Improvement in advanced pancreatic cancer survival with novel chemotherapeutic strategies - experience of a community based hospital.
Background: New chemotherapeutic strategies for locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) have been shown to improve survival in randomized clinical trials. Little is known about the use of such chemotherapies and their benefit in community-based hospitals. This retrospective study analyzes the overall survival of these patients under "real life conditions" before and after the introduction of FOLFIRINOX in 2011. Methods: We retrospectively identified consecutive patients with PDAC who were treated at our hospital from 2011 to June 2014 (2011+ cohort) and 2004 to 2010 (historical cohort). Patients were included if PDAC was diagnosed in a locally advanced or metastatic state and at least 1 cycle of chemotherapy was given. Survival was assessed until April 2016. Patients with FOLFIRINOX were further analyzed regarding drug administration and side effects. Results: 128 patients met the inclusion criteria. Of the 74 patients in the historical cohort, 62 patients received Gemcitabine. Of the 54 patients diagnosed between 2011 and June 2014, 28 patients received FOLFIRINOX and 22 Gemcitabine as the first-line chemotherapy. Only 34 % of the patients in the historical cohort received a second-line chemotherapy in comparison to 69 % in the 2011+ cohort. Median overall survival (OS) showed a survival of 13.1 months (95 % CI; 11.6 - 14.5) for the 2011+ cohort compared to 9.6 months (95 % CI; 6.1 - 13.1) in the historical group. Conclusion: This study shows a marked improvement in survival of patients diagnosed with locally advanced or metastatic PDAC in a community-based hospital during the past 4 years. The most likely reasons are the use of new polychemotherapies like FOLFIRINOX and the use of second-line chemotherapy.


Correlation between pretherapeutic d-dimer levels and response to neoadjuvant chemotherapy in patients with advanced esophageal cancer.
Neoadjuvant chemotherapy may improve survival of responders in esophageal cancer patients but is useless and harmful in non-responders. Thus, it is important to predict the effect of the chemotherapy, and that any predictor must be applicable clinically. The aim of this study is to examine the correlation between pretherapeutic hypercoagulopathy as determined by plasma d-dimer levels and response to chemotherapy. In 71 patients with esophageal cancer who underwent neoadjuvant chemotherapy (cisplatin, adriamycin and 5-fluorouracil) followed by surgery, plasma d-dimer levels were measured before chemotherapy and the clinical and pathological responses to chemotherapy were assessed at 4 weeks after therapy (after surgery). Pretherapeutic plasma d-dimer level was significantly lower in clinical responders (complete response/partial response [CR/PR]; 0.62 +/- 1.10 microg/mL, mean +/- SD) than in non-responders (no change/progressive disease [NC/PD]; 1.15 +/- 1.08 microg/mL, P = 0.0491), and in pathological responders (Grade 1b-3; 0.62 +/- 1.11 microg/mL) and non-responders (Grade 0-1a; 1.15 +/- 1.05 microg/mL, P = 0.0107). The optimal cut-off level of the plasma d-dimer levels for predicting clinical and pathological responses was 0.6 microg/mL. Then, sensitivity and specificity for the prediction of CR/PR were 68% and 73%, and those for Grade 1b-3 were 91% and 69%, respectively. Our results suggested that pretherapeutic plasma d-dimer level correlated significantly with clinical and pathological responses to chemotherapy. Pretherapeutic plasma d-dimer level can be used as a predictor for chemosensitivity.


Critical advancements in achieving high power and stable nonprecious metal catalyst-based MEAs for real-world proton exchange membrane fuel cell applications.
Despite great progress in the development of nonprecious metal catalysts (NPMCs) over the past several decades, the performance and stability of these promising catalysts have not yet achieved commercial readiness for proton exchange membrane fuel cells (PEMFCs). Through rational design of the cathode catalyst layer (CCL), we demonstrate the highest reported performance for an NPMC-based membrane electrode assembly (MEA), achieving a peak power of 570 mW/cm2 under air. This record performance is achieved using a precommercial catalyst for which nearly all pores are <3 nm in diameter, challenging previous beliefs regarding the need for larger catalyst pores to achieve high current densities. This advance is achieved at industrially relevant scales (50 cm2 MEA) using a precommercial NPMC. In situ electrochemical analysis of the CCLs is also used to help gain insight into the degradation mechanism observed during galvanostatic testing. Overall, the performance of this NPMC-based MEA has achieved commercial readiness and will be introduced into an NPMC-based product for portable power applications.


Adolescence physical activity is associated with higher tibial pQCT bone values in adulthood after 28-years of follow-up--the Cardiovascular Risk in Young Finns Study.
High peak bone mass and strong bone phenotype are known to be partly explained by physical activity during growth but there are few prospective studies on this topic. In this 28-year follow-up of Cardiovascular Risk in Young Finns Study cohort, we assessed whether habitual childhood and adolescence physical activity or inactivity at the age of 3-18 years were associated with adult phenotype of weight-bearing tibia and the risk of low-energy fractures. Baseline physical activity and data on clinical, nutritional and lifestyle factors were assessed separately for females and males aged 3-6-years (N=395-421) and 9-18-years (N=923-965). At the age of 31-46-years, the prevalence of low-energy fractures was assessed with a questionnaire and several tibial traits were measured with pQCT (bone mineral content (BMC; mg), total and cortical cross-sectional areas (mm(2)), trabecular (for the distal site only) and cortical (for the shaft only) bone densities (mg/cm(3)), stress-strain index (SSI; mm(3), for the shaft only), bone strength index (BSI; mg(2)/cm(4), for the distal site only) and the cortical strength index (CSI, for the shaft only)). For the statistical analysis, each bone trait was categorized as below the cohort median or the median and above and the adjusted odds ratios (OR) were determined. In females, frequent physical activity at the age of 9-18-years was associated with higher adulthood values of BSI, total and cortical areas, BMC, CSI and SSI at the tibia independently of many health and lifestyle factors (ORs 0.33-0.53, P≤0.05; P-values for trend 0.002-0.05). Cortical density at the tibial shaft showed the opposite trend (P-value for trend 0.03). Similarly in males, frequent physical activity was associated with higher values of adult total and cortical areas and CSI at the tibia (ORs 0.48-0.53, P≤0.05; P-values for trend 0.01-0.02). However, there was no evidence that childhood or adolescence physical activity was associated with lower risk of low energy fractures during the follow-up. In conclusion, frequent habitual physical activity in adolescence seems to confer benefits on tibial bone size and geometry in adulthood.


Introduction and demonstration of a novel Pb(II)-imprinted polymeric membrane with high selectivity and reusability for treatment of lead contaminated water.
Lead contaminant in water has become an issue of great concern due to its high toxicity and easy accumulation in human body. In this study, a novel Pb(II)-imprinted polyvinyl alcohol (PVA)/polyacrylic acid (PAA) membrane (Pb-IM) was prepared based on semi-interpenetrating polymer network for selective lead removal. The chemical stability and lead adsorption performance of the Pb-IM were evaluated. The results revealed that the Pb-IM exhibited high adsorption capacity of 1.003mmol/g for lead, fast adsorption equilibrium within 1.5h, and the adsorption process obeyed Langmuir isotherm model and intraparticle pore diffusion model. The Pb-IM retained high adsorption of lead in the presence of competitive factor, i.e. cadmium. In comparison with non-imprinted PVA/PAA membrane, the Pb-IM possessed a much higher selectivity toward lead versus cadmium, with selectivity coefficient of 70.7. Furthermore, the Pb-IM displayed a high reusability for lead uptake and could maintain 96.32% of the adsorption capacity of virgin Pb-IM after six adsorption/desorption cycles. The FTIR and XPS analyses indicated that carboxyl groups in PAA and hydroxyl groups in PVA were mainly associated with the lead adsorption. Finally, the stability study showed that Pb-IM was quite stable and suitable for water treatment. It can be concluded that the Pb-IM can be provided as a powerful material for the selective removal of lead from aqueous solution.


Transsaccadic identification of highly similar artificial shapes.
Multiple times per second, the visual system succeeds in making a seamless transition between presaccadic and postsaccadic perception. The nature of the transsaccadic representation needed to support this was commonly thought to be sparse and abstract. However, recent studies have suggested that detailed visual information is transferred across saccades as well. Here, we seek to confirm that preview effects of visual detail on postsaccadic perception do indeed occur. We presented subjects with highly similar artificial shapes, preceded by a congruent, an incongruent, or no preview. Postsaccadic recognition performance was measured, while the contrast of presaccadic and postsaccadic stimuli was manipulated independently. The results show that congruent previews provided a benefit to the recognition performance of postsaccadic stimuli, compared to no-preview conditions. Incongruent previews induced a recognition accuracy cost, combined with a recognition speed benefit. A second experiment showed that these effects can disappear when stimulus presentation is interrupted with a postsaccadic visual mask. We conclude that visual detail contained in transsaccadic memory can affect the postsaccadic percept. Furthermore, we find that the transsaccadic representation supporting this process is contrast-independent, but that postsaccadic contrast, through its effect on the reliability of information, can affect the degree to which it is employed.


Staging of 119 patients with renal cell carcinoma: the yield and cost-effectiveness of pelvic CT.
The goal of this study was to determine the yield and cost-effectiveness of pelvic CT in staging renal cell carcinoma. The records of 119 patients who underwent preoperative CT of the abdomen and pelvis during a 6-year interval and then underwent partial or radical nephrectomy for renal cell carcinoma were reviewed for CT findings and pathologic stage. Pelvic CT findings were divided into three categories: benign and likely insignificant, benign and likely significant, and probably malignant. The effect of CT findings on further testing and the scheduling of surgery was assessed. An estimate of the cost of pelvic CT scans and other radiologic tests was made using 1997 Medicare reimbursement rates. Total estimated cost of the 119 CT examinations of the pelvis was $40,698 ($342 each). No findings of probable malignancy were identified. In 27 patients, CT showed benign findings; these results did not cause planned surgery to be delayed. Three of these 27 patients underwent further radiologic tests at an estimated total cost of $243. CT of the pelvis has a negligible yield in the staging of renal cell carcinoma and should not be routinely performed. The findings on CT of the pelvis did not generate a significant number of other tests.


Replication of murine coronavirus defective interfering RNA from negative-strand transcripts.
The positive-strand defective interfering (DI) RNA of the murine coronavirus mouse hepatitis virus (MHV), when introduced into MHV-infected cells, results in DI RNA replication and accumulation. We studied whether the introduction of negative-strand transcripts of MHV DI RNA would also result in replication. At a location downstream of the T7 promoter and upstream of the human hepatitis delta virus ribozyme domain, we inserted a complete cDNA clone of MHV DI RNA in reverse orientation; in vitro-synthesized RNA from this plasmid yielded a negative-strand RNA copy of the MHV DI RNA. When the negative-strand transcripts of the DI RNA were expressed in MHV-infected cells by a vaccinia virus T7 expression system, positive-strand DI RNAs accumulated in the plasmid-transfected cells. DI RNA replication depended on the expression of T7 polymerase and on the presence of the T7 promoter. Transfection of in vitro-synthesized negative-strand transcripts into MHV-infected cells and serial passage of virus samples from RNA-transfected cells also resulted in accumulation of the DI RNA. Positive-strand DI RNA transcripts were undetectable in sample preparations of the in vitro-synthesized negative-strand DI RNA transcripts, and DI RNA did not accumulate after cotransfection of a small amount of positive-strand DI RNA and truncated-replication-disabled negative-strand transcripts; clearly, the DI RNA replicated from the transfected negative-strand transcripts and not from minute amounts of positive-strand DI RNAs that might be envisioned as artifacts of T7 transcription. Sequence analysis of positive-strand DI RNAs in the cells transfected with negative-strand transcripts showed that DI RNAs maintained the DI-specific unique sequences introduced within the leader sequence. These data indicated that positive-strand DI RNA synthesis occurred from introduced negative-strand transcripts in the MHV-infected cells; this demonstration, using MHV, of DI RNA replication from transfected negative-strand DI RNA transcripts is the first such demonstration among all positive-stranded RNA viruses.


Deontological coherence: A framework for commonsense moral reasoning.
We review a broad range of work, primarily in cognitive and social psychology, that provides insight into the processes of moral judgment. In particular, we consider research on pragmatic reasoning about regulations and on coherence in decision making, both areas in which psychological theories have been guided by work in legal philosophy. Armed with these essential prerequisites, we sketch a psychological framework for how ordinary people make judgments about moral issues. Based on a literature review, we show how the framework of deontological coherence unifies findings in moral psychology that have often been explained in terms of a grab-bag of heuristics and biases. (PsycINFO Database Record


Small hook thread (Quill) and soft felt internal splint to increase the primary repair strength of lacerated rabbit Achilles tendons: biomechanical analysis and considerations for hand surgery.
For the prevention of re-rupture during early healing phase, the primary repair strength of repaired lacerated tendons in hand surgery should be maximal and the reconstructed diameter minimal. Two new repair methods (small hook thread and internal splint) were assessed for strength and reconstructed diameter characteristics. Achilles tendons of 43 female New Zealand White rabbits were sectioned 2 cm above the calcaneus. Specimens were divided into 7 groups and repaired as follows: Kirchmayr method 2-strand with 4.0 polypropylene thread; Becker method 4-strand; 6-strand; internal splint; Kirchmayr method small hook 2-strand; Becker method small hook 4-strand, non-modified tendon. Load until failure, load until gap formation, gap length, cross-sectional area and failure stress were determined. The small hook 2-strand suture had 1.3 fold higher loads until failure compared to a conventional 2-strand suture, P<0.05. The internal splint had a similar load until failure (22 N (SD 6)) as the conventional 2-strand suture (23 N (SD 4)); around half the load until failure of the conventional 4-strand suture (38 N (SD 9)). Load until gap formation correlated positively with load until failure (y=0.65+3.6; r(2)=0.72). The running suture increased the cross-sectional area at the repair site by a factor of 1.3. Using a small hook thread instead of a 4.0 polypropylene thread significantly increases the primary repair strength with the same number of strands. Internal splints may be an alternative to conventional 2-strand sutures for bridging large gaps.


V₂ receptor-mediated autocrine role of somatodendritic release of AVP in rat vasopressin neurons under hypo-osmotic conditions.
Arginine vasopressin (AVP) neurons in the hypothalamus are osmosensory neurons that respond to increased or decreased plasma osmolarity by releasing more or less AVP, respectively, from their axon terminals. Here, we found that, in contrast, hypo-osmotic stress enhanced somatodendritic AVP secretion from isolated rat AVP neurons, and this somatodendritic release depended on actin depolymerization. In AVP neurons identified by transgenic expression of green fluorescent protein, hypo-osmotic stimulation led to activation of anion currents and a slow regulatory volume decrease (RVD). Bath application of AVP increased the volume-sensitive anion current and accelerated RVD; these effects were abolished by inhibition of adenylate cyclase or by a specific antagonist of the V(2)-type vasopressin receptor. The V(2) receptor antagonist slowed the RVD rate of AVP neurons even in the absence of exogenous AVP when the volume of bath solution was reduced. Reverse transcription polymerase chain reaction and immunostaining both indicated that the V(2) receptor was present in AVP neurons. We conclude that somatodendritic release of AVP under hypo-osmotic conditions acts through the V(2) receptor as an autocrine signal to enhance volume-sensitive anion channel activity and thereby facilitate cell volume regulation.


Skeletal muscle metabolism during exercise is influenced by heat acclimation.
The influence of heat acclimation on skeletal muscle metabolism during submaximal exercise was studied in 13 healthy men. The subjects performed 30 min of cycle exercise (70% of individual maximal O2 uptake) in a cool [21 degrees C, 30% relative humidity (rh)] and a hot (49 degrees C, 20% rh) environment before and again after they were heat acclimated. Aerobic metabolic rate was lower (0.1 l X min-1; P less than 0.01) during exercise in the heat compared with the cool both before and after heat acclimation. Muscle and plasma lactate accumulation with exercise was greater (P less than 0.01) in the hot relative to the cool environment both before and after acclimation. Acclimation lowered (P less than 0.01) aerobic metabolic rate as well as muscle and plasma lactate accumulation in both environments. The amount of muscle glycogen utilized during exercise in the hot environment did not differ from that in the cool either before or after acclimation. These findings indicate that accumulation of muscle lactate is increased and aerobic metabolic rate is decreased during exercise in the heat before and after heat acclimation; increased muscle glycogen utilization does not account for the increased muscle lactate accumulation during exercise under extreme heat stress; and heat acclimation lowers the aerobic metabolic rate and muscle and blood lactate accumulation during exercise in a cool as well as a hot environment.


Reductive Binding and Ligand-Based Redox Transformations of Nitrosobenzene at a Dinickel(II) Core.
The metal-mediated activation of PhNO represents an important starting point for understanding the reactivity patterns of nitrosoarenes in biological systems and catalysis. Here we report that the pyrazole-based dinickel(II) dihydride complex [KL(NiH)2] (1) reacts with PhNO to eliminate dihydrogen concomitant with binding of the doubly reduced substrate in μ-κ(O):κ(N) mode in the bimetallic pocket of [KLNi2(PhNO)] (2). The addition of [2,2,2]cryptand leads to the ionic complex [K(crypt)][LNi2(PhNO)] (3). Structural and spectroscopic analyses evidence that interaction with the Lewis acidic K+ in 2 causes significant elongation and weakening of the substrate's N-O bond [ dN-O = 1.487(12) Å in 2 vs 1.374(4) Å in 3]. Complex 2 (or 3) reacts with [FeCp*2][PF6] to give LNi2(PhNO) (4), which is shown by electron paramagnetic resonance and IR spectroscopies and density functional theory calculations to feature two low-spin d8 nickel(II) ions and a bridging (PhNO)•- radical anion ligand, with the out-of-plane π*(NO) being the singly occupied molecular orbital. Cyclic voltammetry and UV-vis spectroelectrochemical experiments show that 4 and the anion of 3 can be reversibly interconverted at very low potential ( E1/2 = -1.53 V vs Fc/Fc+). Protonation of 2 leads to the N-phenylhydroxylamine complex [LNi2(ONHPh)] (5) with a long N-O bond of 1.464(2) Å, and titration studies suggest a p Ka of around 23-25 in tetrahydrofuran. This allows one to derive a bond dissociation energy of 62-65 kcal mol-1 for the N-H bond of 5. Accordingly, 5 readily reacts with the phenoxy radical 2,4,6- tBu3C6H2O• to yield 4. This work demonstrates the reductive binding of PhNO without prior formation of unstable nickel(I) species and the redox noninnocence of the PhNO ligand in the less common μ-κ(O):κ(N) bridging mode. Thermodynamic data for H-atom-abstraction chemistry at the activated PhNO may be valuable for understanding the reactivity patterns of the transient but biologically relevant nitroxyl (HNO) ligand.


Identifying essential infection control competencies for newly graduated nurses: a three-phase study in Australia and Taiwan.
Healthcare- and hospital-acquired infection increases patients' morbidity and mortality and increases healthcare costs. Infection prevention and control is a high priority for medical professionals in healthcare settings. To identify essential infection prevention and control competencies for newly graduated nurses. Three phases of research were designed: phase I, Instrument development, which was undertaken from January to May 2008; phase II, Expert panel identification, for which 122 experts were recruited, each nominated by presidents of infection control bodies and heads of nursing schools in Australia (N = 60) and Taiwan (N = 62); and phase III, Delphi surveys, which were conducted in three rounds simultaneously in Australia and Taiwan between July 2008 and May 2009. Ninety-three experts returned the first questionnaire. Response rates of 76.2%, 91.4% and 94.1% were achieved in rounds I, II and III, respectively. Eighty experts participated in all three rounds. Overall, 81 items reached consensus, including seven in the competency area of basic microbiology, 12 in hand hygiene, 30 in standard precautions and additional precautions, 12 in personal protective equipment, nine in cleaning, disinfection and sterilization and 11 in critical assessment skills. The majority of experts (N = 49; 75.4%) agreed that infection control competency levels of newly graduated nurses were inadequate. Eighty-one items of infection prevention and control specific to newly graduated nurses were identified by consensus between expert panellists from Taiwan and Australia. Baseline data from this study may help to develop undergraduate nursing curricula to facilitate nurses' clinical application of infection control principles.


Development and Validation of a Dementia Risk Prediction Model in the General Population: An Analysis of Three Longitudinal Studies.
Identification of individuals at high risk of dementia is essential for development of prevention strategies, but reliable tools are lacking for risk stratification in the population. The authors developed and validated a prediction model to calculate the 10-year absolute risk of developing dementia in an aging population. In a large, prospective population-based cohort, data were collected on demographic, clinical, neuropsychological, genetic, and neuroimaging parameters from 2,710 nondemented individuals age 60 or older, examined between 1995 and 2011. A basic and an extended model were derived to predict 10-year risk of dementia while taking into account competing risks from death due to other causes. Model performance was assessed using optimism-corrected C-statistics and calibration plots, and the models were externally validated in the Dutch population-based Epidemiological Prevention Study of Zoetermeer and in the Alzheimer's Disease Neuroimaging Initiative cohort 1 (ADNI-1). During a follow-up of 20,324 person-years, 181 participants developed dementia. A basic dementia risk model using age, history of stroke, subjective memory decline, and need for assistance with finances or medication yielded a C-statistic of 0.78 (95% CI=0.75, 0.81). Subsequently, an extended model incorporating the basic model and additional cognitive, genetic, and imaging predictors yielded a C-statistic of 0.86 (95% CI=0.83, 0.88). The models performed well in external validation cohorts from Europe and the United States. In community-dwelling individuals, 10-year dementia risk can be accurately predicted by combining information on readily available predictors in the primary care setting. Dementia prediction can be further improved by using data on cognitive performance, genotyping, and brain imaging. These models can be used to identify individuals at high risk of dementia in the population and are able to inform trial design.


Interaction of gold nanoparticles with common human blood proteins.
In order to better understand the physical basis of the biological activity of nanoparticles (NPs) in nanomedicine applications and under conditions of environmental exposure, we performed an array of photophysical measurements to quantify the interaction of model gold NPs having a wide range of NP diameters with common blood proteins. In particular, absorbance, fluorescence quenching, circular dichroism, dynamic light scattering, and electron microscopy measurements were performed on surface-functionalized water-soluble gold NPs having a diameter range from 5 to 100 nm in the presence of common human blood proteins: albumin, fibrinogen, gamma-globulin, histone, and insulin. We find that the gold NPs strongly associate with these essential blood proteins where the binding constant, K, as well as the degree of cooperativity of particle--protein binding (Hill constant, n), depends on particle size and the native protein structure. We also find tentative evidence that the model proteins undergo conformational change upon association with the NPs and that the thickness of the adsorbed protein layer (bare NP diameter <50 nm) progressively increases with NP size, effects that have potential general importance for understanding NP aggregation in biological media and the interaction of NP with biological materials broadly.


Different gvpC length variants are transcribed within single filaments of the cyanobacterium Planktothrix rubescens.
Transcripts of the gas vesicle genes gvpA and gvpC were detected in single filaments of the cyanobacterium Planktothrix rubescens using reverse transcription and quantitative real-time PCR. Primers were designed to amplify short sequences within gvpA and three length variants of gvpC. With genomic template DNA, and using Sybr Green to monitor product accumulation, similar amplification efficiencies were observed for each of these genes. The relative copy numbers of gvpC length variants in genomic DNA from five Planktothrix gas vesicle genotypes determined by real-time PCR were similar to those indicated by sequencing the gas vesicle gene clusters. The precipitation of gvp cDNA reverse-transcribed from cellular RNA from single filaments was required before amplification of the gene fragments; without this step it was not possible to detect the accumulation of the expected amplicons by dissociation analysis. Precipitation was also necessary to ensure the generation of product curves that allowed linear regression in an early stage of PCR, a prerequisite for the quantification of low-input cDNA amounts without the need for standard curves. This report shows that different gvpC length variants are transcribed within single Planktothrix filaments, both from laboratory cultures and from natural samples taken from Lake Zurich. This has implications for the efficiency of buoyancy provision by the possible production of gas vesicles of different strengths within individual cyanobacterial filaments. The hypothesis that post-transcriptional regulation may influence the type of protein (GvpC) present in gas vesicles is presented.


Childhood multiple sclerosis and related disorders.
Multiple sclerosis (MS) in children and adolescents is increasingly recognized worldwide. Demyelinating disorders of the central nervous system may overlap considerably in their clinical presentation and radiological appearance. Therefore an exact categorization might be challenging and might not be readily attainable. Rigorous radiological and laboratory investigations and longitudinal follow up of the patient are needed in order to establish the diagnosis of a chronic demyelinating disorder especially in children. However, in the past few years many advances have been achieved in the field of pediatric MS and other white matter disease such as establishing diagnostic criteria, consensus definitions proposed for pediatric multiple sclerosis and related disorders and advances in treating such disorders. A wealth of knowledge regarding childhood MS have been established with vast speed and greater familiarity with the diagnosis and treatment options should lead to better care of children with such disorders. This review will present the important advances in childhood multiple sclerosis and related disorders that were achieved in the last few years.


Subitizing but not estimation of numerosity requires attentional resources.
The numerosity of small numbers of objects, up to about four, can be rapidly appraised without error, a phenomenon known as subitizing. Larger numbers can either be counted, accurately but slowly, or estimated, rapidly but with errors. There has been some debate as to whether subitizing uses the same or different mechanisms than those of higher numerical ranges and whether it requires attentional resources. We measure subjects' accuracy and precision in making rapid judgments of numerosity for target numbers spanning the subitizing and estimation ranges while manipulating the attentional load, both with a spatial dual task and the "attentional blink" dual-task paradigm. The results of both attentional manipulations were similar. In the high-load attentional condition, Weber fractions were similar in the subitizing (2-4) and estimation (5-7) ranges (10-15%). In the low-load and single-task condition, Weber fractions substantially improved in the subitizing range, becoming nearly error-free, while the estimation range was relatively unaffected. The results show that the mechanisms operating over the subitizing and estimation ranges are not identical. We suggest that pre-attentive estimation mechanisms works at all ranges, but in the subitizing range, attentive mechanisms also come into play.


Intra-articular Fracture of the Distal part of the Triquetrum within the Pisotriquetral Joint: Case Report and Review of Literature.
Intra-articular fractures of the distal part of the triquetrum within the pisotriquetral joint are uncommon, and can be associated with tears of the dorsal carpal ligaments, pisiform subluxation and/or FCU dislocation. Their diagnosis is difficult and requires a high clinical suspicion and a proper radiological examination including oblique wrist x-rays, computed tomography and MRI scan. These fractures can be delayed diagnosed due to late presentation thus leading to painful nonunion, persistent instability and late pisotriquetral arthritis. We present a case of a 40-year-old male who complained about ulnarsided wrist pain after a fall on his extended wrist during bicycling. The diagnosis of triquetrum fracture was suspected on clinical examination and confirmed using standard and oblique radiographs and CT scan evaluation. He was immobilized in a short-arm cast for 6 weeks followed by a progressive return to wrist motion and subsequent strengthening for another 5 weeks. He reported complete resolution of pain and excellent wrist motion and function one year after the injury, demonstrating a Mayo score of 100. Isolated intra-articular fractures of the triquetrum within the pisotriquetral joint are rare injuries and may constitute a subcategory of body fractures other than the dorsal cortical (chip), main body and volar lip avulsion fractures. Early clinical suspicion and proper imagine can lead to a successful outcome.


Cell recognition and pattern formation in the developing nervous system.
The topographic map of cell position in the avian retina is conserved and inverted when retinal ganglion neurons synapse with neurons in the optic tectum. Developmental mechanisms based on molecular gradients that specify positional information and pattern formation have been postulated in the establishment of these topographic maps of cells in retina and optic tectum. Two cell surface proteins in retina, TOP(DV) and TOP(AP), are distributed in dorsoventral and anteroposterior topographic gradients, respectively. Corresponding gradients of TOP molecules present in the tectum are inverted with respect to the retinal gradients. These orthogonal gradients of TOP(DV) and TOP(AP) molecules provide a possible Cartesian coordinate system for designation of cell position at all points in the retinotectal map.


Epidemic history and evolutionary dynamics of hepatitis B virus infection in two remote communities in rural Nigeria.
In Nigeria, hepatitis B virus (HBV) infection has reached hyperendemic levels and its nature and origin have been described as a puzzle. In this study, we investigated the molecular epidemiology and epidemic history of HBV infection in two semi-isolated rural communities in North/Central Nigeria. It was expected that only a few, if any, HBV strains could have been introduced and effectively transmitted among these residents, reflecting limited contacts of these communities with the general population in the country. Despite remoteness and isolation, approximately 11% of the entire population in these communities was HBV-DNA seropositive. Analyses of the S-gene sequences obtained from 55 HBV-seropositive individuals showed the circulation of 37 distinct HBV variants. These HBV isolates belong predominantly to genotype E (HBV/E) (n=53, 96.4%), with only 2 classified as sub-genotype A3 (HBV/A3). Phylogenetic analysis showed extensive intermixing between HBV/E variants identified in these communities and different countries in Africa. Quasispecies analysis of 22 HBV/E strains using end-point limiting-dilution real-time PCR, sequencing and median joining networks showed extensive intra-host heterogeneity and inter-host variant sharing. To investigate events that resulted in such remarkable HBV/E diversity, HBV full-size genome sequences were obtained from 47 HBV/E infected persons and P gene was subjected to Bayesian coalescent analysis. The time to the most recent common ancestor (tMRCA) for these HBV/E variants was estimated to be year 1952 (95% highest posterior density (95% HPD): 1927-1970). Using additional HBV/E sequences from other African countries, the tMRCA was estimated to be year 1948 (95% HPD: 1924-1966), indicating that HBV/E in these remote communities has a similar time of origin with multiple HBV/E variants broadly circulating in West/Central Africa. Phylogenetic analysis and statistical neutrality tests suggested rapid HBV/E population expansion. Additionally, skyline plot analysis showed an increase in the size of the HBV/E-infected population over the last approximately 30-40 years. Our data suggest a massive introduction and relatively recent HBV/E expansion in the human population in Africa. Collectively, these data show a significant shift in the HBV/E epidemic dynamics in Africa over the last century.


Investigation of association of serotonin transporter and monoamine oxidase-A genes with Alzheimer's disease and depression in the VITA study cohort: a 90-month longitudinal study.
Alzheimer's disease (AD) and depression (DE) are common psychiatric disorders strongly intertwined with one another. Nevertheless, etiology and early diagnosis of the disorders are still elusive. Several genetic variations have been suggested to associate with AD and DE, particularly in genes involved in the serotonergic system such as the serotonin transporter (SERT/SLC6A4), responsible for the removal from the synaptic cleft, and the monoamine-oxidase-A (MAOA), responsible for the presynaptic degradation of serotonin. Here, we attempt to characterize this pleiotropic effect for the triallelic SERT gene-linked polymorphic region (5HTTLPR) and for the MAOA-uVNTR, in participants in the Vienna-Transdanube-Aging (VITA)-study. The VITA-study is a community-based longitudinal study following a birth cohort (75 years old at baseline examination, n = 606) from Vienna for a period of 90 months with a regular follow-up interval of 30 months. Our main finding, confirming previous reports, is that the 5HTTLPR S-allele is a risk allele for DE (OR = 1.55 CI 95% 1.03-2.32) and its carriers had a steeper increase in SGDS sum score. No association to AD was found. MAOA-uVNTR did not associate with either AD or DE. However, in AD MAOA-uVNTR S-allele carriers a steeper increase of HAMD and STAI1 sum scores (P < 0.05) was observed. Although the VITA-study cohort is rather small with low power to detect gene alterations, the uniqueness of this very thoroughly investigated and homogenous cohort strengthens the results through exceptional data collection. Still, reinvestigation in a larger cohort similar to this, as well as a meta-analysis, is important to confirm these results.


Psychological state during pregnancy is associated with sleep quality: preliminary findings from MY-CARE cohort study.
Psychological distress during pregnancy may increase the risk of adverse maternal and infant outcomes. Past studies have demonstrated the association between circadian disturbances with psychological health. However, the roles of chronotype and social jetlag on psychological state during pregnancy are yet to be identified. We aimed to examine the psychological state in pregnant women and its relations to chronotype, social jetlag (SJL), sleep quality and cortisol rhythm. The current study included a subsample of participants from an ongoing cohort study. A total of 179 primigravidas (mean age 28.4 ± 4.0 years) were recruited. Chronotype and sleep quality during the second trimester were assessed using the Morning-Eveningness Questionnaire (MEQ) and Pittsburgh Sleep Quality Index (PSQI), respectively. SJL was calculated based on the difference between mid-sleep on workdays and free days. Psychological state of participants was evaluated using the Depression, Anxiety, and Stress Scale-21 (DASS-21). Subsamples (n = 70) provided salivary samples at 5 time points over a 24 h period during the second trimester for cortisol assay. A higher proportion of pregnant women experienced moderate to severe anxiety symptoms (n = 77, 43.0%), followed by depressive (n = 17, 9.5%) and stress (n = 14, 7.8%) symptoms. No association was observed between chronotype and psychological distress during pregnancy. There was no significant difference in cortisol rhythms in relation to psychological distress. SJL and sleep quality were significantly associated with stress symptoms among pregnant women in the second trimester. Poor sleep quality, particularly daytime dysfunction (β = 0.37, p = .006) and sleep disturbances (β = 0.23, p = .047), were significantly associated with psychological distress (depressive, anxiety and stress symptoms) during the second trimester. The findings suggest that sleep is a potential modifiable lifestyle factor that can be targeted to improve psychological health among pregnant women.


Raindrop impact on sand: a dynamic explanation of crater morphologies.
As a droplet impacts upon a granular substrate, both the intruder and the target undergo deformation, during which the liquid may penetrate into the substrate. These three aspects together distinguish it from other impact phenomena in the literature. We perform high-speed, double-laser profilometry measurements and disentangle the dynamics into three aspects: the deformation of the substrate during the impact, the maximum spreading diameter of the droplet, and the penetration of the liquid into the substrate. By systematically varying the impact speed and the packing fraction of the substrate, (i) the substrate deformation indicates a critical packing fraction ϕ* ≈ 0.585; (ii) the maximum droplet spreading diameter is found to scale with a Weber number corrected by the substrate deformation; and (iii) a model of the liquid penetration is established and is used to explain the observed crater morphology transition.


A microarray data-based semi-kinetic method for predicting quantitative dynamics of genetic networks.
Elucidating the dynamic behaviour of genetic regulatory networks is one of the most significant challenges in systems biology. However, conventional quantitative predictions have been limited to small networks because publicly available transcriptome data has not been extensively applied to dynamic simulation. We present a microarray data-based semi-kinetic (MASK) method which facilitates the prediction of regulatory dynamics of genetic networks composed of recurrently appearing network motifs with reasonable accuracy. The MASK method allows the determination of model parameters representing the contribution of regulators to transcription rate from time-series microarray data. Using a virtual regulatory network and a Saccharomyces cerevisiae ribosomal protein gene module, we confirmed that a MASK model can predict expression profiles for various conditions as accurately as a conventional kinetic model. We have demonstrated the MASK method for the construction of dynamic simulation models of genetic networks from time-series microarray data, initial mRNA copy number and first-order degradation constants of mRNA. The quantitative accuracy of the MASK models has been confirmed, and the results indicated that this method enables the prediction of quantitative dynamics in genetic networks composed of commonly used network motifs, which cover considerable fraction of the whole network.


Free-radical oxidation and superoxide dismutase activity in synovial fluid of patients with temporomandibular disorders.
To measure the activity of oxygen free radicals and the level of antioxidant enzyme superoxide dismutase (SOD) in the synovial fluid (SF) of the temporomandibular joints (TMJs) of patients with temporomandibular disorders (TMD). Thirty-two patients were divided into 3 subgroups: anterior disc displacement with reduction, anterior disc displacement without reduction, and osteoarthrosis. Six healthy volunteers served as controls. A pumping procedure was used to take SF from the superior TMJ space. The concentration of lipid peroxidation products was assessed by means of the thiobarbituric acid reaction, and the level of SOD was assessed with spectrophotometry. SF levels of lipid peroxides (LPO) in the control and patient groups were 0.010 (+/- 0.004) x 10(-3) nmol/mg protein and 0.61 (+/- 0.121) x 10(-3) nmol/mg protein, respectively. SF SOD levels were 4.61 (+/- 1.30) NU/mg protein and 9.83 (+/- 2.66) NU/mg protein, respectively. Both the concentration of LPO and the level of SOD activity were significantly higher in the TMD patients than in the normal control subjects (P < .001 and P < .01, respectively). There were no significant differences in the level of LPO or SOD between the 3 subgroups. These results demonstrate oxygen free radicals and antioxidant enzymes may be connected in the pathogenesis of TMD.


Among Low-Income Respondents With Diabetes, High-Deductible Versus No-Deductible Insurance Sharply Reduces Medical Service Use.
To contrast the effect of private insurance and deductibles (by size) on medical service use, health status, and medical debt for adult respondents with diabetes with low and high incomes. Using the 2011-2013 Medical Expenditure Panel Survey, bivariate and regression analyses were conducted to compare demographic characteristics, medical service use, diabetes care, and health status among privately insured adult respondents with diabetes, aged 18-64 years (N = 1,461) by lower (<200% of the federal poverty level) and higher (≥200% of the federal poverty level) income and deductible vs. no deductible (ND), low deductible ($1,000/$2,400) (LD), and high deductible (>$1,000/$2,400) (HD). The National Health Interview Survey 2012-2014 was used to analyze differences in medical debt and delayed/avoided needed care among adult respondents with diabetes (n = 4,058) by income. Compared with privately insured respondents with diabetes with ND, privately insured lower-income respondents with diabetes with an LD report significant decreases in service use for primary care, checkups, and specialty visits (27%, 39%, and 77% lower, respectively), and respondents with an HD decrease use by 42%, 65%, and 86%, respectively. Higher-income respondents with an LD report significant decreases in specialty (28%) and emergency department (37%) visits. Diabetes care measures are similar by income and insurance; there were no changes in physical health status. Medical debt is similar by income, but deferred service use is two times greater for those indebted and with lower income. Private insurance with a deductible substantially and problematically reduces medical service use for lower-income insured respondents with diabetes who have an HD; these patients are more likely to report forgoing needed medical services.


Oral inflammation, tooth loss, risk factors, and association with progression of Alzheimer's disease.
Periodontitis is a polymicrobial chronic inflammatory disease of tooth-supporting tissues with bacterial etiology affecting all age groups, becoming chronic in a subgroup of older individuals. Periodontal pathogens Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola are implicated in the development of a number of inflammatory pathologies at remote organ sites, including Alzheimer's disease (AD). The initial inflammatory hypothesis proposed that AD hallmark proteins were the main contributors of central nervous system (CNS) inflammation. This hypothesis is expanding to include the role of infections, lifestyle, and genetic and environmental factors in the pathogenesis of AD. Periodontal disease (PD) typifies a condition that encompasses all of the above factors including pathogenic bacteria. These bacteria not only are the source of low-grade, chronic infection and inflammation that follow daily episodes of bacteremia arising from everyday tasks such as brushing, flossing teeth, chewing food, and during dental procedures, but they also disseminate into the brain from closely related anatomical pathways. The long-term effect of inflammatory mediators, pathogens, and/or their virulence factors, reaching the brain systemically or otherwise would, over time, prime the brain's own microglia in individuals who have inherent susceptibility traits. Such susceptibilities contribute to inadequate neutralization of invading agents, upon reaching the brain. This has the capacity to create a vicious cycle of sustained local inflammatory milieu resulting in the loss of cytoarchitectural integrity and vital neurons with subsequent loss of function (deterioration in memory). The possible pathways between PD and AD development are considered here, as well as environmental factors that may modulate/exacerbate AD symptoms.


Structure of the Wnt signaling enhancer LYPD6 and its interactions with the Wnt coreceptor LRP6.
Ly6/urokinase-type plasminogen activator receptor (uPAR) (LU) domain containing 6 (LYPD6) is a Wnt signaling enhancer that promotes phosphorylation of the Wnt coreceptor low density lipoprotein receptor-related protein 6 (LRP6). It also binds the nicotinic acetylcholine receptor (nAChR). We report here the 1.25 Å resolution structure of the LYPD6 extracellular LU domain and map its interaction with LRP6 by mutagenesis and surface plasmon resonance. The LYPD6LU structure reveals a 'trifingered protein domain' fold with the middle fingertip bearing an 'NxI' motif, a tripeptide motif associated with LRP5/6 binding by Wnt inhibitors. Of the Ly6 protein family members, only LYPD6 has an NxI motif. Since mutations in the LYPD6 NxI motif abolish or severely reduce interaction with LRP6, our results indicate its key role in the interaction of LYPD6 with LRP6.


Apolipoprotein-D expression is increased during development and maturation of the human prefrontal cortex.
Apolipoprotein D (apoD) is a lipid binding protein expressed in the brain where its function is largely unknown. Based on changes in lipid metabolism and deposition that occur in the human brain during postnatal development, we investigated changes in apoD expression in the prefrontal cortex in 69 normal cases ranging in age from 40 days to 49 years utilizing gene microarray, quantitative PCR and western blotting methods. In contrast to the high expression of apolipoprotein E (APOE), low-density lipoprotein receptor-related protein 8 (LRP8) and 3-hydroxy-3-methyl-glutaryl-CoA reducatase (HMGCR) (genes that play a role in lipid-related pathways in brain development) early in life, apoD expression was low in neonates and increased in expression throughout life resulting in six- to eight-fold higher levels at the mRNA and protein levels in adults. Recent studies suggest that apoD has a novel antioxidant function in the brain and we found that the increased apoD expression throughout development and into adulthood was correlated with the expression of antioxidant genes superoxide dismutase 1 (SOD1) and glutathione peroxidase 3 (GPX3) as well as proteins that were modified by the lipid peroxidation end-product 4-hydroxynonenal. These studies reveal that apoD expression is increased throughout life in the human prefrontal cortex and that this is correlated with genetic and biochemical markers of oxidative stress.


Vitamin effects on the immune system: vitamins A and D take centre stage.
Vitamins are essential constituents of our diet that have long been known to influence the immune system. Vitamins A and D have received particular attention in recent years as these vitamins have been shown to have an unexpected and crucial effect on the immune response. We present and discuss our current understanding of the essential roles of vitamins in modulating a broad range of immune processes, such as lymphocyte activation and proliferation, T-helper-cell differentiation, tissue-specific lymphocyte homing, the production of specific antibody isotypes and regulation of the immune response. Finally, we discuss the clinical potential of vitamin A and D metabolites for modulating tissue-specific immune responses and for preventing and/or treating inflammation and autoimmunity.


Does Left Atrial Appendage Closure Reduce Mortality? A Vital Status Analysis of the Randomized PROTECT AF and PREVAIL Clinical Trials.
Compared with warfarin, left atrial appendage closure (LAAC) reduced mortality in an analysis of the PROTECTAF and PREVAIL trials. However, these data were limited by patient drop-out.We sought to estimatethe mortality benefit with LAACusing updated vital status information.In PROTECT AF and PREVAIL, 227 of 1114 randomized subjects failed to complete 5-year follow-up. Centers were manually queried for updated vital status on 76 subjects (33%).During median follow-up 5.0 years (interquartile range 3.8, 5.1), 112 of 732 LAAC subjects (15.3%) and 79 of 382 controls (20.7%) died. The hazard ratio for all-cause mortality with LAAC compared with warfarin was 0.70 (95% CI 0.53-0.94, p=0.017).Subgroup analyses suggested that subjects <75 years and those with higher CHA2DS2-VASc score, history of transient ischemic attack or stroke, and permanent AF derived particular benefit, although interaction terms were not significant.The number needed to treat(NNT) with LAAC to prevent one death over 5 years was 16 (95% CI 10-82). Despite competing mortality risks in this elderly cohort, updated vital status data from PROTECT AF and PREVAIL revealed that LAAC was associated with 30% improved survival compared with warfarin, with an NNT of 16.


Expression and regulation of the abd-A gene of Drosophila.
We have developed a specific polyclonal antibody that recognizes the protein products of the abdominal-A (abd-A) gene, a member of the bithorax complex of Drosophila. The normal expression domain extends from parasegments 7 to 13, in good correspondence with previous genetic and molecular results. However, while the anterior border of expression is precisely demarcated by a parasegmental boundary, the posterior border does not coincide with a lineage boundary. Within the normal domain, the expression of abd-A shows intrametameric modulation; the amount of product is higher in posterior compartments and in the most anterior cells of the anterior compartments and then gradually decreases. We have examined the effect on abd-A expression of a number of mutations, some mapping within and others outside the abd-A transcription unit. Those mapping to the transcription unit eliminate or severely reduce the amount of abd-A antigen, while those mapping outside produce an abnormal distribution of abd-A protein. Finally, we show that the abd-A gene is down-regulated in part of the Abdominal-B (Abd-B) domain, precisely in those regions where the Abd-B gene is expressed at high levels.


Regulation of serum 1alpha,25-dihydroxyvitamin D3 by calcium and phosphate in the rat.
A new radioreceptor assay was used to quantify changes in serum concentration of 1alpha,25-dihydroxyvitamin D3 in rats with low calcium or low phosphate diets. Low availability of either ion elicits a fivefold increase in the circulating concentration of 1alpha,25-dihydroxyvitamin D3. The enhancement of 1alpha,25-dihydroxyvitamin D3 concentration in response to calcium deficiency is dependent on the presence of the parathyroid or thyroid glands (or both), suggesting that this effect is mediated by parathyroid hormone. In contrast, the response of phosphate deficiency is independent of these glands and may result from an action of low serum phosphate concentration or some factor associated with phosphate depletion on the renal synthesis of the 1alpha,25-dihydroxyvitamin D3 hormone.


Genome-wide approaches to dissect the roles of RNA binding proteins in translational control: implications for neurological diseases.
Translational control of messenger RNAs (mRNAs) is a key aspect of neurobiology, defects of which can lead to neurological diseases. In response to stimuli, local translation of mRNAs is activated at synapses to facilitate long-lasting forms of synaptic plasticity, the cellular basis for learning, and memory formation. Translation, as well as all other aspects of RNA metabolism, is controlled in part by RNA binding proteins (RBPs) that directly interact with mRNAs to form mRNA-protein complexes. Disruption of RBP function is becoming widely recognized as a major cause of neurological diseases. Thus understanding the mechanisms that govern the interplay between translation control and RBP regulation in both normal and diseased neurons will provide new opportunities for novel diagnostics and therapeutic intervention. As a means of studying translational control, genome-wide methods are emerging as powerful tools that have already begun to unveil mechanisms that are missed by single-gene studies. Here, we describe the roles of RBPs in translational control, review genome-wide approaches to examine translational control, and discuss how the application of these approaches may provide mechanistic insight into the pathogenic underpinnings of RBPs in neurological diseases.


Modeling of the general astigmatic Gaussian beam and its propagation through 3D optical systems.
The paper introduces the complete model of the general astigmatic Gaussian beam as the most general case of the Gaussian beam in the fundamental mode. This includes the laws of propagation, reflection, and refraction as well as the equations for extracting from the complex-valued beam description its real-valued parameters, such as the beam spot radii and the radii of curvature of the wavefront. The suggested model is applicable to the case of an oblique incidence of the beam at any 3D surface that can be approximated by the second-order equation at the point of incidence. Thus it can be used in simulations of a large variety of 3D optical systems. The provided experimental validation of the model shows good agreement with simulations.


Lymphoma and lung cancer in offspring born to pregnant mice dosed with dibenzo[a,l]pyrene: the importance of in utero vs. lactational exposure.
The fetus and neonate cannot be viewed as "little adults"; they are highly sensitive to toxicity from environmental chemicals. This phenomenon contributes to the fetal basis of adult disease. One example is transplacental carcinogenesis. Animal models demonstrate that environmental chemicals, to which pregnant women are daily exposed, can increase susceptibility of the offspring to cancer. It is uncertain to what degree in utero vs. lactational exposure contributes to cancer, especially for hydrophobic chemicals such as polyhalogenated biphenyls, ethers, dioxins, furans, etc., which can partition into breast milk. We developed a pregnant mouse model in which exposure to the polycyclic aromatic hydrocarbon (PAH), dibenzo[a,l]pyrene (DBP), during late gestation, produces an aggressive T-cell lymphoma in offspring between 3 and 6 months of age. Survivors exhibit multiple lung and liver (males) tumors. Here, we adopt a cross-foster design with litters born to dams treated with DBP exchanged with those born to dams treated with vehicle. Exposure to DBP in utero (about 2 days) produced significantly greater mortality than residual DBP exposure only through breast milk (3 weeks of lactation). As previously observed pups in all groups with an ahr(b-1/d) ("responsive") genotype were more susceptible to lymphoma mortality than ahr(d/d) ("non-responsive") siblings. At termination of the study at 10 months, mice exposed in utero also had greater lung tumor multiplicity than mice exposed only during lactation. Our results demonstrate that short exposure to DBP during late gestation presents a greater risk to offspring than exposure to this very hydrophobic PAH following 3 weeks of nursing.


IFT81, encoding an IFT-B core protein, as a very rare cause of a ciliopathy phenotype.
Bidirectional intraflagellar transport (IFT) consists of two major protein complexes, IFT-A and IFT-B. In contrast to the IFT-B complex, all components of IFT-A have recently been linked to human ciliopathies when defective. We therefore hypothesised that mutations in additional IFT-B encoding genes can be found in patients with multisystemic ciliopathies. We screened 1628 individuals with reno-ocular ciliopathies by targeted next-generation sequencing of ciliary candidate genes, including all IFT-B encoding genes. Consequently, we identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. Further, we detected a loss-of-stop mutation with extension of the deduced protein by 10 amino acids in an individual with neuronal ceroid lipofuscinosis-1. This proband presented with retinal dystrophy and brain lesions including cerebellar atrophy, a phenotype to which the IFT81 variant might contribute. Cultured fibroblasts of this latter affected individual showed a significant decrease in ciliated cell abundance compared with controls and increased expression of the transcription factor GLI2 suggesting deranged sonic hedgehog signalling. This work describes identification of mutations of IFT81 in individuals with symptoms consistent with the clinical spectrum of ciliopathies. It might represent the rare case of a core IFT-B complex protein found associated with human disease. Our data further suggest that defects in the IFT-B core are an exceedingly rare finding, probably due to its indispensable role for ciliary assembly in development.


How do health extension workers in Ethiopia allocate their time?
Governments are increasingly reliant on community health workers to undertake health promotion and provide essential curative care. In 2003, the Government of Ethiopia launched the Health Extension Programme and introduced a new cadre, health extension workers (HEWs), to improve access to care in rural communities. In 2013, to inform the government's plans for HEWs to take on an enhanced role in community-based newborn care, a time and motion study was conducted to understand the range of HEW responsibilities and how they allocate their time across health and non-health activities. The study was administered in 69 rural kebeles in the Southern Nations Nationalities and People's Region and Oromia Region that were intervention areas of a trial to evaluate a package of community-based interventions for newborns. Over 4 consecutive weeks, HEWs completed a diary and recorded all activities undertaken during each working day. HEWs were also surveyed to collect data on seasonal activities and details of the health post and kebele in which they work. The average proportion of productive time (excluding breaks) that HEWs spent on an activity, at a location, or with a recipient each week, was calculated. The self-reported diary was completed by 131 HEWs. Over the course of a week, HEWs divided their time between the health post (51%) and the community (37%), with the remaining 11% of their time spent elsewhere. Curative health activities represented 16% of HEWs' time each week and 43% of their time was spent on health promotion and prevention. The remaining time included travel, training and supervision, administration, and community meetings. HEWs spent the majority (70%) of their time with individuals, families, and community members. HEWs have wide-ranging responsibilities for community-based health promotion and curative care. Their workload is diverse and they spend time on activities relating to family health, disease prevention and control, hygiene and sanitation, as well as other community-based activities. Reproductive, maternal, newborn, and child health activities represent a major component of the HEW's work and, as such, they can have a critically important role in improving the health outcomes of mothers and children in Ethiopia.


Oligonucleotide capture sequencing of the SARS-CoV-2 genome and subgenomic fragments from COVID-19 individuals.
The newly emerged and rapidly spreading SARS-CoV-2 causes coronavirus disease 2019 (COVID-19). To facilitate a deeper understanding of the viral biology we developed a capture sequencing methodology to generate SARS-CoV-2 genomic and transcriptome sequences from infected patients. We utilized an oligonucleotide probe-set representing the full-length genome to obtain both genomic and transcriptome (subgenomic open reading frames [ORFs]) sequences from 45 SARS-CoV-2 clinical samples with varying viral titers. For samples with higher viral loads (cycle threshold value under 33, based on the CDC qPCR assay) complete genomes were generated. Analysis of junction reads revealed regions of differential transcriptional activity among samples. Mixed allelic frequencies along the 20kb ORF1ab gene in one sample, suggested the presence of a defective viral RNA species subpopulation maintained in mixture with functional RNA in one sample. The associated workflow is straightforward, and hybridization-based capture offers an effective and scalable approach for sequencing SARS-CoV-2 from patient samples.


Plasmin-induced redistribution of platelet glycoprotein Ib.
Platelet membrane glycoprotein Ib (GPIb), a receptor for von Willebrand factor and thrombin, is present on the platelet surface membrane, in intraplatelet stores, and in plasma (as the proteolytic fragment glycocalicin). We examined the hypothesis that after plasmin-mediated cleavage of platelet surface GPIb, platelets can replenish their surface GPIb pool. Incubation of washed platelets with plasmin (1 hour, 22 degrees C) resulted in loss of platelet surface GPIb, but further incubation (3 hours, 37 degrees C) in autologous plasma resulted in restoration of platelet surface GPIb, as determined by ristocetin-induced platelet agglutination and a flow cytometric assay of platelet binding of three GPIb-specific monoclonal antibodies. Despite the restoration of platelet surface GPIb after the 3-hour incubation of plasmin-treated platelets in autologous plasma, the whole platelet GPIb content (measured by enzyme-linked immunosorbent assay [ELISA], sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and flow cytometry) remained reduced, quantitatively corresponding to an increase in plasma glycocalicin concentration (measured by ELISA). The loss and restoration of platelet surface GPIb occurred on all platelets and, as evidenced by lack of inhibition by prostaglandin E1, EDTA, and cytochalasins, was not mediated by cyclic AMP, extracellular Ca2+, or the platelet microfilament system. In summary, this study shows that after plasmin-mediated cleavage of platelet surface GPIb, platelets can replenish their surface GPIb pool by recruitment of GPIb molecules from the intraplatelet pool (or from a sequestered surface site).


A multi-year estimate of methane fluxes in Alaska from CARVE atmospheric observations.
Methane (CH4) fluxes from Alaska and other arctic regions may be sensitive to thawing permafrost and future climate change, but estimates of both current and future fluxes from the region are uncertain. This study estimates CH4 fluxes across Alaska for 2012-2014 using aircraft observations from the Carbon in Arctic Reservoirs Vulnerability Experiment (CARVE) and a geostatistical inverse model (GIM). We find that a simple flux model based on a daily soil temperature map and a static map of wetland extent reproduces the atmospheric CH4 observations at the state-wide, multi-year scale more effectively than global-scale, state-of-the-art process-based models. This result points to a simple and effective way of representing CH4 flux patterns across Alaska. It further suggests that contemporary process-based models can improve their representation of key processes that control fluxes at regional scales, and that more complex processes included in these models cannot be evaluated given the information content of available atmospheric CH4 observations. In addition, we find that CH4 emissions from the North Slope of Alaska account for 24% of the total statewide flux of 1.74 ± 0.44 Tg CH4 (for May-Oct.). Contemporary global-scale process models only attribute an average of 3% of the total flux to this region. This mismatch occurs for two reasons: process models likely underestimate wetland area in regions without visible surface water, and these models prematurely shut down CH4 fluxes at soil temperatures near 0°C. As a consequence, wetlands covered by vegetation and wetlands with persistently cold soils could be larger contributors to natural CH4 fluxes than in process estimates. Lastly, we find that the seasonality of CH4 fluxes varied during 2012-2014, but that total emissions did not differ significantly among years, despite substantial differences in soil temperature and precipitation; year-to-year variability in these environmental conditions did not affect obvious changes in total CH4 fluxes from the state.


Clinicopathologic and molecular analysis of high-grade dysplasia and early adenocarcinoma in short- versus long-segment Barrett esophagus.
Barrett esophagus, especially dysplastic Barrett mucosa, has been regarded as a preneoplastic lesion for esophageal adenocarcinoma. However, the etiology and pathogenesis of dysplasia and early adenocarcinoma in short- (SSBE) and long- (LSBE) segment Barrett esophagus have not been studied in detail. The aims of this study were to clarify clinicopathologic and genetic differences between high-grade dysplasia (HGD) and early adenocarcinoma in SSBE versus LSBE. We analyzed the clinicopathologic features from 47 patients (19 SSBE [<3 cm] and 28 LSBE [> or =3 cm]) with esophagectomy for HGD/T1 adenocarcinoma. Allelic losses on chromosomes 3p (FIHT), 5q (APC), 9p (p16), and 17p (p53) were compared in 12 HGD and 9 T1 tumors from 19 cases of SSBE and in 23 HGD and 15 T1 tumors from 28 cases of LSBE. Patients with SSBE were more likely to be smokers than were patients with LSBE (94.7% v 57.1%; P =.004). HGD or T1 tumors arising from SSBE were less likely to show adjoining nondysplastic Barrett mucosa than those from LSBE (73.6% v 100%; P =.02). LSBE more frequently showed a circumferential pattern of Barrett mucosa than did SSBE (96.4% v 47.3%; P =.0002). Chromosomal allelic losses on 3p, 5q, 9p, and 17p were detected in 19% (4 of 21), 43% (15 of 35), 40% (14 of 35), and 48% (16 of 33) of HGD, respectively, and 26% (5 of 19), 35% (8 of 23), 35% (8 of 23), and 57% (13 of 23) of T1 tumor, respectively. There were no significant differences in allelic loss of 3p, 5q, 9p, or 17p in HGD or T1 tumors from SSBE versus LSBE. These results suggest that both HGD and early adenocarcinoma in SSBE and LSBE may occur through similar genetic alterations, whereas there are some clinicopathologic differences between SSBE and LSBE. HUM PATHOL


Reactive oxygen species generating systems meeting challenges of photodynamic cancer therapy.
The reactive oxygen species (ROS)-mediated mechanism is the major cause underlying the efficacy of photodynamic therapy (PDT). The PDT procedure is based on the cascade of synergistic effects between light, a photosensitizer (PS) and oxygen, which greatly favors the spatiotemporal control of the treatment. This procedure has also evoked several unresolved challenges at different levels including (i) the limited penetration depth of light, which restricts traditional PDT to superficial tumours; (ii) oxygen reliance does not allow PDT treatment of hypoxic tumours; (iii) light can complicate the phototherapeutic outcomes because of the concurrent heat generation; (iv) specific delivery of PSs to sub-cellular organelles for exerting effective toxicity remains an issue; and (v) side effects from undesirable white-light activation and self-catalysation of traditional PSs. Recent advances in nanotechnology and nanomedicine have provided new opportunities to develop ROS-generating systems through photodynamic or non-photodynamic procedures while tackling the challenges of the current PDT approaches. In this review, we summarize the current status and discuss the possible opportunities for ROS generation for cancer therapy. We hope this review will spur pre-clinical research and clinical practice for ROS-mediated tumour treatments.


A retrospective analysis of mortality in captive pygmy hippopotamus (Choeropsis liberiensis) from 1912 to 2014.
The pygmy hippopotamus (Choeropsis liberiensis) is an IUCN Red List Endangered species (CITES Appendix II) that has been housed in zoological collections since 1912. As wild populations continue to decline throughout the species' range, successful ex situ breeding and management, including an understanding of morbidity and mortality, are of utmost importance. This study is the first comprehensive review of mortality data from the captive population since 1982 and significantly expands on previous analyses. We solicited necropsy reports from 129/187 zoological institutions worldwide that currently or previously held pygmy hippos and received data for 404 animals (177 ♂, 220 ♀, 7 undermined sex), representing 43% of pygmy hippos that have died in captivity. Mortality in neonates was primarily due to perinatal causes (51.8%-stillbirth, failure to thrive, weakness, poor suckling reflex, maternal neglect) or parent-inflicted trauma (28%). Common causes of mortality in adult and geriatric animals included cardiovascular disease (16%), degenerative musculoskeletal conditions (10%), obstructive gastrointestinal disease (9%), and renal insufficiency (13%), sometimes associated with advanced polycystic kidney disease (PKD). Although not the direct cause of mortality, a number of adult and geriatric pygmy hippos were also overweight to obese. Infectious causes of mortality in included leptospirosis and encephalomyocarditis virus, the latter usually presenting as acute death due to cardiovascular demise. This comprehensive overview presents a useful guide for recommendations in preventative veterinary care and for improved husbandry and management of pygmy hippos in captivity. Zoo Biol. 35:556-569, 2016. © 2016 Wiley Periodicals, Inc.


Risk of human immunodeficiency virus (HIV-1) infection among laboratory workers.
In a prospective cohort study of 265 laboratory and affiliated workers, one individual with no recognized risk factors for human immunodeficiency virus type 1 (HIV-1) infection was HIV-1 seropositive at the time of entry into the study. Molecular analyses of two HIV-1 isolates derived in two independent laboratories from a blood sample from this worker showed that the isolates were indistinguishable from a genotypic form of HIV-1 present in the H9/HTLV-IIIB cell line. Exposure to this strain of virus most probably occurred during work with concentrated virus or culture fluids from virus-producing cell lines under standard Biosafety Level 3 containment. Although no specific incident leading to this infection has been identified, undetected skin contact with virus culture supernatant might have occurred. This worker was the only one found to be positive among the subgroup of 99 workers who shared a work environment involving exposure to concentrated virus. The incidence rate of 0.48 per 100 person-years exposure indicates that prolonged laboratory exposure to concentrated virus is associated with some risk of HIV-1 infection, which is comparable to the risk for health care workers experiencing a needle stick exposure. While none of the ten workers with parenteral exposure to HIV-1 in this cohort became infected, a worker in another laboratory did seroconvert following an injury with a potentially contaminated needle. Strict Biosafety Level 3 containment and practices should be followed when working with concentrated HIV-1 preparations, and further refinement of the procedures may be necessary.


Probabilistic inversion of expert assessments to inform projections about Antarctic ice sheet responses.
The response of the Antarctic ice sheet (AIS) to changing global temperatures is a key component of sea-level projections. Current projections of the AIS contribution to sea-level changes are deeply uncertain. This deep uncertainty stems, in part, from (i) the inability of current models to fully resolve key processes and scales, (ii) the relatively sparse available data, and (iii) divergent expert assessments. One promising approach to characterizing the deep uncertainty stemming from divergent expert assessments is to combine expert assessments, observations, and simple models by coupling probabilistic inversion and Bayesian inversion. Here, we present a proof-of-concept study that uses probabilistic inversion to fuse a simple AIS model and diverse expert assessments. We demonstrate the ability of probabilistic inversion to infer joint prior probability distributions of model parameters that are consistent with expert assessments. We then confront these inferred expert priors with instrumental and paleoclimatic observational data in a Bayesian inversion. These additional constraints yield tighter hindcasts and projections. We use this approach to quantify how the deep uncertainty surrounding expert assessments affects the joint probability distributions of model parameters and future projections.


Frequency and fate of microRNA editing in human brain.
Primary transcripts of certain microRNA (miRNA) genes (pri-miRNAs) are subject to RNA editing that converts adenosine to inosine (A-->I RNA editing). However, the frequency of the pri-miRNA editing and the fate of edited pri-miRNAs remain largely to be determined. Examination of already known pri-miRNA editing sites indicated that adenosine residues of the UAG triplet sequence might be edited more frequently. In the present study, therefore, we conducted a large-scale survey of human pri-miRNAs containing the UAG triplet sequence. By direct sequencing of RT-PCR products corresponding to pri-miRNAs, we examined 209 pri-miRNAs and identified 43 UAG and also 43 non-UAG editing sites in 47 pri-miRNAs, which were highly edited in human brain. In vitro miRNA processing assay using recombinant Drosha-DGCR8 and Dicer-TRBP (the human immuno deficiency virus transactivating response RNA-binding protein) complexes revealed that a majority of pri-miRNA editing is likely to interfere with the miRNA processing steps. In addition, four new edited miRNAs with altered seed sequences were identified by targeted cloning and sequencing of the miRNAs that would be processed from edited pri-miRNAs. Our studies predict that approximately 16% of human pri-miRNAs are subject to A-->I editing and, thus, miRNA editing could have a large impact on the miRNA-mediated gene silencing.


BK virus replication in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis.
BK virus (BKV) is an important cause of renal dysfunction in kidney transplant (KTX) recipients. Immunosuppression intensity is a major risk factor for BKV replication in these patients. The prevalence of BKV replication in immunosuppressed patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) without transplant is not known. Consecutive patients (n = 37) with a diagnosis of GPA (n = 25) or MPA (n = 12) without history of KTX were evaluated for plasma BKV replication by quantitative PCR (group A). Descriptive data were collected. BKV replication in this nontransplant immunosuppressed vasculitis cohort was compared with a historical cohort of vasculitis KTX recipients (group B). Group A patients had mean disease duration of 75 months. Mean age was 57 years and 54% were female. Mean time from vasculitis onset to BKV testing was 36 months, and 19/37 patients were tested within 24 months of induction therapy. At the time of BKV testing, 73% were on prednisone (P) with azathioprine, mycophenolate mofetil (MMF), methotrexate or leflunomide. None of the nontransplanted vasculitis patients had detectable plasma BKV. Among 35 patients in group B, 16 were tested for BKV; 5/16 (31%) had detectable virus in plasma at a mean of 6 months after TX (p = 0.002). Most (94%) were on maintenance therapy with MMF, P and tacrolimus. Immunosuppressed patients with GPA/MPA without KTX had no evidence of plasma BKV. However, BKV was common in GPA/MPA patients after KTX, suggesting that replication may be related to differences in immunosuppression, alloimmune activation or differences in host defense mechanisms.


The staphylococcal alpha-toxin pore has a flexible conformation.
The alpha-toxin from Staphylococcus aureus undergoes several conformational changes from the time it is released from the bacterium to the moment it forms a channel in the plasma membrane of its target cell. It is initially a soluble monomer, which undergoes membrane binding and oligomerization into a heptameric ring and finally inserts into the lipid bilayer to form a pore. Here we have analyzed the stability of different forms of the alpha-toxin (monomer as well as heptamers in solution, bound to the membrane and membrane-inserted) by differential scanning calorimetry and limited proteolysis. Data presented here show that, in contrast to both the membrane-bound prepore complex and the monomer in solution, the membrane-inserted alpha-toxin channel does not undergo cooperative unfolding and is highly susceptible to proteases. These observations suggest that the channel has a looser conformation. Interestingly, resistance to proteases could be recovered upon solubilization of the channel, indicating that the loss of rigid tertiary packing only occurred upon membrane insertion. Far-UV CD data, however, suggest that the transmembrane beta-barrel must be stably folded and that therefore only the Cap and Rim domains of the channel are loosely packed. All together, our data show that the alpha-toxin channel is not a rigid complex within the membrane but adopts a rather flexible conformation.


Bioinspired Carbon/SnO2 Composite Anodes Prepared from a Photonic Hierarchical Structure for Lithium Batteries.
A carbon/SnO2 composite (C-SnO2) with hierarchical photonic structure was fabricated from the templates of butterfly wings. We have investigated for the first time its application as the anode material for lithium-ion batteries. It was demonstrated to have high reversible capacities, good cycling stability, and excellent high-rate discharge performance, as shown by a capacitance of ∼572 mAh g(-1) after 100 cycles, 4.18 times that of commercial SnO2 powder (137 mAh g(-1)); a far better recovery capability of 94.3% was observed after a step-increase and sudden-recovery current. An obvious synergistic effect was found between the porous, hierarchically photonic microstructure and the presence of carbon; the synergy guarantees an effective flow of electrolyte and a short diffusion length of lithium ions, provides considerable buffering room, and prevents aggregation of SnO2 particles in the discharge/charge processes. This nature-inspired strategy points out a new direction for the fabrication of alternative anode materials.


Cu(Ir₁ - xCrx)₂S₄: a model system for studying nanoscale phase coexistence at the metal-insulator transition.
Increasingly, nanoscale phase coexistence and hidden broken symmetry states are being found in the vicinity of metal-insulator transitions (MIT), for example, in high temperature superconductors, heavy fermion and colossal magnetoresistive materials, but their importance and possible role in the MIT and related emergent behaviors is not understood. Despite their ubiquity, they are hard to study because they produce weak diffuse signals in most measurements. Here we propose Cu(Ir₁ - xCrx)₂S₄ as a model system, where robust local structural signals lead to key new insights. We demonstrate a hitherto unobserved coexistence of an Ir(4+) charge-localized dimer phase and Cr-ferromagnetism. The resulting phase diagram that takes into account the short range dimer order is highly reminiscent of a generic MIT phase diagram similar to the cuprates. We suggest that the presence of quenched strain from dopant ions acts as an arbiter deciding between the competing ground states.


Pharmacological interventions for the prevention of fetal growth restriction: protocol for a systematic review and network meta-analysis.
Fetal growth restriction (FGR) includes different conditions in which a fetus fails to reach the own full growth, and accounts for 28%-45% of non-anomalous stillbirths. The management of FGR is based on the prolongation of pregnancy long enough for fetal organs to mature while preventing starvation. As for pharmacological management, most guidelines recommend treatment with low-dose aspirin and/or with heparin, although this approach is still controversial and innovative promising therapies are under investigation. As no firm evidence exists to guide clinicians towards the most effective therapeutic intervention, this protocol describes methods for a systematic review and network meta-analysis (NetMA) of pharmacological treatments for FGR prevention. We will search MEDLINE and Embase for clinical trials and observational studies performed on gestating women with clinically diagnosed risk of FGR. Experimental interventions will include heparin and low-molecular-weight heparin, acetylsalicylic acid, antiplatelet agents, phosphodiesterase type 3 and 5 inhibitors, maternal vascular endothelial growth factor gene therapy, nanoparticles, microRNA, statins, nitric oxide donors, hydrogen sulphide, proton pump inhibitors, melatonin, creatine and N-acetylcysteine, and insulin-like growth factors, compared between each other or to placebo or no treatment. Primary efficacy outcome is FGR. Secondary efficacy outcomes will be preterm birth, fetal or neonatal death and neonatal complications. For the safety outcome, all adverse events reported in included studies and experienced by either mothers, fetuses or newborns will be considered. Two review authors will independently screen title, abstract and full paper text, and will independently extract data from included studies. Where possible and appropriate, for primary and secondary efficacy outcomes, a NetMA will be performed using a random-effects model within a frequentist framework. Adverse events will be narratively described. Results will be disseminated through a peer-reviewed scientific journal, and by scientific congresses and meetings. CRD42019122831.


[Assessment of coronary heart diseases by echocardiography].
Echocardiography plays an important role in deciding the operative indication in patients with coronary artery diseases. On deciding the indication of coronary artery bypass graft, dobutamine stress echocardiography provides accurate information on presence or absence of myocardial ischemia and of myocardial viability in each coronary artery territory. Assessment of the coronary blood flow velocity using high-frequency Doppler enables us to examine the presence of coronary stenosis and the patency of bypass graft. Left ventricular remodeling is a cause of progressive heart failure after myocardial infarction, and echocardiography allows us to measure the left ventricular volume and ejection fraction. Real-time 3-dimensional echocardiography has made this measurement process accurate and easy. Dyssynchrony is another mechanism that worsens ventricular contractile performance, and several echocardiographic indexes were proposed to diagnose it. Cardiac resynchronization therapy, if it is performed with cardiac surgery, can correct the dyssynchrony and enhance the functional improvement. Severity of diastolic dysfunction can predict the prognosis of patients with coronary artery diseases, and we can assess it from the mitral flow velocity pattern; normal, abnormal, pseudonormal and restrictive. Thus, echocariography provides a potential method to evaluate myocardial viability, myocardial ischemia, and pathophysiology of heart failure.


Determination of Force Coresponding to Maximal Lactate Steady State in Tethered Swimming.
The main aim of the present investigation was to verify if the aerobic capacity (AC) measured in tethered swimming corresponds to the maximal lactate steady state (MLSS) and its correlation with 30 min and 400m free style swimming. Twenty-five swimmers were submitted to an incremental tethered swimming test (ITS) with an initial load of 20N and increments of 10N each 3min. After each stage of 3min, the athletes had 30s of interval to blood sample collections that were used to measure blood lactate concentrations ([La-]). The ACBI was determined by the abrupt increase in [La-] versus force (F). The points obtained between [La-] versus force (N) were adjusted by an exponential curve model to determine AC corresponding to 3.5mmol.l-1 (AC3.5) and 4.0mmol.l-1 (AC4.0). After these procedures, the swimmers performed maximal efforts of 30min and 400m in free style swimming. We used the distance performed in 30min and the time performed in 400m to calculate the median velocities (i.e. V30 and V400) of these protocols. After one week, in order to measure the MLSS, nine athletes performed three 30-min tethered swimming efforts with intensities of 90, 100, and 110% of ACBI. The ANOVA one-way was used to compare the ACBI, AC3.5 and AC4.0. Correlations between ACs, and between ACs and V30 and V400 (p<0.05) were determined using the Pearson's correlation coefficient. The intensity corresponding to 100% of ACBI was similar to the MLSS. It was observed significant correlations of the aerobic capacities (i.e. ACBI, AC3.5 and AC4.0) with V30 (r>0.91) and V400 (r>0.63). According to our results, it is possible to conclude that the ACBI corresponds to the MLSS, and both the AC - individually determined - and the AC - determined using fixed blood lactate concentrations of 3.5 and 4.0mmol.l-1 - can be used to predict the mean velocity of 30min and 400m in free style swimming. In addition to that, the tethered swimming system can be used for aerobic development in places where official sized swimming pools are not available, such as rehabilitation clinics and health clubs.


Complete genome sequence of Riemerella anatipestifer type strain (ATCC 11845).
Riemerella anatipestifer (Hendrickson and Hilbert 1932) Segers et al. 1993 is the type species of the genus Riemerella, which belongs to the family Flavobacteriaceae. The species is of interest because of the position of the genus in the phylogenetic tree and because of its role as a pathogen of commercially important avian species worldwide. This is the first completed genome sequence of a member of the genus Riemerella. The 2,155,121 bp long genome with its 2,001 protein-coding and 51 RNA genes consists of one circular chromosome and is a part of the Genomic Encyclopedia of Bacteria and Archaea project.


CB1 cannabinoid receptor enrichment in the ependymal region of the adult human spinal cord.
Cannabinoids are involved in the regulation of neural stem cell biology and their receptors are expressed in the neurogenic niches of adult rodents. In the spinal cord of rats and mice, neural stem cells can be found in the ependymal region, surrounding the central canal, but there is evidence that this region is largely different in adult humans: lacks a patent canal and presents perivascular pseudorosettes, typically found in low grade ependymomas. Using Laser Capture Microdissection, Taqman gene expression assays and immunohistochemistry, we have studied the expression of endocannabinoid system components (receptors and enzymes) at the human spinal cord ependymal region. We observe that ependymal region is enriched in CB1 cannabinoid receptor, due to high CB1 expression in GFAP+ astrocytic domains. However, in human spinal cord levels that retain central canal patency we found ependymal cells with high CB1 expression, equivalent to the CB1(HIGH) cell subpopulation described in rodents. Our results support the existence of ependymal CB1(HIGH) cells across species, and may encourage further studies on this subpopulation, although only in cases when central canal is patent. In the adult human ependyma, which usually shows central canal absence, CB1 may play a different role by modulating astrocyte functions.


Myocardial metabolism of triacylglycerol-rich lipoproteins in type 2 diabetes.
Cardiac utilisation of very-low-density lipoprotein (VLDL) and chylomicrons (CM) was investigated in the ZDF rat model of type 2 diabetes, in order to define the role of triacylglycerol (TAG) metabolism in the development of contractile dysfunction. Hearts from obese diabetic and lean littermate control rats were perfused with VLDL and CM from diabetic and control rats. Metabolic fate of the lipoprotein TAG and contractile function were examined. Myocardial utilisation of both VLDL- and CM-TAG was increased in the diabetic state. Diabetic hearts oxidised diabetic lipoprotein-TAG to a greater extent than control lipoproteins; glucose oxidation was decreased. There was no difference in lipoprotein-TAG assimilation into diabetic heart lipids; diabetic lipoproteins were, however, a poor substrate for control heart tissue lipid accumulation. Although the proportion of exogenous lipid incorporated into tissue TAG was increased in diabetic hearts perfused with control lipoproteins, this effect was not seen in diabetic hearts perfused with diabetic lipoproteins. Myocardial heparin-releasable lipoprotein lipase (LPL) activity was moderately increased in the diabetic state, and diabetic lipoproteins increased tissue-residual LPL activity. Cardiac hydraulic work was decreased only in diabetic hearts perfused with diabetic CM. Compositional analysis of diabetic variant lipoproteins indicated changes in size and apoprotein content. Alterations in cardiac TAG-rich lipoprotein metabolism in type 2 diabetes are due to changes in both the diabetic myocardium and the diabetic lipoprotein particle; decreased contractile function is not related to cardiac lipid accumulation from TAG-rich lipoproteins but may be associated with changes in TAG-fatty acid oxidation.


Educational and skills-based interventions for preventing relationship and dating violence in adolescents and young adults.
Educational and skills-based interventions are often used to prevent relationship and dating violence among young people. To assess the efficacy of educational and skills-based interventions designed to prevent relationship and dating violence in adolescents and young adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, PsycINFO, six other databases and a trials register on 7 May 2012. We handsearched the references lists of key articles and two journals (Journal of Interpersonal Violence and Child Abuse and Neglect). We also contacted researchers in the field. Randomised, cluster-randomised and quasi-randomised studies comparing an educational or skills-based intervention to prevent relationship or dating violence among adolescents and young adults with a control. Two review authors independently assessed study eligibility and risk of bias. For each study included in the meta-analysis, data were extracted independently by GF and one other review author (either CH, JN, SH or DS). We conducted meta-analyses for the following outcomes: episodes of relationship violence, behaviours, attitudes, knowledge and skills. We included 38 studies (15,903 participants) in this review, 18 of which were cluster-randomised trials (11,995 participants) and two were quasi-randomised trials (399 participants). We included 33 studies in the meta-analyses. We included eight studies (3405 participants) in the meta-analysis assessing episodes of relationship violence. There was substantial heterogeneity (I(2) = 57%) for this outcome. The risk ratio was 0.77 (95% confidence interval (CI) 0.53 to 1.13). We included 22 studies (5256 participants) in the meta-analysis assessing attitudes towards relationship violence. The standardised mean difference (SMD) was 0.06 (95% CI -0.01 to 0.15). We included four studies (887 participants) in the meta-analysis assessing behaviour related to relationship violence; the SMD was -0.07 (95% CI -0.31 to 0.16). We included 10 studies (6206 participants) in the meta-analysis assessing knowledge related to relationship violence; the results showed an increase in knowledge in favour of the intervention (SMD 0.44, 95% CI 0.28 to 0.60) but there was substantial heterogeneity (I(2) = 52%). We included seven studies (1369 participants) in the meta-analysis assessing skills related to relationship violence. The SMD was 0.03 (95% CI -0.11 to 0.17). None of the included studies assessed physical health, psychosocial health or adverse outcomes. Subgroup analyses showed no statistically significant differences by intervention setting or type of participants. The quality of evidence for all outcomes included in our meta-analysis was moderate due to an unclear risk of selection and detection bias and a high risk of performance bias in most studies. Studies included in this review showed no evidence of effectiveness of interventions on episodes of relationship violence or on attitudes, behaviours and skills related to relationship violence. We found a small increase in knowledge but there was evidence of substantial heterogeneity among studies. Further studies with longer-term follow-up are required, and study authors should use standardised and validated measurement instruments to maximise comparability of results.


Safety evaluation of the food enzyme cyclomaltodextrin glucanotransferase from Paenibacillus illinoisenis strain 107.
The food enzyme cyclomaltodextrin glucanotransferase ((1→4)-α-d-glucan:(1→4)-α-d-glucan 4-α-d-[(1→4)-α-d-glucano]-transferase; EC 22.214.171.124) is produced with the non-genetically modified Paenibacillus illinoisenis strain 107 by Hayashibara Co., Ltd. The cyclomaltodextrin glucanotransferase food enzyme is intended to be used solely by the applicant in-house in starch processing for trehalose production. Since residual amounts of total organic solids (TOS) are removed by the purification steps applied during the production of trehalose, dietary exposure was not calculated. Genotoxicity tests did not raise a safety concern. The systemic toxicity was assessed by means of a repeated dose 90-day oral toxicity study in rats. The Panel identified a no-observed-adverse-effect level (NOAEL) of 39 mg TOS/kg body weight per day, the highest dose tested. Similarity of the amino acid sequence to those of known allergens was searched and one match was found. The Panel considered that, under the intended condition of use, the risk of allergic sensitisation and elicitation reactions upon dietary exposure cannot be excluded, but the likelihood for such reactions to occur is considered to be low. Based on the data provided, the Panel concluded that this food enzyme does not give rise to safety concerns under the intended conditions of use.


Immunological identification of an inward rectifier K+ channel (Kir4.1) in the intermediate cell (melanocyte) of the cochlear stria vascularis of gerbils and rats.
The cochlear stria vascularis produces the positive endocochlear potential (EP) and the endolymph. Both the EP and the endolymph are essential for the physiological function of hair cells. The intermediate cell is one of several cell types constituting the stria vascularis. It is known that inward rectifier K+ channels can play a constitutive role in the determination of the resting membrane potential. Localization of a member of the inward rectifier K+ channel family, Kir4.1, in the stria vascularis of gerbils and rats was investigated by immunological methods. A polyclonal antibody specific to the C-terminus of the rat Kir4.1 channel was raised in rabbits. Immunostaining of dissociated cells revealed that the Kir4.1 channel was localized to the intermediate cell, but not to the epithelial marginal cell. Subcellular localization of the Kir4.1 channel to the plasma membrane of the intermediate cell was confirmed by immunoelectron microscopy. Immunostaining of whole-tissue preparations revealed a network-like structure composed of intermediate cells. It seems likely that the Kir4.1 channel mediates the inwardly rectifying K+ current in the intermediate cell as shown previously by electrophysiological methods, and that this channel plays key roles in the production of the EP and K+ transport in the stria vascularis.