the cohort using Cox proportional hazard regression. FH of PC was associated with an increased PC risk [odds ratio (OR) = 2.68; 95% confidence interval (CI): 2.27-4.06] when compared with cancer-free FH, the risk being greater when ≥ 2 FDRs suffered PC (OR = 3.88; 95% CI: 2.96-9.73) and among current smokers (OR = 3.16; 95% CI: 2.56-5.78, interaction FHPC*smoking P-value = 0.04). PC cumulative risk by age 75 was 2.2% among FDRs of cases and 0.7% in those of controls [hazard ratio (HR) = 2.42; 95% CI: 2.16-2.71]. PC risk was significantly associated with FH of cancer (OR = 1.30; 95% CI: 1.13-1.54) and diabetes (OR = 1.24; 95% CI: 1.01-1.52), but not with FH of other diseases. The concordant findings using both approaches strengthen the notion that FH of cancer, PC or diabetes confers a higher PC risk. Smoking notably increases PC risk associated with FH of PC. Further evaluation of these associations should be undertaken to guide PC prevention strategies.


A multi-centre randomised controlled trial of Transfusion Indication Threshold Reduction on transfusion rates, morbidity and healthcare resource use following cardiac surgery: study protocol.
Thresholds for red blood cell transfusion following cardiac surgery vary by hospital and surgeon. The TITRe2 multi-centre randomised controlled trial aims to randomise 2000 patients from 17 United Kingdom centres, and tests the hypothesis that a restrictive transfusion threshold will reduce postoperative morbidity and health service costs compared to a liberal threshold. Patients consent to take part in the study pre-operatively but are only randomised if their haemoglobin falls below 9 g/dL during their post-operative hospital stay. The primary outcome is a binary composite outcome of any serious infectious or ischaemic event in the first three months after randomisation. Many challenges have been encountered in the set-up and running of the study.


Analysis of differentially expressed genes associated with tryptophan-dependent pigment synthesis in M. furfur by cDNA subtraction technology.
Malassezia species are associated with pityriasis versicolor (PV) and its depigmented variant pityriasis versicolor alba (PVa), widespread fungal skin infections in humans. The pathogenesis of PV and PVa remains unclear, including their clinical and histological symptoms such as hyper- and depigmentation, reduced responsiveness to ultraviolet radiation and lack of inflammatory reaction despite high fungal load. Pigments produced by M. furfur are possibly involved in the pathogenesis of PV. In vitro, M. furfur produces a wide range of pigments and fluorochromes when cultured with tryptophan as the sole nitrogen source. We have begun to analyse the molecular basis of pigment production by searching for genes associated with tryptophan-based pigment production. A suppression subtractive hybridization (SSH) protocol was used to identify genes expressed in M. furfur cells producing pigments, but not in non-induced cells. SSH was performed 3 and 5 h after onset of pigment induction. Up-regulation of genes in the pigment-producing cells was confirmed by reverse northern analysis. More than 1,500 cDNA sequences of both the indicated time points were analysed. We identified a wide variety of genes associated with metabolism and several genes with unknown function are specifically expressed during pigment production. Furthermore, a fraction of genes possibly involved in different steps of the newly discovered indolic pathway of M. furfur were expressed in pigment producing cells. These data provide the first molecular insight into pigment production of M. furfur.


Leaching of dissolved phosphorus from tile-drained agricultural areas.
We investigated leaching of dissolved phosphorus (P) from 45 tile-drains representing animal husbandry farms in all regions of Denmark. Leaching of P via tile-drains exhibits a high degree of spatial heterogeneity with a low concentration in the majority of tile-drains and few tile-drains (15% in our investigation) having high to very high concentration of dissolved P. The share of dissolved organic P (DOP) was high (up to 96%). Leaching of DOP has hitherto been a somewhat overlooked P loss pathway in Danish soils and the mechanisms of mobilization and transport of DOP needs more investigation. We found a high correlation between Olsen-P and water extractable P. Water extractable P is regarded as an indicator of risk of loss of dissolved P. Our findings indicate that Olsen-P, which is measured routinely in Danish agricultural soils, may be a useful proxy for the P leaching potential of soils. However, we found no straight-forward correlation between leaching potential of the top soil layer (expressed as either degree of P saturation, Olsen-P or water extractable P) and the measured concentration of dissolved P in the tile-drain. This underlines that not only the source of P but also the P loss pathway must be taken into account when evaluating the risk of P loss.


Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation.
VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro. A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo. The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens. In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit. NCT00865904.


ALK2 mutation in a patient with Down's syndrome and a congenital heart defect.
Down's syndrome (DS), resulting from an additional copy of chromosome 21 (trisomy 21), is frequently associated with congenital heart defects (CHDs). Although the increased dosage of chromosome 21 sequences is likely to be part of the etiology of cardiac defects, only a proportion of DS patients exhibit a congenital heart defect (birth prevalence 40-60%). Through a large-candidate gene-sequencing screen in patients with atrioventricular septal defects, substitutions were identified in bone morphogenetic protein (BMP) type I receptor ALK2 and two other genes in a patient with DS and a primum-type atrial septal defect. Structural modeling of the cytoplasmic domain of the ALK2 receptor suggests that H286 is in close proximity to the nucleotide-binding site of the kinase domain. We investigated whether this p.His286Asp substitution altered ALK2 function by using both in vitro as well as in vivo assays. The p.His286Asp variant demonstrated impaired functional activity as measured by BMP-specific transcriptional response assays. Furthermore, mild dominant-interfering activity was observed in vivo compared with wild-type ALK2 as determined by RNA injection into zebrafish embryos. These data indicate that in the context of a DS background, ALK2-mediated reduction of BMP signaling may contribute to CHDs.


Nephrotoxicity With Vancomycin in the Pediatric Population: A Systematic Review and Meta-Analysis.
Vancomycin is frequently used to treat methicillin-resistant Staphylococcus aureus infections in pediatric patients. Vancomycin exposure may lead to an increase in frequency of nephrotoxicity. Our aim was to conduct a systematic review to describe predictors of nephrotoxicity associated with vancomycin, including documented trough concentrations ≥15 mg/L. We also aimed to use a meta-analysis to assess the impact of a vancomycin trough ≥15 mg/L on nephrotoxicity. A literature search was performed using PubMed, Cochrane Library, Embase and Web of Sciences database. We included randomized clinical trials and observational studies evaluating the relationship between vancomycin troughs and nephrotoxicity in pediatric-age patients. Studies not measuring troughs or defining a different cut-off point than 15 mg/L were excluded. Data on age, exclusion criteria, nephrotoxicity definition, risk factors for nephrotoxicity and vancomycin trough levels were extracted from selected papers. Ten studies were identified for meta-analysis. All subjects had comparatively normal baseline serum creatinine values. Common risk factors identified included elevated (≥15 mg/L) trough levels, renal impairment, hypovolemia and concurrent use of nephrotoxic medications. Troughs ≥15 mg/L increased nephrotoxicity by 2.7-fold (odds ratio (OR), 2.71; 95% confidence interval: 1.82-4.05; I(2) = 40%; Q = 0.09). These odds were further increased among patients in the pediatric intensive care unit (OR, 3.61; 95% confidence interval: 1.21-10.74; I(2) = 45%; Q = 0.18). Though the rate of vancomycin-induced nephrotoxicity is increased in pediatric patients with higher vancomycin troughs, other factors such as intensive care unit admission, hypovolemia and concurrent nephrotoxic drug use appear to contribute to the development of nephrotoxicity.


The role of parkinson's disease-associated receptor GPR37 in the hippocampus: functional interplay with the adenosinergic system.
GPR37 is an orphan G protein-coupled receptor mostly enriched in brain areas such as the cerebellum, striatum, and hippocampus. Identified as a substrate of parkin, GPR37 has been suggested to play a role in Parkinson's disease. Distributed throughout the brain, the function of GPR37, however, remains unknown. We now provide the first mapping of GPR37 within the hippocampus, where GPR37 is widely expressed and localized at the level of the extrasynaptic plasma membrane of dendritic spines, dendritic shafts, and axon terminals. GPR37 per se does not appear to play a role in learning and memory, since knocking out GPR37 (GPR37-KO) did not alter the performance in different hippocampal-related memory tasks. This is in agreement with slice electrophysiology experiments showing no differences both in short-term plasticity paired-pulse facilitation and long-term potentiation between WT and GPR37-KO mice. However, we report a potential functional interaction between GPR37 and adenosine A2A receptors (A2 A R) in the hippocampus, with A2 A R modulating the GPR37-associated phenotype. Thus, the absence of GPR37 appeared to sensitize mice to hippocampal A2 A R-mediated signaling, as observed by the effect of the A2 A R antagonist SCH58261 increasing synaptic depotentiation, reducing novel object recognition memory and reverting the anxiolytic effect of GPR37 deletion. Collectively, these findings afford insight into the localization and role of the orphan GPR37 within the hippocampus with potential involvement in A2 A R function (i.e., A2 A R sensitization). GPR37 is an orphan G protein-coupled receptor widely expressed in the hippocampus and localized at the level of the extrasynaptic plasma membrane of dendritic spines, dendritic shafts and axon terminals. This orphan receptor per se does not appear to directly control the learning and memory processes; however knocking-out GPR37 triggers anxiolytic-like effects and sensitizes mice to hippocampal A2A R-mediated signalling.


The evolution of major histocompatibility class I genes in primates.
MHC class I genes evolve by recombination, largely within loci, and selection (presumably pathogen-driven) maintains these new alleles in the population. Although chimpanzees and humans share an A locus allelic lineage, the B locus molecules of the chimpanzee were less similar to human B locus molecules. The A and B locus molecules in rhesus and cynomolgus monkeys were even less similar to their human counterparts, with little conservation of allelic lineages between macaques and humans. In contrast to the instability of MHC class I alleles and allelic lineages, the MHC class I loci themselves are well conserved during the evolution of Great Ape and Old World primates. Homologues of HLA-A, -B, -E, and -F have been found in macaques. The C locus, however, has only been found in gorillas and chimpanzees, whereas in orangutans and rhesus monkeys it is possible that the A and B loci have been duplicated. Classical New World monkey MHC class I genes are all more similar to the nonclassical HLA-G gene and a nonclassical F-like gene is present in the cotton-top tamarin. Duplication and either subsequent deletion or expansion of MHC class I loci, therefore, appear to be the modus operandi of the evolution of these genes in primates.