Relationship between the kinetics and kinematics of a unilateral horizontal drop jump to sprint performance.
The aim of this study was to investigate the relationship between the kinematics and kinetics of a single-leg horizontal drop jump (SLDJ) to sprint performance. Twenty regional-level male team-sport athletes gave informed consent to participate in this study. All subjects performed a series of 25-m sprints (measured by dual-beam infrared timing lights) and SLDJ (with both legs) in randomized block order during the same testing session. The SLDJ required the subjects to step downwards off a 20-cm box, land on the force plate (operating at 500 Hz) with the specified foot, and jump for maximal horizontal distance while minimizing ground-contact time. Jump distance, particularly when normalized to a subject's height, was the strongest correlate to sprinting time for all three (5, 10, and 25 m) distances (-0.44 < r < -0.65). Multiple linear regression analyses indicated that the SLDJ could account for a high level of variance in sprint time (0.49 < r2 < 0.68) and that these predictions had a relatively low standard error of estimate (0.02-0.10 seconds). These results further support the contention that jump (particularly horizontal) and sprint ability for short distances are highly related. Whereas practitioners should consider using more horizontal than vertical jumps in the training and testing of most team-sport athletes, additional research into the kinetic determinants of jumping and sprinting may allow a more specific and individualized exercise prescription for improving certain aspects of sprinting such as step length or step rate or the vertical vs. horizontal contributions to propulsion.


Patient preferences and willingness-to-pay for a home or clinic based program of chronic heart failure management: findings from the Which? trial.
Beyond examining their overall cost-effectiveness and mechanisms of effect, it is important to understand patient preferences for the delivery of different modes of chronic heart failure management programs (CHF-MPs). We elicited patient preferences around the characteristics and willingness-to-pay (WTP) for a clinic or home-based CHF-MP. A Discrete Choice Experiment was completed by a sub-set of patients (n = 91) enrolled in the WHICH? trial comparing home versus clinic-based CHF-MP. Participants provided 5 choices between hypothetical clinic and home-based programs varying by frequency of nurse consultations, nurse continuity, patient costs, and availability of telephone or education support. Participants (aged 71±13 yrs, 72.5% male, 25.3% NYHA class III/IV) displayed two distinct preference classes. A latent class model of the choice data indicated 56% of participants preferred clinic delivery, access to group CHF education classes, and lower cost programs (p<0.05). The remainder preferred home-based CHF-MPs, monthly rather than weekly visits, and access to a phone advice service (p<0.05). Continuity of nurse contact was consistently important. No significant association was observed between program preference and participant allocation in the parent trial. WTP was estimated from the model and a dichotomous bidding technique. For those preferring clinic, estimated WTP was ≈AU$9-20 per visit; however for those preferring home-based programs, WTP varied widely (AU$15-105). Patient preferences for CHF-MPs were dichotomised between a home-based model which is more likely to suit older patients, those who live alone, and those with a lower household income; and a clinic-based model which is more likely to suit those who are more socially active and wealthier. To optimise the delivery of CHF-MPs, health care services should consider their patients' preferences when designing CHF-MPs.


Factors influencing engagement of patients in a novel intervention for CFS/ME: a qualitative study.
To establish what factors are important for patients to engage in a new intervention for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and make recommendations to general practitioners (GPs) on preparing a patient for referral to such a service. NICE guidelines recommend a prominent role for primary care in the management of patients with CFS/ME, with prompt diagnosis and appropriate referral for evidence-based treatments. A qualitative study nested within a multi-centre randomised controlled trial of two new nurse therapist delivered interventions. Semi-structured interviews carried out with 19 patients who had received pragmatic rehabilitation (PR) in the trial. Interviews were transcribed verbatim and an iterative approach used to develop themes from the data set. Factors that influence whether or not a patient engages with PR for CFS/ME are ensuring that the patient feels accepted and believed, that they accept the diagnosis, and that the model implicated by the treatment offered to the patient matches the model of illness held by the patient. If patients hold a clearly incompatible model of their illness, it is unlikely that they will engage with, and successfully complete, therapy. It is vital that the GP elicits and explores such illness beliefs either before making a referral to maximise patient engagement in therapy, or that an initial session with the therapist explores attitudes to the treatment model offered and then works with the patient's model.


The natural history of hereditary angioedema and the impact of treatment with human C1-inhibitor concentrate during pregnancy: a long-term survey.
The course of hereditary angioedema (HAE) and the efficacy and safety of human C1-INH concentrate were appraised during pregnancy and the postpartum period, in patients with HAE. Retrospective analysis of clinical data on 118 pregnancies (82 full-term and 36 abortions) in 41 female patients, extracted from the National HAE Registry, medical charts and patient diaries. HAE attack frequency increases in 48% of pregnancies, whereas 33% of pregnancies were associated with mitigation of clinical signs and 19% of the pregnancies had no influence on the course of HAE, as compared to disease severity seen during the 2-year period preceding the pregnancy. During 46 full-term pregnancies, 26 patients reported attacks; 52% of these occurred in the third trimester. Abdominal attacks are the most common presentation of HAE during pregnancy. Attack number was significantly higher in patients who had sustained their initial attack before 8 years of age. Attack number increased during the third trimester if the fetus was afflicted by HAE. During the postpartum period, attacks occurred in 6/82 pregnancies. Patients received 91 vials of C1-INH concentrate altogether for the relief of acute attacks and for short- or long-term prophylaxis during pregnancy. This therapy was effective in all instances; no adverse effects were observed. Pregnancy can either aggravate or mitigate edematous attacks, or alternatively, it may have no influence on the severity of the disease. According to our experience, C1-INH concentrate is an effective and safe therapeutic option during pregnancy.


Adherence and satisfaction with oral hypoglycemic medications: a pilot study in Palestine.
Diabetes mellitus is a chronic progressive disease characterized by numerous health complications. Medication adherence is an important determinant of therapeutic outcome. Few studies on medication adherence have been published from the Arab countries. Therefore, the objective of this pilot study was to assess hypoglycemic medication adherence and its association with treatment satisfaction. Military Medical Services clinic in Nablus, Palestine. This is a cross sectional descriptive study. A convenience sample of 131 diabetic patients was studied. The 8-item Morisky Medication Adherence Scale (MMAS-8) and Treatment Satisfaction Questionnaire for Medication were used to assess adherence and treatment satisfaction, respectively. Statistical Package for Social Sciences was used for statistical analysis. Level of adherence, treatment satisfaction and association between adherence and treatment satisfaction among diabetic patients. According to MMAS-8, 50 patients (38.5%) had a high adherence, 58 (44.6%) had a medium adherence and 22 (16.9%) had a low adherence rate. The mean scores of satisfaction domains were 71 ± 17.6 and 95 ± 16.4 for effectiveness (EFF) and side effects (SE), respectively. Adherence score was a positively and significantly correlated with EFF satisfaction domain (P < 0.01) and age (P = 0.01). Similar significant correlation was found between adherence level and duration of illness (P = 0.047). However, adherence was not significantly associated with gender (P = 0.2), number of hypoglycemic medications (P = 0.5) or SE satisfaction domain (P = 0.2). The majority of diabetic patients in this pilot study were non-adherent. Improving patients' treatment satisfaction will improve treatment adherence.


The Ras GTPase-activating-protein-related human protein IQGAP2 harbors a potential actin binding domain and interacts with calmodulin and Rho family GTPases.
We previously described IQGAP1 as a human protein related to a putative Ras GTPase-activating protein (RasGAP) from the fission yeast Schizosaccharomyces pombe. Here we report the identification of a liver-specific human protein that is 62% identical to IQGAP1. Like IQGAP1, the novel IQGAP2 protein harbors an N-terminal calponin homology motif which functions as an F-actin binding domain in members of the spectrin, filamin, and fimbrin families. Both IQGAPs also harbor several copies of a novel 50- to 55-amino-acid repeat, a single WW domain, and four IQ motifs and have 25% sequence identity with almost the entire S. pombe sar1 RasGAP homolog. As predicted by the presence of IQ motifs, IQGAP2 binds calmodulin. However, neither full-length nor truncated IQGAP2 stimulated the GTPase activity of Ras or its close relatives. Instead, IQGAP2 binds Cdc42 and Racl but not RhoA. This interaction involves the C-terminal half of IQGAP2 and appears to be independent of the nucleotide binding status of the GTPases. Although IQGAP2 shows no GAP activity towards Cdc42 and Rac1, the protein did inhibit both the intrinsic and RhoGAP-stimulated GTP hydrolysis rates of Cdc42 and Rac1, suggesting an alternative mechanism via which IQGAPs might modulate signaling by these GTPases. Since IQGAPs harbor a potential actin binding domain, they could play roles in the Cdc42 and Rac1 controlled generation of specific actin structures.


Correlation of gene expression and genome mutation in single B-cells.
High-throughput measurement of gene-expression and immune receptor repertoires have recently become powerful tools in the study of adaptive immune response. However, despite their now-widespread use, both tend to discard cell identity by treating cell populations in bulk, and therefore lose the correlation between genetic variability and gene-expression at the single cell level. In order to recover this information, we developed a method to simultaneously measure gene expression profiles and genome mutations in single cells. We applied this method by quantifying the relationships between gene expression and antibody mutation in ensembles of individual B-cells from immunized mice. The results reveal correlations reflecting the manner in which information propagates between a B-cell's antigen receptors, its gene expression, and its mutagenic machinery, and demonstrate the power of this approach to illuminate both heterogeneity and physiology in cell populations.


SU-E-T-461: Fractionation Schedule Optimization for Lung Cancer Treatments Using Radiobiological and Dose Distribution Characteristics.
Lung cancer radiotherapy treatments employ a wide variety of fractionation protocols. The choice among protocols mostly depends on the size of the target volume (GTV or ITV) and the volume of normal tissue receiving a critical dose. Rigorous mathematical criteria for normal tissue (NT) dose distributions were derived to determine the type of dose per fraction schedule that maximizes linear-quadratic tumor effect. Selecting the individual doses per fraction that maximize a linear-quadratic effect in the tumor while constraining the normal tissue complication probability according to the Lyman-Kutcher-Burman model leads to an optimization problem. For time-independent parameters, the solution is always an equal dose per fraction schedule; depending on parameter values, two different class solutions are suggested: minimal number of fractions clinically realized with hypo-fractionation, or minimizing dose per fraction clinically realized with standard- or hyper-fractionation. The value of a single scale-free "bifurcation" number, derived from the DVH of the NT dose distribution suggests which solution is preferred for a given plan with respect to a given normal tissue. The clinical relevance of the bifurcation number in selecting fractionation schemes was tested for 30 patients previously treated for non-small-cell lung cancer according to various fractionation protocols. The bifurcation numbers for both lung and esophagus were a good classifier for the hypofractionated and the conventional fractionation groups. The variability of the numbers within patients of the conventional fractionation group was much smaller than the variability of the treated ITV volumes or the ITV to lung volume ratios. The prescribed fractionations were also consisted with the currently accepted alpha-beta values for tumor (10) and radiation-induced pneumonities in the lung (4). Model-based criteria such as the bifurcation number may replace the more empirical volume criteria to decide the optimal fractionation protocol once the dose distribution has been optimized.


Construction of plants resistant to TYLCV by using artificial zinc-finger proteins.
Previously, we have demonstrated that plant DNA virus replication could be inhibited in Arabidopsis thaliana by using an artificial zinc-finger protein (AZP) and created AZP-based transgenic A. thaliana resistant to DNA virus infection. Here we apply the AZP technology to tomato yellow leaf curl virus (TYLCV) causing serious damage to an important agricultural crop, tomato. An AZP was designed to block binding of the TYLCV replication protein (Rep) to the replication origin. The designed AZP had much higher affinities towards the replication origin than did the Rep, and efficiently blocked Rep binding in vitro. The AZP gene was then introduced into a plant genome with the help of Agrobacterium tumefaciens to generate the transgenic plants. The current status of the construction of the AZP-expressing transgenic plants will be reported.


Measures of prefrontal functional near-infrared spectroscopy in visuomotor learning.
Functional near-infrared spectroscopy (fNIRS) is a promising technique for non-invasively assessing cortical brain activity during learning. This technique is safe, portable, and, compared to other imaging techniques, relatively robust to head motion, ocular and muscular artifacts and environmental noise. Moreover, the spatial resolution of fNIRS is superior to electroencephalography (EEG), a more commonly applied technique for measuring brain activity non-invasively during learning. Outcomes from fNIRS measures during learning might therefore be both sensitive to learning and to feedback on learning, in a different way than EEG. However, few studies have examined fNIRS outcomes in learning and no study to date additionally examined the effects of feedback. To address this apparent gap in the literature, the current study examined prefrontal cortex activity measured through fNIRS during visuomotor learning and how this measure is affected by task feedback. Activity in the prefrontal cortex decreased over the course of learning while being unaffected by task feedback. The findings demonstrate that fNIRS in the prefrontal cortex is valuable for assessing visuomotor learning and that this measure is robust to task feedback. The current study highlights the potential of fNIRS in assessing learning even under different task feedback conditions.


Real-Time Cognitive Workload Monitoring Based on Machine Learning Using Physiological Signals in Rescue Missions.
High levels of cognitive workload decreases human's performance and leads to failures with catastrophic outcomes in risky missions. Today, reliable cognitive workload detection presents a common major challenge, since the workload is not directly observable. However, cognitive workload affects several physiological signals that can be measured non-invasively. The main goal of this work is to develop a reliable machine learning algorithm to identify the cognitive workload induced during rescue missions, which is evaluated through drone control simulation experiments. In addition, we aim to minimize the computing resources usage while maximizing the cognitive workload detection accuracy for a reliable real-time operation. We perform an experiment in which 24 subjects played a rescue mission simulator while respiration, electrocardiogram, photoplethysmogram, and skin temperature signals were measured. State-of-the-art feature-based machine learning algorithms are investigated for cognitive workload characterization using learning curves, data augmentation, and cross-validation techniques. The best classification algorithm is selected, optimized, and the most informative features are selected. Finally, the generalization power of the optimized model is evaluated on an unseen test set. We obtain an accuracy level of 86% on the new unseen datasets using the proposed and optimized eXtreme Gradient Boosting (XGB) algorithm. Then, we reduce the complexity of the machine learning model for future implementation on resource-constrained wearable embedded systems, by optimizing the model and selecting the 26 most important features. Overall, a generalizable and low-complexity machine learning model for cognitive workload detection based on physiological signals is presented for the first time in the literature.


Developing a sensor layer for the optical detection of amines during food spoilage.
A colourimetric sensor layer has been developed for ammonia and biogenic amines. Amine exposure induces a traffic light colour change from green to red. Recognition is performed by a pH indicator dye, covalently immobilised onto cellulose microparticles. The sensor microparticles are embedded into food-grade silicone. Selectivity of the pH indicator dye towards gaseous amine is obtained by complete embedding of the sensor particles within the ion-impermeable silicone. A response time of 1.5h has been achieved, with a reverse response occurring after 20h. This time frame is considered sufficient for spoilage processes. Cytotoxicity studies confirm the layers are non-toxic.


Genomic structural variations for cardiovascular and metabolic comorbidity.
The objective of this study was to identify genes targeted by both copy number and copy-neutral changes in the right coronary arteries in the area of advanced atherosclerotic plaques and intact internal mammary arteries derived from the same individuals with comorbid coronary artery disease and metabolic syndrome. The artery samples from 10 patients were screened for genomic imbalances using array comparative genomic hybridization. Ninety high-confidence, identical copy number variations (CNVs) were detected. We also identified eight copy-neutral changes (cn-LOHs) > 1.5 Mb in paired arterial samples in 4 of 10 individuals. The frequencies of the two gains located in the 10q24.31 (ERLIN1) and 12q24.11 (UNG, ACACB) genomic regions were evaluated in 33 paired arteries and blood samples. Two patients contained the gain in 10q24.31 (ERLIN1) and one patient contained the gain in 12q24.11 (UNG, ACACB) that affected only the blood DNA. An additional two patients harboured these CNVs in both the arteries and blood. In conclusion, we discovered and confirmed a gain of the 10q24.31 (ERLIN1) and 12q24.11 (UNG, ACACB) genomic regions in patients with coronary artery disease and metabolic comorbidity. Analysis of DNA extracted from blood indicated a possible somatic origin for these CNVs.


Stimuli-responsive supramolecular nano-systems based on pillar[n]arenes and their related applications.
Stimuli-responsive supramolecular nano-systems (SRNS) have been a trending interdisciplinary research area due to flexibly being able to switch functions through exposure to appropriate stimuli, which makes the systems very attractive in multiple fields where precise control is key. Pillar[n]arenes, as a new generation of macrocyclic host molecules, possess captivating properties including versatile chemical modifiability, rigid electron-rich structure and tuneable size of the cavity, and have become extremely valuable molecules/building blocks in constructing SRNS via non-covalent interactions. Significantly, numerous SRNS based on pillar[n]arenes have been fabricated in the past few years and found extensive applications in hydrogels, sensors, bioimaging, diagnosis, and, importantly, controlled drug release. In this review, we highlight the advances of SRNS based on pillar[n]arenes, which are categorised in terms of response factors including pH, redox, enzymes, temperature, light and ions. The related applications of pillar[n]arenes are then summarized into the following areas: fluorescent chemosensors, drug delivery, molecular switches, and other functional materials. In addition, the future potential for construction of SRNS based on pillar[n]arenes and their applications are discussed.


Characterisation of eppin function: expression and activity in the lung.
Eppin is a serine protease inhibitor expressed in male reproductive tissues.The aim of this study was to investigate the localisation and regulation of eppin expression in myeloid and epithelial cell lines, and explore its potential role as a multifunctional host defence protein.Using immunohistochemistry and Western blotting, eppin was detected in the lungs of patients with acute respiratory distress syndrome and cystic fibrosis lung disease. Expression of eppin in monocytic cells was unaffected by stimulation with Toll-like receptor agonists, cytokines and hormone receptor agonists. However, upregulated expression and secretion of eppin was observed following treatment of monocytes with epidermal growth factor. Incubation of recombinant eppin with monocytic cells resulted in significant inhibition of lipopolysaccharide-induced chemokine production. Furthermore, eppin inhibited lipopolysaccharide-induced NF-κB activation by a mechanism which involved accumulation of phosphorylated IκBα. In an in vivo model of lung inflammation induced by lipopolysaccharide, eppin administration resulted in decreased recruitment of neutrophils to the lung with a concomitant reduction in the levels of the neutrophil chemokine macrophage inflammatory protein-2.Overall, these results suggest a role for eppin outside of the reproductive tract and that eppin may have a role in the innate immune response in the lung.


Vibrational relaxation pathways of AI and AII modes in N-methylacetamide clusters.
We studied the pathways of vibrational energy relaxation of the amide I (~1660 cm⁻¹) and amide II (~1560 cm⁻¹) vibrational modes of N-methylacetamide (NMA) in CCl₄ solution using two-color femtosecond vibrational spectroscopy. We measured the transient spectral dynamics upon excitation of each of these amide modes. The results show that there is no energy transfer between the amide I (AI) and amide II (AII) modes. Instead we find that the vibrational energy is transferred on a picosecond time scale to a common combination tone of lower-frequency modes. By use of polarization-resolved femtosecond pump-probe measurements we also study the reorientation dynamics of the NMA molecules and the relative angle between the transition dipole moments of the AI and AII vibrations. The spectral dynamics at later times after the excitation (>40 ps) reveal the presence of a dissociation process of the NMA aggregates, trimers, and higher order structures into dimers and monomers. By measuring the dissociation kinetics at different temperatures, we determined the activation energy of this dissociation E(a) = 35 ± 3 kJ mol⁻¹.


Effect of magnetic fields on antioxidative defense and fitness-related traits of Baculum extradentatum (insecta, phasmatodea).
This study aimed to determine the effect of magnetic fields on the antioxidative defense and fitness-related traits of Baculum extradentatum. Following exposure to magnetic fields, antioxidative defense (superoxide dismutase (SOD), catalase (CAT) activities, and total glutathione (GSH) content) and fitness-related traits (egg mortality, development dynamics, and mass of nymphs) were monitored in nymphs. The experimental groups were: control (kept out of influence of the magnets), a group exposed to a constant magnetic field (CMF) of 50 mT, and a group exposed to an alternating magnetic field (AMF) of 50 Hz, 6 mT. We found increased SOD and CAT activities in animals exposed to constant and AMFs, whereas GSH activity was not influenced by experimental magnetic fields. No differences were found in egg mortality between control and experimental groups. Significant differences in the time of development between the control and the CMF group were observed, as well as between the CMF and the AMF group. No differences were found in the mass of the nymphs between the three experimental groups. In conclusion, CMF and AMF have the possibility to modulate the antioxidative defense and some of the fitness-related traits in B. extradentatum.


A phase III, open-label, randomised multicentre study to evaluate the immunogenicity and safety of a booster dose of two different reduced antigen diphtheria-tetanus-acellular pertussis-polio vaccines, when co-administered with measles-mumps-rubella vaccine in 3 and 4-year-old healthy children in the UK.
To evaluate the immunogenicity and safety of a reduced antigen diphtheria-tetanus-acellular pertussis-inactivated poliovirus (dTap-IPVB) vaccine (Boostrix-IPV, GSK) as a pre-school booster in 3-4 year old children as compared to dTap-IPVR (Repevax, Sanofi Pasteur), when co-administered with mumps-measles-rubella vaccine (MMRV). This phase III, open label, randomised study was conducted in the UK between April 2011 and April 2012. Children due their pre-school dTap-IPV booster vaccination were randomised 2:1 to receive one of two different dTap-IPV vaccines (dTap-IPVB or dTap-IPVR) with blood sample for immunogenicity assessment just prior and one month after vaccination. Immune responses to diphtheria, tetanus and polio antigens were compared between the study vaccines (inferential comparison). In the absence of an accepted pertussis correlate of protection, the immunogenicity of dTap-IPVB vaccine against pertussis was compared with historical pertussis efficacy data (inferential comparison). Safety and reactogenicity of both study vaccines were evaluated. 387 children were randomised and 385 vaccinated: 255 in the dTap-IPVB group and 130 in the dTap-IPVR group. Prior to vaccination, ≥76.8% of children had anti-diphtheria and ≥65.5% had anti-tetanus titres above the protection threshold; for pertussis, the pre-vaccination seropositivity rate ranged between 18.1 and 70.6%. Both vaccines were immunogenic with 99.2-100% of children achieving titres above the pre-specified seroprotection/seropositivity thresholds. One serious adverse event not considered as causally related to the study vaccination by the study investigator was reported in the dTap-IPVB group. Non-inferiority of dTap-IPVB to dTap-IPVR was demonstrated. Both vaccines had a clinically acceptable safety and reactogenicity profile when co-administered with MMRV to children 3-4 years old. NCT01245049 (ClinicalTrials.gov).


Adverse events associated with testosterone administration.
Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied. Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group. A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load. In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy. (ClinicalTrials.gov number, NCT00240981.)


Ascorbic acid deficiency changes hepatic gene expression of acute phase proteins in scurvy-prone ODS rats.
The ODS rat (genotype od/od), which has a hereditary defect in ascorbic acid biosynthesis, was used to investigate the effects of ascorbic acid deficiency on the hepatic gene expression of both the positive acute phase proteins, haptoglobin and alpha1-acid glycoprotein, and the negative acute phase proteins, apolipoprotein A-I and albumin. Male ODS rats (6 wk old, body weight approximately 140 g) were fed a basal diet containing ascorbic acid (300 mg/kg diet) or a diet without ascorbic acid for 14 d. Ascorbic acid deficiency significantly elevated the serum concentration of haptoglobin and significantly lowered those of apolipoprotein A-I and albumin. The hepatic mRNA levels of haptoglobin and alpha1-acid glycoprotein in the ascorbic acid-deficient rats were significantly elevated on d 12, and reached 260 (P < 0.05) and 360% (P < 0.01) of respective values in the control rats on d 14. On the contrary, the hepatic mRNA levels of apolipoprotein A-I and albumin in the ascorbic acid-deficient rats were lowered to 68 (P < 0.01) and 71% (P < 0.05) of respective values in the control rats on d 14. Although ascorbic acid deficiency significantly elevated the serum corticosterone concentration on d 14, the changes in mRNA levels of haptoglobin, alpha1-acid glycoprotein, apolipoprotein A-I and albumin due to ascorbic acid deficiency were not affected by adrenalectomy, as assessed in a separate experiment. The serum concentration of interleukin-6, an inflammatory cytokine that stimulates gene expression of some acute phase proteins, was significantly higher in the ascorbic acid-deficient rats on d 14 than in the control rats. These results suggest that ascorbic acid deficiency causes physiologic changes similar to those that occur in the acute phase response.


Vitamin D Receptor Polymorphisms Associated with Autism Spectrum Disorder.
Vitamin D is endowed with a number of biological properties, including down-regulation of inflammation, and might contribute to the pathogenesis of autism spectrum disorders (ASD). Vitamin D binds to the vitamin D Receptor (VDR); the biological activity of the ensuing complex depends on VDR FokI, BsmI, ApaI, and TaqI gene polymorphisms. We evaluated such Single Nucletoide Polymorphismsm (SNPs) in a cohort of 100 Italian families with ASD children. FokI genotype distribution was skewed in ASD children compared with their healthy sibs (Pc = 0.03 2 df) and to a group of 170 Italian healthy women (HC) (Pc = 0.04 2 df). FokI genotype and allelic distribution skewing were also observed in mothers of ASD children compared to HC (Pc = 0.04 2 df). Both Transmission Disequilibrium Test for single loci and haplotype analysis distribution revealed a major FokI (C) allele-mediated protective effect, which was more frequently transmitted (73%) than not transmitted to healthy sibs (P = 0.02). A protective FokI-, BsmI-, ApaI-, and TaqI (CCAG) haplotype was more frequently carried by healthy sibs than by ASD children (P = 1 × 10-4 ; OR: 0.1, 95% CI: 0.03-0.4) too. Finally, a strong gene-dose association of FokI (T) allele with both higher Childhood Autism Rating Scale score (Pc = 0.01) and, particularly, with hyperactivity behavior (Pc = 0.006) emerged in ASD children. Because the protein produced by the FokI (T) allele is transcriptionally less active than that produced by the FokI (C) allele, the reduced biological activity of the vitamin D/VDR complex prevalent in ASD could favor ASD- and maternal immune activation- associated inflammation. Vitamin D supplementation might be useful in preventative and rehabilitation protocols for ASD. Autism Res 2020, 13: 680-690. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Vitamin D deficiency and Vitamin D receptor (VDR) polymorphisms are associated with structural and functional brain abnormalities and behavioral disorders. We analyzed the association of VDR gene polymorphisms in a cohort of 100 Italian families with ASD children. A strong correlation between one of the VDR polymorphisms and hyperactivity behavior was evidenced in ASD children. In healthy mothers, the same VDR polymorphism was also correlated with an increased risk of giving birth to children with ASD.


The neurodevelopmental hypothesis of schizophrenia, revisited.
While multiple theories have been put forth regarding the origin of schizophrenia, by far the vast majority of evidence points to the neurodevelopmental model in which developmental insults as early as late first or early second trimester lead to the activation of pathologic neural circuits during adolescence or young adulthood leading to the emergence of positive or negative symptoms. In this report, we examine the evidence from brain pathology (enlargement of the cerebroventricular system, changes in gray and white matters, and abnormal laminar organization), genetics (changes in the normal expression of proteins that are involved in early migration of neurons and glia, cell proliferation, axonal outgrowth, synaptogenesis, and apoptosis), environmental factors (increased frequency of obstetric complications and increased rates of schizophrenic births due to prenatal viral or bacterial infections), and gene-environmental interactions (a disproportionate number of schizophrenia candidate genes are regulated by hypoxia, microdeletions and microduplications, the overrepresentation of pathogen-related genes among schizophrenia candidate genes) in support of the neurodevelopmental model. We relate the neurodevelopmental model to a number of findings about schizophrenia. Finally, we also examine alternate explanations of the origin of schizophrenia including the neurodegenerative model.


The effect of simulated microgravity on human mesenchymal stem cells cultured in an osteogenic differentiation system: a bioinformatics study.
One proposed strategy for bone regeneration involves ex vivo tissue engineering, accomplished using bone-forming cells, biodegradable scaffolds, and dynamic culture systems, with the goal of three-dimensional tissue formation. Rotating wall vessel bioreactors generate simulated microgravity conditions ex vivo, which lead to cell aggregation. Human mesenchymal stem cells (hMSCs) have been extensively investigated and shown to possess the potential to differentiate into several cell lineages. The goal of the present study was to evaluate the effect of simulated microgravity on all genes expressed in hMSCs, with the underlying hypothesis that many important pathways are affected during culture within a rotating wall vessel system. Gene expression was analyzed using a whole genome microarray and clustering with the aid of the National Institutes of Health's Database for Annotation, Visualization and Integrated Discovery database and gene ontology analysis. Our analysis showed 882 genes that were downregulated and 505 genes that were upregulated after exposure to simulated microgravity. Gene ontology clustering revealed a wide variety of affected genes with respect to cell compartment, biological process, and signaling pathway clusters. The data sets showed significant decreases in osteogenic and chondrogenic gene expression and an increase in adipogenic gene expression, indicating that ex vivo adipose tissue engineering may benefit from simulated microgravity. This finding was supported by an adipogenic differentiation assay. These data are essential for further understanding of ex vivo tissue engineering using hMSCs.


Effect of the quality of water used for dialysis on the efficacy of hemodialysis: a single-center experience from Morocco.
The quality of the water used for dialysis has been suggested as a factor causing inflammation in patients on hemodialysis (HD). We therefore conducted this study to identify the effect of quality of the water on nutritional state, inflammation and need for human recombinant erythropoietin (EPO) in patients undergoing HD at Agadir, Morocco. This prospective study included patients on HD for at least one year. The water treatment was done according to the standard protocol, which was followed by additional enhancement of ultrafiltration using an additional polysulfone filter (diasafe, Fresenius, Bad Homburg, Germany) before the dialyser. Water was monitored regularly during the study period to ensure acceptable levels of bacterial count as well as endotoxin levels. Various parameters including dry weight, systolic and diastolic blood pressure (PA) before and after an HD session, need for human recombinant EPO, levels of hemoglobin (Hb), albumin, ferritin, C-reactive protein (CRP), and the dose of dialysis delivered (Kt/V) were measured first at the beginning of the study and thereafter, in the third, sixth and 12 th months of the study. The study involved 47 patients, and after 12 months of the study, an improvement in median dry weight (1.2 kg, P = 0017) and a simultaneous median reduction of 20.7 IU/kg/week of EPO, with an in-crease of the median level of Hb, was noted. The results of our study suggest that by improving the biocompatibility of HD with the use of good quality water, patients acquire a better nutritional, inflammatory and hematologic status.


Traditional Korean East Asian medicines and herbal formulations for cognitive impairment.
Hanbang, the Traditional Korean Medicine (TKM), is an inseparable component of Korean culture both within the country, and further afield. Korean traditional herbs have been used medicinally to treat sickness and injury for thousands of years. Oriental medicine reflects our ancestor's wisdom and experience, and as the elderly population in Korea is rapidly increasing, so is the importance of their health problems. The proportion of the population who are over 65 years of age is expected to increase to 24.3% by 2031. Cognitive impairment is common with increasing age, and efforts are made to retain and restore the cognition ability of the elderly. Herbal materials have been considered for this purpose because of their low adverse effects and their cognitive-enhancing or anti-dementia activities. Herbal materials are reported to contain several active compounds that have effects on cognitive function. Here, we enumerate evidence linking TKMs which have shown benefits in memory improvements. Moreover, we have also listed Korean herbal formulations which have been the subject of scientific reports relating to memory improvement.


Progressive derailment of cell cycle regulators in endometrial carcinogenesis.
Derailments of the control mechanisms of the cell cycle can initiate carcinogenesis, and play a role in progression to cancer. To explore the expression of cell cycle proteins in normal, premalignant and malignant endometrial lesions representing the morphologically well defined stepwise model of human endometrial carcinogenesis Observational study. Paraffin-embedded specimens from inactive endometrium (n = 16), endometrial hyperplasia (n = 23) and endometrioid endometrial carcinoma (n = 39) were stained immunohistochemically for cyclin A, cyclin B1, cyclin D1, cyclin E, cdk2, p16, p21, p27, p53 and Ki67(MIB-1)). Differences in expression between the tissues, and correlation with classical prognostic factors for the carcinomas were analysed. Expression of cyclin A and Ki67 gradually increased from normal through hyperplasia to carcinoma, indicating that proliferation increases over the carcinogenetic spectrum. cdk2, p16 and p21 gradually increased from normal through hyperplasia to carcinoma, indicating their potential importance in both early and late carcinogenesis. Cyclin D1, cyclin E and p53 especially increased and p27 decreased from hyperplasia to carcinoma, underlining their role in late carcinogenesis. In cancers, expression of cyclin A, p53 and Ki67 was positively correlated to grade, and cyclin A was positively correlated with cdk2, p21, Ki67, cyclin E and p53. During (endometrioid) endometrial carcinogenesis, there is increasing proliferation paralleled by progressive derailment of cyclin B1, cyclin D1, cyclin E, p16, p21, p27, p53, and cdk2, indicating the importance of these cell cycle regulators in endometrial carcinogenesis.


[Counterproductive behaviors and moral disengagement of nurses as potential consequences of stress-related work: validity and reliability of measurement scales].
Several studies, but no one in the nursing, have shown that work stress can facilitate the adoption of specific behaviors that the literature identifies as Counterproductive Work Behaviors (CWB). Individuals, however, not giving up to their moral principles, may transgress social, organizational, moral and ethical norms, through the adoption of moral disengagement (MD). The purpose of this study is to validate two specific scales of deviant behaviors and MD in nursing: the Nursing Counterproductive Work Behaviours Scale (Nursing CWBS) and Nursing Moral Disengagement Scale (Nursing MDS). 460 nurses participated in the study. After the adaptation of the Counterproductive Work Behavior Checklist by Spector and Fox to Nursing context (Nursing CWBS) and the ex novo development of the Nursing MDS, the psychometric properties of the two scales were tested. Also, the two scales were correlated. Through a cross-validation approach and based on the results of exploratory factor analysis (EFA) and confirmatory factor analysis (CFA), we have shown that the scales have good psychometric properties. Furthermore, the results, attest that the nurse with high levels of MD implements more CWB in the workplace. The Nursing CWBS and Nursing MDS represent a valid starting point for the study of such phenomena in this specific context where stress among nursing staff is sometimes of considerable extent, especially in specific contexts of clinical care.


Accuracy of motor axon regeneration across autograft, single-lumen, and multichannel poly(lactic-co-glycolic acid) nerve tubes.
The accuracy of motor axon regeneration becomes an important issue in the development of a nerve tube for motor nerve repair. Dispersion of regeneration across the nerve tube may lead to misdirection and polyinnervation. In this study, we present a series of methods to investigate the accuracy of regeneration, which we used to compare regeneration across autografts and single-lumen poly(lactic-co-glycolic acid) (PLGA) nerve tubes. We also present the concept of the multichannel nerve tube that may limit dispersion by separately guiding groups of regenerating axons. The simultaneous tracing of the tibial and peroneal nerves with fast blue and diamidino yellow was performed 8 weeks after the repair of a 1-cm nerve gap in the rat sciatic nerve to determine the percentage of double-projecting motoneurons. Sequential tracing of the peroneal nerve with diamidino yellow 1 week before repair and fast blue 8 weeks after repair was performed to determine the percentage of correctly directed peroneal motoneurons. In the cases in which there was successful regeneration across single-lumen nerve tubes, more motoneurons had double projections to both the tibial and peroneal nerve branches after single-lumen nerve tube repair (21.4%) than after autograft repair (5.9%). After multichannel nerve tube repair, this percentage was slightly reduced (16.9%), although not significantly. The direction of regeneration was nonspecific after all types of repair. Retrograde tracing techniques provide new insights into the process of regeneration across nerve tubes. The methods and data presented in this study can be used as a basis for the development of a nerve tube for motor nerve repair.


Local continuity of myocardial blood flow studied by monochromatic synchrotron radiation-excited x-ray fluorescence spectrometry.
We have developed a monochromatic synchrotron radiation-excited system for two-dimensional mapping of x-ray fluorescence evoked from heavy element-loaded microspheres, which can evaluate myocardial blood flow in small contiguous regions with a small methodological error: 10.8 +/- 2.4% of the average of difference of the dual flow for 7- to 10-mg myocardial tissue (4 dogs). The fractal D value obtained from the slope of the log relative dispersion-log mass plot was 1.21 +/- 0.08 for a voxel size of 7 to 1260 mg (5 dogs) and that for a voxel size of 2.5 to 40 mg (1.12 +/- 0.06) was smaller than that for a voxel size of 40 to 1280 mg (1.25 +/- 0.14, P < .05, ANOVA, 4 dogs). The distance-correlation coefficient relation for paired myocardial regions was attenuated (correlation analysis), and the correlation coefficients between the original grouping and the two aggregates of the adjacent regions were dissociated (extended correlation analysis) under reduction of coronary perfusion pressure (6 dogs). Suppression of myocardial contraction with lidocaine (3 dogs) and vasodilation with adenosine partly improved the distance-correlation coefficient relation under reduced coronary perfusion pressure. Thus, an x-ray fluorescence system designed for precise flow measurement shows that the fractal nature of local flow distribution can be extended into regions smaller than previously reported, that in these regions the flow becomes more homogeneous, and that the self similarity and continuity of local flow are attenuated by the reduction of coronary perfusion pressure and improved by contractile suppression and coronary vasodilation.


Circulating CD4+ T cells that produce IL4 or IL17 when stimulated by melan-A but not by NY-ESO-1 have negative impacts on survival of patients with stage IV melanoma.
We initially observed that the presence of circulating NY-ESO-1- and/or Melan-A-specific T cells in patients with stage IV melanoma was significantly associated with prolonged survival. Here, we report the ways in which the phenotypes and functions of these T cells differentially affect survival in patients preselected for NY-ESO-1 and/or Melan-A reactivity. We assayed functional antigen-reactive T cells recognizing NY-ESO-1 and/or Melan-A after in vitro stimulation using overlapping peptide pools. After restimulation, we assayed six cytokines simultaneously by intracellular cytokine staining. This allowed us to analyze the functional antigen response of both CD4(+) and CD8(+) T cells at the single-cell level. We observed that NY-ESO-1 stimulated mainly CD4(+) T cells, whereas Melan-A more often stimulated CD8(+) T cells. NY-ESO-1 reactivity was not associated with an additional impact on survival, whether CD4(+) T cells, CD8(+) T cells, or both types of T cells were responding. In contrast, recognition of Melan-A by CD4(+) T cells was associated with reduced survival in our cohort of patients preselected for NY-ESO-1 and/or Melan-A reactivity (that is, in patients with exceptionally long survival). We further observed a negative effect on survival in patients with CD4(+) T cells producing IL4 and IL17 upon Melan-A stimulation. Their prognosis was comparable to patients without any Melan-A reactivity. The nature and prognostic impact of specific T-cell responses is different according to targeted antigen. Independent from phenotype and functional aspects, NY-ESO-1 reactivity is associated with good prognosis. In terms of Melan-A, antigen-specific CD8(+) but not CD4(+) responses are associated with prolonged survival. Clin Cancer Res; 20(16); 4390-9. ©2014 AACR.


Response to planned treatment interruptions in HIV infection varies across childhood.
To evaluate clinical, immunological and virological consequences of CD4-guided antiretroviral therapy (ART) planned treatment interruptions (PTIs) compared with continuous therapy in children with chronic HIV infection in the Paediatric European Network for Treatment of AIDS 11 trial. This was a multicentre, 72-week, open, randomized, phase II trial. One hundred and nine children with HIV-RNA below 50 copies/ml and CD4% of at least 30% (2-6 years) or at least 25% and CD4 cell count of at least 500 cells/microl (7-15 years) were randomized to continuous therapy (53) or PTI (56). In PTI, ART was restarted if confirmed CD4% was less than 20% or more than 48 weeks had been spent off ART. The primary outcome was Centers for Disease Control and Prevention (CDC) stage C event, death or CD4% less than 15% (and CD4 cell count less than 200 cells/microl for children aged 7-15 years). At baseline, median (interquartile range) age was 9 (6-12) years, CD4% 37% (33-41), CD4 cell count 966 (793-1258) cells/microl, nadir CD4% before combination ART 18% (10-27), time on ART 6 (3-6) years and 26% were CDC stage C. After median (range) 130 (33-180) weeks of follow-up, 4 versus 48% of time was spent off ART in continuous therapy and PTI, respectively. No child died or had a new CDC stage C event; one (2%) continuous therapy versus four (7%) PTI children had a primary outcome based on CD4%/cell count (P = 0.2). Lower nadir CD4% predicted faster CD4% decline after stopping ART. Younger age and higher nadir CD4% predicted being off ART for at least 48 weeks and better CD4% recovery following PTI. In this first paediatric trial of PTI, there were no serious clinical outcomes. Younger children had better CD4% recovery after PTIs. Immunology substudies and long-term follow-up in Paediatric European Network for Treatment of AIDS 11 trial are ongoing. Further research into the role of treatment interruption in children is required, particularly, as guidelines now recommend early ART for all infected infants.


Therapeutic potential of turmeric in Alzheimer's disease: curcumin or curcuminoids?
Alzheimer's disease (AD) is the most common form of dementia. There is limited choice in modern therapeutics, and drugs available have limited success with multiple side effects in addition to high cost. Hence, newer and alternate treatment options are being explored for effective and safer therapeutic targets to address AD. Turmeric possesses multiple medicinal uses including treatment for AD. Curcuminoids, a mixture of curcumin, demethoxycurcumin, and bisdemethoxycurcumin, are vital constituents of turmeric. It is generally believed that curcumin is the most important constituent of the curcuminoid mixture that contributes to the pharmacological profile of parent curcuminoid mixture or turmeric. A careful literature study reveals that the other two constituents of the curcuminoid mixture also contribute significantly to the effectiveness of curcuminoids in AD. Therefore, it is emphasized in this review that each component of the curcuminoid mixture plays a distinct role in making curcuminoid mixture useful in AD, and hence, the curcuminoid mixture represents turmeric in its medicinal value better than curcumin alone. The progress in understanding the disease etiology demands a multiple-site-targeted therapy, and the curcuminoid mixture of all components, each with different merits, makes this mixture more promising in combating the challenging disease.


Differences in the relationship of weight to height, and thus the meaning of BMI, according to age, sex, and birth year cohort.
Background: Weight can be adjusted for height using the Benn parameter (kg/mB), where B is the power that minimises the correlation with height.Aim: To investigate how the Benn parameter changes across age (10-65 years) and time (1956-2015) and differs between sexes.Subjects and methods: The sample comprised 49,717 individuals born in 1946, 1958, 1970 or 2001. Cross-sectional estimates of the Benn parameter were produced and cohort differences at ages 10/11 and 42/43 years were examined using linear regression. Multilevel modelling was used to develop trajectories showing how the Benn parameter changed over age from childhood to mid-adulthood in the three older cohorts.Results: The Benn parameter was closest to 2 in childhood but consistently lower across adulthood, particularly in females and the most recent cohort. At ages 10/11 years, the Benn parameter was greater than 3 in both sexes in the 2001 cohort but between 2.2 and 2.7 in the three older cohorts. This difference was estimated to be +0.67 (0.53, 0.81) in males and +0.53 (0.38, 0.68) in females, compared to the 1946 cohort, and was driven by a much higher weight SD in the 2001 cohort. Conversely, at ages 42/43 years, the Benn parameter was lowest in the 1970 cohort due to a slightly lower weight-height correlation. This difference was estimated to be -0.12 (-0.34, 0.10) in males and -0.15 (-0.42, 0.13) in females, compared to the 1946 cohort.Conclusions: Changes over time in the obesogenic environment appear to have firstly reduced the Benn parameter due to a lowering of the weight-height correlation but secondly and more drastically increased the Benn parameter due to increasing weight variation.


Perioperative Management of Lactic Acidosis in End-Stage Liver Disease Patient.
Lactic acidosis (LA) in end-stage liver disease (ESLD) patients has been recognized as one of the most complicated clinical problems and is associated with increased morbidity and mortality. Multiple-organ failure, associated with advanced stages of cirrhosis, exacerbates dysfunction of numerous parts of lactate metabolism cycle, which manifests as increased lactate production and impaired clearance, leading to severe LA-induced acidemia. These problems become especially prominent in ESLD patients, that undergo partial hepatectomy and, particularly, liver transplantation. Perioperative management of LA and associated severe acidemia is an inseparable part of anesthesia, post-operative and critical care for this category of patients, presenting a wide variety of challenges. In this review, lactic acidosis applied pathophysiology, clinical implications for ESLD patients, diagnosis, role of intraoperative factors, such as anesthesia and surgery-related, vasoactive agents impact, and also current treatment options and modalities have been discussed.


Shear-induced migration of confined flexible fibers.
We report an experimental study of the shear-induced migration of flexible fibers in suspensions confined between two parallel plates. Non-Brownian fiber suspensions are imaged in a rheo-microscopy setup, where the top and the bottom plates counter-rotate and create a Couette flow. Initially, the fibers are near the bottom plate due to sedimentation. Under shear, the fibers move with the flow and migrate towards the center plane between the two walls. Statistical properties of the fibers, such as the mean values of the positions, orientations, and end-to-end lengths of the fibers, are used to characterize the behaviors of the fibers. A dimensionless parameter Λeff, which compares the hydrodynamic shear stress and the fiber stiffness, is used to analyze the effective flexibility of the fibers. The observations show that the fibers that are more likely to bend exhibit faster migration. As Λeff increases (softer fibers and stronger shear stresses), the fibers tend to align in the flow direction and the motions of the fibers transition from tumbling and rolling to bending. The bending fibers drift away from the walls to the center plane. Further increasing Λeff leads to more coiled fiber shapes, and the bending is more frequent and with larger magnitudes, which leads to more rapid migration towards the center. Different behaviors of the fibers are quantified with Λeff, and the structures and the dynamics of the fibers are correlated with the migration.


Molecular Mechanism of Facilitated Dissociation of Fis Protein from DNA.
Fis protein is a nucleoid-associated protein that plays many roles in transcriptional regulation and DNA site-specific recombination. In contrast to the naïve expectation based on stoichiometry, recent single-molecule studies have shown that the dissociation of Fis protein from DNA is accelerated by increasing the concentration of the Fis protein. Because the detailed molecular mechanism of facilitated dissociation is still not clear, in this study, we employ computational methods to explore the binding landscapes of Fis:DNA complexes with various stoichiometries. When two Fis molecules are present, simulations uncover a ternary complex, where the originally bound Fis protein is partially dissociated from DNA. The simulations support a three-state sequential kinetic model (N ⇄ I → D) for facilitated dissociation, thus explaining the concentration-dependent dissociation.


Management of Primary Dysmenorrhea among University Students in the South of Spain and Family Influence.
The present study analyses the management of primary dysmenorrhea by university students in the south of Spain. In this cross-sectional observational study, 224 women participated, using an ad hoc self-report questionnaire about menstrual pain and self-care and including sociodemographic and gynecological variables. Some 76.8% of participants consumed analgesics and the majority self-medicated with non-steroidal anti-inflammatory drugs (NSAIDs) without consulting a health professional, with a correlation between pain intensity and the number of pills ingested during menstruation (r = 0.151, p < 0.05). The higher proportion of women who found their analgesia effective were those who took medication after being prescribed by a health care provider (60.8%) compared to those who self-medicated (40%; p < 0.01). Only 43.8% employed non-pharmaceutical methods, most commonly antalgic positions, massages and local heat. These choices were not related to the intensity of menstrual pain nor with the severity of the dysmenorrhea, nor did these most common methods prove to be the most effective. However, a higher percentage of women using non-pharmacological methods was identified in women with family members suffering from dysmenorrhea (73.2%) compared to those without (60%; p = 0.040), which may indicate that the choice of remedies is more related to learning self-care in the family context. This study identifies the need for education on self-care and management of menstrual pain.


The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. European Network for Understanding Mechanisms of Severe Asthma.
Since severe asthma is a poorly understood, major health problem, 12 clinical specialist centres in nine European countries formed a European Network For Understanding Mechanisms Of Severe Asthma (ENFUMOSA). In a cross-sectional observational study, a total of 163 subjects with severe asthma were compared with 158 subjects whose asthma was controlled by low doses of inhaled corticosteroids (median dose of beclomethasone equivalents 666 microg). Despite being treated with higher doses of inhaled corticosteroids (median dose 1773 microg) and for a third of the severe asthmatics also being treated with regular, oral-steroid therapy (median daily dose 19 mg), the subjects with severe asthma met the inclusion criteria. The criteria required subjects to have undergone at least one asthma exacerbation in the past year requiring oral steroid treatment. Females dominated the severe asthma group (female/male ratio 4.4:1 versus 1.6:1 in the controlled asthmatics), and compared with controlled asthmatics, they had a predominantly neutrophilic inflammation (sputum neutrophils, 36 versus 28%) and evidence of ongoing mediator release but less atopy. From these findings and other physiological and clinical data reported in this paper, it is suggested that severe asthma might be a different form of asthma rather than an increase in asthma symptoms. The findings prompt for longitudinal studies and interventions to define the mechanisms in severe asthma.


The involvement of Smac/DIABLO, p53, NF-kB, and MAPK pathways in apoptosis of keratinocytes from perilesional vitiligo skin: Protective effects of curcumin and capsaicin.
Oxidative stress has been suggested as the initial pathogenetic event in melanocyte degeneration in vitiligo. Our previous results indicate that keratinocytes from perilesional skin show the features of damaged cells. In the present study, biopsies were taken from the perilesional skin of 12 patients suffering from nonsegmental vitiligo. The intracellular pathways involved in keratinocyte damage and apoptosis and the antioxidant protection of curcumin and capsaicin in these cells were investigated. In keratinocytes from perilesional vitiligo skin, we observed high levels of activated p38, NF-kB p65 subunit, p53, and Smac/DIABLO proteins. In contrast, low levels of ERK phosphorylation were present. To investigate the relationship between these pathways, we used specific inhibitors and evaluated the alteration of each pathway. For the first time, our study demonstrates the pivotal role of p38 MAP kinase as an upstream signal of perilesional keratinocyte damage, and the important contribution of p38 and NF-kB on p53 accumulation. Curcumin and capsaicin also increase ERK phosphorylation, thus inhibiting apoptosis. Moreover, pretreatment with such natural antioxidants inhibited caspase activation, increased total antioxidant capacity, repressed intracellular ROS generation and lipid peroxidation, and improved mitochondrial activity. These results suggest that antioxidants might represent an alternative approach to protect against vitiligo progression.


Closed kinetic chain alone compared to combined open and closed kinetic chain exercises for quadriceps strengthening after anterior cruciate ligament reconstruction with respect to return to sports: a prospective matched follow-up study.
Rehabilitation after anterior cruciate ligament (ACL) reconstruction has focused over the past decade on closed kinetic chain (CKC) exercises due to presumably less strain on the graft than with isokinetic open kinetic chain exercises (OKC); however, recent reports suggest that there are only minor differences in ACL strain values between some CKC and OKC exercises. We studied anterior knee laxity, thigh muscle torque, and return to preinjury sports level in 44 patients with unilateral ACL; group 1 carried out quadriceps strengthening only with CKC while group 2 trained with CKC plus OKC exercises starting from week 6 after surgery. Anterior knee laxity was determined with a KT-1000 arthrometer; isokinetic concentric and eccentric quadriceps and hamstring muscle torque were studied with a Kin-Com dynamometer before and 6 months after surgery. At an average of 31 months after surgery the patients answered a questionnaire regarding their current knee function and physical activity/sports to determine the extent and timing of their recovery. No significant differences in anterior knee laxity were noted between the groups 6 months postsurgery. Patients in group 2 increased their quadriceps torque significantly more than those in group 1, but no differences were found in hamstring torque between the groups. A significantly higher number of patients in group 2 (n = 12) than in group 1 (n = 5) returned to sports at the same level as before the injury (P < 0.05). Patients from group 2 who returned to sports at the same level did so 2 months earlier than those in group 1. Thus the addition of OKC quadriceps training after ACL reconstruction results in a significantly better improvement in quadriceps torque without reducing knee joint stability at 6 months and also leads to a significantly higher number of athletes returning to their previous activity earlier and at the same level as before injury.


Cryptogenic stroke: how to define it? How to treat it?
Stroke is a leading cause of disability worldwide. Cryptogenic strokes (CS) account for almost a quarter of ischemic strokes despite modern diagnostic evaluation. A working definition of CS based on stroke classification systems is essential for accurate conceptualization of this common entity. Mechanistic categories (potential paradoxical embolism; atherosclerotic disease of the aorta or supra-aortic vasculature; and occult arrhythmia) should aide in parsing the often heterogeneous mix of conditions included in the CS subtype. Despite efforts to unravel mechanisms of CS, specific or targeted recurrent stroke prevention strategies are lacking. For example, recent trials have shown no clear benefit of patent foramen ovale closure in stroke prevention after CS. There are promising ongoing clinical trials that will address appropriate diagnostic evaluations in CS as well as novel therapeutic interventions. Overall, a standardized approach must be framed to diagnose and manage patients with CS and guide clinical practice and future research.


Injuries to elite wheelchair athletes.
The purpose of this project was to describe the nature, type, and frequency of athletic injuries incurred by the elite wheelchair athlete. Nineteen athletes participated in a 1-year injury recall study at an elite wheelchair training camp. An injury was defined as anything the athlete expressed concern about and (a) caused a loss of participation due to an injury or illness or (b) an injury in which a fracture, dislocation, or subluxation occurred and the athlete was able to continue participation. There were 10 male and 9 female subjects who reported their injuries from 1 June 1987 to 31 May 1988. Fifty injuries were reported, strains and muscular injuries accounted for almost half of the injuries. Physicians were the primary care provider for 37% of the injuries, followed by physical therapists and athletic trainers at 26% and 15% respectively. Slightly over 57% of the injuries were classified as minor, missing 7 days or less of participation and 32% were classified as major, missing 22 days or more of participation. The upper extremity was the most frequently injured, followed by the lower extremity, head and spine, and illnesses. Conventional treatments of ice, heat, modalities, and medications, were the most common methods of treating these injuries. Flexibility and strength training programmes should be implemented throughout the competitive season. Careful consideration of the training programme and workout intensity should also be evaluated.


The use of psychosocial support services among Japanese breast cancer survivors.
This study aimed to investigate the use of psychosocial support services, the intention to use these services, and to elucidate the characteristics of survivors most likely to use support services among Japanese breast cancer survivors. We invited breast cancer survivors to complete an online questionnaire via an email sent to subscribers of a non-profit organization mailing list. We asked participants questions related to demographics, opinions on the state of psychosocial support services, and their interest in using these services. Participants were also asked to complete the Hospital Anxiety and Depression Scale and the Brief Cancer Worry Inventory (BCWI). We analyzed the data of 171 participants. Those who used some form of psychosocial support service constituted 50.9% of the participant population. Participants used cancer consulting and support center services (13.5%), hospital and non-hospital support groups (12.9%, respectively), psychiatry (11.1%), hospital and non-hospital cancer salons (8.8%, respectively), psychosomatic medicine (8.2%), therapist counseling (6.4%) and psycho-oncology department services (4.1%). Non-users who suffered from adjustment disorders or major depression (52.1%) reported higher total BCWI and the subscale scores had no concrete plans to use psychosocial support services. The usage levels of psychiatry, psychosomatic medicine and psycho-oncology services in our study were higher than those reported in any previous Japanese study within the psycho-oncology field. Participants joining a breast cancer survivors' mailing list, or their being female, may have led to a higher use of such services. A high degree of distress does not necessarily lead cancer survivors to seek psychosocial support services.


Does the correlation of acute cholecystitis on ultrasound and at surgery reflect a mirror image?
It remains unclear if sonography accurately describes the severity of gallstone disease. Patients were prospectively enrolled if urgent cholecystectomy was indicated. Two radiologists, blinded to operative findings, evaluated the patients' ultrasound imagings. Laparoscopic cholecystectomy was performed within 48 hours. The operative findings regarding gallbladder wall thickness and inflammation were compared to ultrasound results and histology. Fifty-five patients completed the study. Ultrasound studies exhibited a sensitivity of 60% for the diagnosis of acute cholecystitis compared to the findings at operation and 52% relative to the histologic findings. Specificity for acute cholecystitis diagnosed on ultrasound examination was 77% compared to findings at operation and 71% relative to histologic findings. The correlation coefficient of the wall thickness at ultrasound and surgery was 0.18: 0.24 for ultrasound and histology and 0.5 for surgery and histology. Ultrasound's ability to predict acute cholecystitis in patients with clinical symptoms appears limited.


The EMT Transcription Factor ZEB2 Promotes Proliferation of Primary and Metastatic Melanoma While Suppressing an Invasive, Mesenchymal-Like Phenotype.
Epithelial-to-mesenchymal transition (EMT)-inducing transcription factors (TF) are well known for their ability to induce mesenchymal states associated with increased migratory and invasive properties. Unexpectedly, nuclear expression of the EMT-TF ZEB2 in human primary melanoma has been shown to correlate with reduced invasion. We report here that ZEB2 is required for outgrowth for primary melanomas and metastases at secondary sites. Ablation of Zeb2 hampered outgrowth of primary melanomas in vivo, whereas ectopic expression enhanced proliferation and growth at both primary and secondary sites. Gain of Zeb2 expression in pulmonary-residing melanoma cells promoted the development of macroscopic lesions. In vivo fate mapping made clear that melanoma cells undergo a conversion in state where ZEB2 expression is replaced by ZEB1 expression associated with gain of an invasive phenotype. These findings suggest that reversible switching of the ZEB2/ZEB1 ratio enhances melanoma metastatic dissemination. SIGNIFICANCE: ZEB2 function exerts opposing behaviors in melanoma by promoting proliferation and expansion and conversely inhibiting invasiveness, which could be of future clinical relevance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/14/2983/F1.large.jpg.


Wearable Haptic Systems for the Fingertip and the Hand: Taxonomy, Review, and Perspectives.
In the last decade, we have witnessed a drastic change in the form factor of audio and vision technologies, from heavy and grounded machines to lightweight devices that naturally fit our bodies. However, only recently, haptic systems have started to be designed with wearability in mind. The wearability of haptic systems enables novel forms of communication, cooperation, and integration between humans and machines. Wearable haptic interfaces are capable of communicating with the human wearers during their interaction with the environment they share, in a natural and yet private way. This paper presents a taxonomy and review of wearable haptic systems for the fingertip and the hand, focusing on those systems directly addressing wearability challenges. The paper also discusses the main technological and design challenges for the development of wearable haptic interfaces, and it reports on the future perspectives of the field. Finally, the paper includes two tables summarizing the characteristics and features of the most representative wearable haptic systems for the fingertip and the hand.


[Factors modulating ageing and longevity: Linear or more complex relationships?].
It is often accepted that various factors modulate ageing and longevity in a linear way, a higher/lower level of the factor delaying ageing and/or increasing longevity. However, many examples (e.g. the effects of diet restriction or antioxidants and of telomere attrition) show that this view can be wrong. For instance, mild stress has often positive effects on ageing and longevity, and severe stress opposite effects. The dose-response relationship is thus not linear but has an inverted U-shape. Therefore, in many cases, the concept of factors modulating ageing and longevity in a linear way should be rejected, and this has consequences for physicians' guidance.


Affiliate stigma and caregiver burden in intractable epilepsy.
Intractable epilepsy can be challenging for patients and for their families. Disability rates in patients are high, causing tremendous physical and emotional burden on family caregivers. Additionally, caregivers may experience affiliate stigma, where they perceive and internalize the negative societal views of a condition and exhibit a psychological response. Affiliate stigma has been rarely studied in caregivers of those with intractable epilepsy. This study examined the relationship between affiliate stigma and the levels of burden experienced by caregivers, as well as how these levels may vary between those caring for children and adults. This cross-sectional approach used a self-administered survey offered to caregivers of family members with confirmed diagnoses of intractable epilepsy. We measured burden with the 30-item Carer's Assessment of Difficulties Index (CADI) and affiliate stigma with a six-item scale examining caregivers' perceptions of stigma directed toward themselves and their family members with epilepsy. Four nested ordinary-least-squares regression models were estimated using stigma scale scores to predict levels of perceived burden adjusting for demographic variables. Age of the patient with epilepsy was dichotomized (pediatric/adult) to assess a possible moderating effect of patient's age on the relationship between stigma and caregiver burden. Respondents (N = 136) were predominantly White (83%), female (75%), and married (69%), with an average age of 43 years. Patients with epilepsy were 52% male with ages ranging from 2 to 82 years. Each of the regression models yielded positive associations (p < 0.001) between perceived levels of caregiver burden and affiliate stigma. Additionally, the age of the family member with epilepsy moderated (p < 0.05) the effect, with the relationship stronger for caregivers of adults. In a highly select group of patients with refractory epilepsy recruited mostly from a cannabidiol (CBD) clinic, this study demonstrated that caregivers experience affiliate stigma, which is significantly associated with higher burden levels. Additionally, this study identified specific needs, which when met, may improve caregivers' physical and mental health.


Simian immunodeficiency virus infection of macaque bone marrow macrophages correlates with disease progression in vivo.
The pathogenesis of hematopoietic abnormalities associated with infection of susceptible hosts with either simian immunodeficiency virus (SIV) or human immunodeficiency virus (HIV) is not fully understood. To determine if bone marrow cells are infected with SIV and if the pattern of viral infection is correlated with the severity of disease and abnormalities in hematopoiesis, 23 SIV-infected rhesus monkeys were examined by immunohistochemistry and in situ hybridization. By immunohistochemistry, only four monkeys were positive for SIV core protein p27, while in situ hybridization revealed viral RNA in the bone marrow of 15 monkeys. Simian immunodeficiency virus RNA was consistently expressed in the bone marrow from monkeys with severe lymphoid depletion (11 of 11), but less so in monkeys with follicular hyperplasia (0 of 2) or mild lymphoid depletion (4 of 10). In animals with mild lymphoid depletion, bone marrow cells infected with SIV were mainly mononuclear cells that appeared to be of myelomonocytic lineage. In contrast, monkeys with severe lymphoid depletion had SIV RNA localized to larger mononuclear cells with abundant cytoplasm often located in small lucent areas of the stroma. These SIV RNA-positive mononuclear cells were positive for the macrophage determinant CD68 as demonstrated by immunohistochemistry. Furthermore the stage of simian acquired immune deficiency syndrome, as indicated by lymphoid morphology, and SIV localization in the bone marrow were correlated with the incidence of anemia, bone marrow hyperplasia, and abnormal distribution of macrophages in the bone marrow. These results indicate that, in common with other animal lentiviral infections, the macrophage is a major target of SIV infections in the bone marrow.


Recycling manure as cow bedding: Potential benefits and risks for UK dairy farms.
Material obtained from physical separation of slurry (recycled manure solids; RMS) has been used as bedding for dairy cows in dry climates in the US since the 1970s. Relatively recently, the technical ability to produce drier material has led to adoption of the practice in Europe under different climatic conditions. This review collates the evidence available on benefits and risks of using RMS bedding on dairy farms, with a European context in mind. There was less evidence than expected for anecdotal claims of improved cow comfort. Among animal health risks, only udder health has received appreciable attention. There are some circumstantial reports of difficulties of maintaining udder health on RMS, but no large scale or long term studies of effects on clinical and subclinical mastitis have been published. Existing reports do not give consistent evidence of inevitable problems, nor is there any information on clinical implications for other diseases. The scientific basis for guidelines on management of RMS bedding is limited. Decisions on optimum treatment and management may present conflicts between controls of different groups of organisms. There is no information on the influence that such 'recycling' of manure may have on pathogen virulence. The possibility of influence on genetic material conveying antimicrobial resistance is a concern, but little understood. Should UK or other non-US farmers adopt RMS, they are advised to do so with caution, apply the required strategies for risk mitigation, maintain strict hygiene of bed management and milking practices and closely monitor the effects on herd health.


The beneficial effects of Tai Chi Chuan on blood pressure and lipid profile and anxiety status in a randomized controlled trial.
To evaluate the effects on blood pressure, lipid profile, and anxiety status on subjects received a 12-week Tai Chi Chuan exercise program. Randomized controlled study of a Tai Chi Chuan group and a group of sedentary life controls. Taipei Medical University Hospitals and University campus in the Taipei, Taiwan, area. Two (2) selected groups of 76 healthy subjects with blood pressure at high-normal or stage I hypertension. A 12-week Tai Chi Chuan exercise training program was practiced regularly with a frequency of 3 times per week. Each session included 10-minute warm-up, 30-minute Tai Chi exercise, 10-minute cool-down. Exercise intensity was estimated to be approximately 64% of maximal heart rate. Blood pressure, lipid profile and anxiety status (State-Trait Anxiety Inventory; STAI) were evaluated. After 12-weeks of Tai Chi training, the treatment group showed significant decrease in systolic blood pressure of 15.6 mm Hg and diastolic blood pressure 8.8 mm Hg. The serum total cholesterol level decreased 15.2 mg/dL and high-density lipoprotein cholesterol increased 4.7 mg/dL. By using STAI evaluation, both trait anxiety and state anxiety were decreased. This study shows that under well-designed conditions, Tai Chi exercise training could decrease blood pressure and results in favorable lipid profile changes and improve subjects' anxiety status. Therefore, Tai Chi could be used as an alternative modality in treating patients with mild hypertension, with a promising economic effect.


Analysis of NK cell activity, lymphocyte reactivity to mitogens and serotest PSA and TPS values in patients with primary and disseminated prostate cancer, PIN and BPH.
In a total of 59 prostate cancer (PCa) patients, 9 patients with PIN. 29 subjects with BPH and 26 healthy men serum TPS and PSA values were measured together with NK cell activity, number and proportion of CD16+ cells, and reactivity of lymphocytes to mitogens (Con A. PHA and PWM). NK activity data indicate highly significant differences between both of patients with local tumor and those with disseminated disease (P < 0.01) and b) responders and nonresponding patients to hormonal therapy (P < 0.01). The number and proportion of CD16+ cells is lowest in BPH patients in comparison with controls and PCa patients. Since benign enlargement is attributed mainly to stromal cell proliferation in the absence of cell death in this compartment, gene expressions which control these events may participate in the surprisingly low CD16+ cell proportion. The reactivity of lymphocytes to mitogens (PHA. Con A and PWM) showed lower numerical values in all categories of PCa and BPH patients when compared with healthy men. The reactivity of T and B lymphocytes reported herein as immunological responses to mitogens (PHA. Con A and PWM) was performed 4-6 months after the beginning of therapy. Our data fit in well with those previously reported. Numerically lowest respective reactivity parameters to all mitogens were assessed in PIN subjects. Reported results show the specific significance of the changes in NK cell activity in regard with both metastatic extention of PCa and tumor response to therapy. These alterations match in their reliability changes with tumor marker values related to prostate cancer activity (TPS) and tumor differentiation (PSA). Lymphocyte reactivity to mitogens (Con A. PHA. PWM) may help in a subclinical discrimination between BPH and PIN patients that is still an important goal of clinical urology.


Ionic liquids as modulators of physicochemical properties and nanostructures of sodium dodecyl sulfate in aqueous solutions and potential application in pesticide microemulsions.
Emulsifiers for pesticide microemulsions contain a part of volatile organic compounds (VOCs), and ionic liquids (ILs) are becoming potential substitutes. In order to apply ILs in pesticide microemulsions, the study of interaction between ILs and surfactants is necessary. Therefore, the surface properties and aggregation of anionic surfactant sodium dodecyl sulfate (SDS) in ILs, including N-hexyl-N-methylmorpholinyl bromide ([C6mm][Br]), N-hexyl-N-methylpiperidyl bromide ([C6mp][Br]), N-hexyl-N-methylpyrrolidyl bromide ([C6mpyr][Br]), N-octyl-N-methylpyrrolidyl bromide ([C8mpyr][Br]), N-dodecyl-N-methylpyrrolidyl bromide ([C12mpyr][Br]) and N-hexadecyl-N-methylpyrrolidyl bromide ([C16mpyr][Br]), were investigated in terms of surface tension, conductivity, dynamic light scattering (DLS), viscosity, fluorescence, pseudo-ternary phase diagram and 1H NMR measurements. Generally in agreement, the methods afforded the evaluation of various micellar parameters such as critical micelle concentration (CMC), degree of counterion ionization (α), the maximum surface excess concentration (Γmax), the minimum area per surfactant headgroup (Amin) as well as some thermodynamic parameters, including standard free energy of micellization (ΔG), standard enthalpy of micellization (ΔH) and standard entropy of micellization (ΔS). The results indicated a hydrophobic effect as the primary force of a spontaneous, exothermic, entropy driven micellization process. 1H NMR technique was applied to reveal the solubilization site and interaction of ILs in aqueous SDS micellar solutions. Fluorescence, DLS and viscosity measurements revealed considerable micellar morphologies and various phase behaviors. Furthermore, the 10% difenoconazole microemulsion was successfully prepared and showed good stability and spreadability in mixtures which indicated ILs' potential application in pesticide formulation.


Evidence incriminating midges (Diptera: Ceratopogonidae) as potential vectors of Leishmania in Australia.
The first autochthonous Leishmania infection in Australia was reported by Rose et al. (2004) and the parasite was characterised as a unique species. The host was the red kangaroo (Macropus rufus) but the transmitting vector was unknown. To incriminate the biological vector, insect trapping by a variety of methods was undertaken at two field sites of known Leishmania transmission. Collected sand flies were identified to species level and were screened for Leishmania DNA using a semi-quantitative real-time PCR. Collections revealed four species of sand fly, with a predominance of the reptile biter Sergentomyia queenslandi (Hill). However, no Leishmania-positive flies were detected. Therefore, alternative vectors were investigated for infection, giving startling results. Screening revealed that an undescribed species of day-feeding midge, subgenus Forcipomyia (Lasiohelea) Kieffer, had a prevalence of up to 15% for Leishmania DNA, with high parasitemia in some individuals. Manual gut dissections confirmed the presence of promastigotes and in some midges material similar to promastigote secretory gel, including parasites with metacyclic-like morphology. Parasites were cultured from infected midges and sequence analysis of the Leishmania RNA polymerase subunit II gene confirmed infections were identical to the original isolated Leishmania sp. Phylogenetic analysis revealed the closest known species to be Leishmania enriettii, with this and the Australian species confirmed as members of Leishmania sensu stricto. Collectively the results strongly suggest that the day-feeding midge (F. (Lasiohelea) sp. 1) is a potential biological vector of Leishmania in northern Australia, which is to our knowledge the first evidence of a vector other than a phlebotomine sand fly anywhere in the world. These findings have considerable implications in the understanding of the Leishmania life cycle worldwide.


Calreticulin binds hYRNA and the 52-kDa polypeptide component of the Ro/SS-A ribonucleoprotein autoantigen.
Calreticulin (CR) is a multifunctional, calcium-binding protein that has recently been shown to bind to and promote the replication of the rubella virus genome in mammalian cells. While CR is now widely recognized as a new human autoantigen, the relationship between CR and the Ro/SS-A ribonucleo-protein (RNP) autoantigen has been somewhat controversial. In this work, we demonstrate that unphosphorylated human rCR binds specifically and distinctly to in vitro transcribed forms of hYRNA, the RNA backbone of the Ro/SS-A RNP particle. This interaction appears to be mediated by binding through the N- and C-terminal domains of CR, but not by the central proline-rich domain. Furthermore, our studies indicate that CR can facilitate the binding of the 60-kDa polypeptide component of the Ro/SS-A RNP (Ro60) to hYRNA. In addition, CR and the 52-kDa Ro/SS-A polypeptide (Ro52) appear to be capable of interacting through direct protein-protein binding. These studies confirm that CR is an hYRNA-binding protein, and provide for the first time a molecular mechanism by which Ro52 can be linked physically to hYRNA. Through these molecular interactions and its known functional role as a chaperone, it is suggested that CR plays a supportive role in the formation of the Ro/SS-A RNP complex. The capacity of CR to interact with RNA viruses such as rubella provides an additional argument for an infectious trigger for autoantibody production against self RNP particles such as Ro/SS-A.


Types of indwelling urethral catheters for short-term catheterisation in hospitalised adults.
Urinary tract infection (UTI) is the most common hospital-acquired infection. The major associated cause is indwelling urethral catheters. Several measures have been introduced to reduce catheter-associated urinary tract infections (CAUTIs). One of these measures is the introduction of specialised urethral catheters that have been designed to reduce the risk of infection. These include antiseptic-coated and antimicrobial-impregnated catheters. The primary objective of this review was to compare the effectiveness of different types of indwelling urethral catheters in reducing the risk of UTI and to assess their impact on other outcomes in adults who require short-term urethral catheterisation in hospitals. We searched the Cochrane Incontinence Group's Specialised Trials Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE in process, ClinicalTrials.gov, WHO ICTRP and handsearching of journals and conference proceedings (searched 9 September 2014). We also examined the bibliographies of relevant articles and contacted catheter manufacturer representatives for trials. We included all randomised controlled trials (RCTs) and quasi-RCTs comparing types of indwelling urethral catheters for short-term catheterisation in hospitalised adults. 'Short-term' is defined as a duration of catheterisation which is intended to be less than or equal to 14 days. At least two review authors independently screened abstracts, extracted data and assessed risk of bias of the included trials. Any disagreement was resolved by discussion or consultation with a third party. We processed data as described in the Cochrane Handbook for Systematic Reviews of Interventions. We assessed the quality of evidence using the GRADE approach. Twenty-six trials met the inclusion criteria involving 12,422 hospitalised adults in 25 parallel group trials, and 27,878 adults in one large cluster-randomised cross-over trial. No trials compared one antiseptic catheter versus another, nor an antimicrobial catheter versus another. Antiseptic-coated indwelling urethral catheters versus standard indwelling urethral cathetersThe primary outcome, symptomatic CAUTI was reported in one large trial with a low risk of bias, comparing silver alloy hydrogel-coated latex catheter (antiseptic-coated) against a standard polytetrafluoroethylene (PTFE)-coated latex catheter (control). The trial used a pragmatic, US Centers for Disease Control and Prevention (CDC)-based definition for symptomatic CAUTI. For the comparison between silver alloy-coated catheter versus standard catheter, there was no significant difference in symptomatic CAUTI incidence (RR 0.99, 95% CI 0.85 to 1.16).For secondary outcomes, the included trials reported on two types of antiseptic catheters (coated with either silver oxide or silver alloy). For the outcome of bacteriuria, silver oxide catheters were not associated with any statistically significant reduction (RR 0.90, 95% CI 0.72 to 1.13). These catheters are no longer manufactured. Silver alloy catheters achieved a slight but statistically significant reduction in bacteriuria (RR 0.82, 95% CI 0.73 to 0.92). However, the one large trial with a low risk of bias did not support this finding (RR 0.99, 95% CI 0.85 to 1.16). The randomised cross-over trial of silver alloy catheters versus standard catheters was excluded from the pooled results because data were not available prior to crossover. The results of this trial showed less bacteriuria in the silver alloy catheter group.For the outcome of discomfort whilst the catheter was in-situ, fewer patients with silver alloy catheters complained of discomfort compared with standard catheters (RR 0.84, 95% CI 0.74 to 0.96). Antimicrobial-impregnated indwelling urethral catheters versus standard indwelling urethral cathetersThe primary outcome measure, symptomatic CAUTI was reported in one large trial with a low risk of bias, comparing nitrofurazone-impregnated silicone catheter (antimicrobial-impregnated) against a standard PTFE-coated latex catheter (control). The nitrofurazone catheter achieved a reduction in symptomatic CAUTI incidence which was of borderline statistical significance (RR 0.84, 95% CI 0.71 to 0.99).For secondary outcomes, the included trials reported on two types of antimicrobial catheters (impregnated with either nitrofurazone or minocycline/rifampicin). Antimicrobial-impregnated catheters, compared with standard catheters, were found to lower the rate of bacteriuria in the antimicrobial group for both minocycline and rifampicin (RR 0.36, 95% CI 0.18 to 0.73), and nitrofurazone (RR 0.73, 95% CI 0.64 to 0.85). The minocycline and rifampicin catheter is no longer manufactured.For the outcome of discomfort whilst the catheter was in-situ, more patients with nitrofurazone catheters complained of pain whilst the catheter was in-situ compared with standard catheters (RR 1.26, 95% CI 1.12 to 1.41). For the period after catheter removal, more patients with nitrofurazone catheters complained of pain than standard catheters (RR 1.43, 95% CI 1.30 to 1.57). Antimicrobial-impregnated indwelling urethral catheters versus antiseptic-coated indwelling urethral cathetersOne large trial compared antimicrobial-impregnated (nitrofurazone) catheters versus silver alloy-coated (antiseptic-coated) catheters. The results showed people were less likely to have a symptomatic CAUTI with nitrofurazone-impregnated catheters (228/2153, 10.6%) compared with silver alloy-coated catheters (263/2097, 12.5%), but this was of borderline statistical significance (RR 0.84, 95% CI 0.71 to 1.00). They did, however, have significantly less bacteriuria (RR 0.78, 95% CI 0.67 to 0.91),While the catheter was in-situ (RR 1.50, 95% CI 1.32 to 1.70), and on removal (RR 1.32, 95% CI 1.20 to 1.45), nitrofurazone catheters were associated with more discomfort compared with silver-coated catheters. One type of standard indwelling urethral catheter versus another type of standard indwelling urethral catheterNone of the trials comparing standard catheters versus other types of standard catheters measured symptomatic CAUTI. In terms of reducing bacteriuria, individual trials were too small to show whether one type of standard catheter was superior to another type. For the outcome of urethral reactions, fully siliconised catheters appeared to be superior to latex-based catheters. However, the trials involved small numbers of participants. There were no statistically significant differences between the different catheters for all other outcomes. Silver alloy-coated catheters were not associated with a statistically significant reduction in symptomatic CAUTI, and are considerably more expensive. Nitrofurazone-impregnated catheters reduced the risk of symptomatic CAUTI and bacteriuria, although the magnitude of reduction was low and hence may not be clinically important. However, they are more expensive than standard catheters. They are also more likely to cause discomfort than standard catheters.


Salt-inducible kinases (SIKs) regulate TGFβ-mediated transcriptional and apoptotic responses.
The signalling pathways initiated by members of the transforming growth factor-β (TGFβ) family of cytokines control many metazoan cellular processes, including proliferation and differentiation, epithelial-mesenchymal transition (EMT) and apoptosis. TGFβ signalling is therefore strictly regulated to ensure appropriate context-dependent physiological responses. In an attempt to identify novel regulatory components of the TGFβ signalling pathway, we performed a pharmacological screen by using a cell line engineered to report the endogenous transcription of the TGFβ-responsive target gene PAI-1. The screen revealed that small molecule inhibitors of salt-inducible kinases (SIKs) attenuate TGFβ-mediated transcription of PAI-1 without affecting receptor-mediated SMAD phosphorylation, SMAD complex formation or nuclear translocation. We provide evidence that genetic inactivation of SIK isoforms also attenuates TGFβ-dependent transcriptional responses. Pharmacological inhibition of SIKs by using multiple small-molecule inhibitors potentiated apoptotic cell death induced by TGFβ stimulation. Our data therefore provide evidence for a novel function of SIKs in modulating TGFβ-mediated transcriptional and cellular responses.


Developing scales measuring disorder-specific intolerance of uncertainty (DSIU): a new perspective on transdiagnostic.
Intolerance of uncertainty (IU) is a construct of growing prominence in literature on anxiety disorders and major depressive disorder. Existing measures of IU do not define the uncertainty that respondents perceive as distressing. To address this limitation, we developed eight scales measuring disorder-specific intolerance of uncertainty (DSIU) relating to various anxiety disorders and major depressive disorder. We used exploratory factor analysis and item characteristic curves in two large undergraduate samples (Ns=627 and 628) to derive eight three-item DSIU scales (24 items total) that exhibited excellent psychometric properties. Confirmatory factor analysis supported the factor structures of the scales and the transdiagnostic nature of IU. Each scale predicted unique variance in its respective symptom measure beyond a traditional measure of IU. DSIU represents a theoretically proximal and causal intermediary between known vulnerability factors and disorder symptomatology. The DSIU scales can be used to advance theories of psychopathology and inform case conceptualization and treatment planning.