A role for glia in the progression of Rett's syndrome.
Rett's syndrome (RTT) is an X-chromosome-linked autism spectrum disorder caused by loss of function of the transcription factor methyl-CpG-binding protein 2 (MeCP2). Although MeCP2 is expressed in most tissues, loss of MeCP2 expression results primarily in neurological symptoms. Earlier studies suggested the idea that RTT is due exclusively to loss of MeCP2 function in neurons. Although defective neurons clearly underlie the aberrant behaviours, we and others showed recently that the loss of MECP2 from glia negatively influences neurons in a non-cell-autonomous fashion. Here we show that in globally MeCP2-deficient mice, re-expression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern, and greatly prolonged lifespan compared to globally null mice. Furthermore, restoration of MeCP2 in the mutant astrocytes exerted a non-cell-autonomous positive effect on mutant neurons in vivo, restoring normal dendritic morphology and increasing levels of the excitatory glutamate transporter VGLUT1. Our study shows that glia, like neurons, are integral components of the neuropathology of RTT, and supports the targeting of glia as a strategy for improving the associated symptoms.


Large-scale STI services in Avahan improve utilization and treatment seeking behaviour amongst high-risk groups in India: an analysis of clinical records from six states.
Avahan, the India AIDS Initiative, implemented a large HIV prevention programme across six high HIV prevalence states amongst high risk groups consisting of female sex workers, high risk men who have sex with men, transgenders and injecting drug users in India. Utilization of the clinical services, health seeking behaviour and trends in syndromic diagnosis of sexually transmitted infections amongst these populations were measured using the individual tracking data. The Avahan clinical monitoring system included individual tracking data pertaining to clinical services amongst high risk groups. All clinic visits were recorded in the routine clinical monitoring system using unique identification numbers at the NGO-level. Visits by individual clinic attendees were tracked from January 2005 to December 2009. An analysis examining the limited variables over time, stratified by risk group, was performed. A total of 431,434 individuals including 331,533 female sex workers, 10,280 injecting drug users, 82,293 men who have sex with men, and 7,328 transgenders visited the clinics with a total of 2,700,192 visits. Individuals made an average of 6.2 visits to the clinics during the study period. The number of visits per person increased annually from 1.2 in 2005 to 8.3 in 2009. The proportion of attendees visiting clinics more than four times a year increased from 4% in 2005 to 26% in 2009 (p<0.001). The proportion of STI syndromes diagnosed amongst female sex workers decreased from 39% in 2005 to 11% in 2009 (p<0.001) while the proportion of STI syndromes diagnosed amongst high risk men who have sex with men decreased from 12% to 3 % (p<0.001). The proportion of attendees seeking regular STI check-ups increased from 12% to 48% (p<0.001). The proportion of high risk groups accessing clinics within two days of onset of STI-related symptoms and acceptability of speculum and proctoscope examination increased significantly during the programme implementation period. The programme demonstrated that acceptable and accessible services with marginalised and often difficult-to-reach populations can be brought to a very large scale using standardized approaches. Utilization of these services can dramatically improve health seeking behaviour and reduce STI prevalence.


Guiding the osteogenic fate of mouse and human mesenchymal stem cells through feedback system control.
Stem cell-based disease modeling presents unique opportunities for mechanistic elucidation and therapeutic targeting. The stable induction of fate-specific differentiation is an essential prerequisite for stem cell-based strategy. Bone morphogenetic protein 2 (BMP-2) initiates receptor-regulated Smad phosphorylation, leading to the osteogenic differentiation of mesenchymal stromal/stem cells (MSC) in vitro; however, it requires supra-physiological concentrations, presenting a bottleneck problem for large-scale drug screening. Here, we report the use of a double-objective feedback system control (FSC) with a differential evolution (DE) algorithm to identify osteogenic cocktails of extrinsic factors. Cocktails containing significantly reduced doses of BMP-2 in combination with physiologically relevant doses of dexamethasone, ascorbic acid, beta-glycerophosphate, heparin, retinoic acid and vitamin D achieved accelerated in vitro mineralization of mouse and human MSC. These results provide insight into constructive approaches of FSC to determine the applicable functional and physiological environment for MSC in disease modeling, drug screening and tissue engineering.


Epidemiology of human immunodeficiency virus infection in Central Americans treated in Harris County, Texas Hospital District facilities.
The prevalence of human immunodeficiency virus (HIV) infection among Central Americans is increasing. The purpose of this study was to describe the epidemiology of HIV infection among local Central American immigrants in the United States. Medical records of HIV-infected Central Americans treated at Harris County Hospital District (HCHD) facilities, the major source of indigent care in Houston, Texas, were retrospectively reviewed. Between January 1, 1990 and February 28, 1995, 18,156 Central Americans were seen at HCHD facilities, of whom 56 (13 females and 43 males) were identified as HIV-infected (0.3% versus 1.3% of all locally treated patients; P < 0.001, by test of binomial proportions). Most were from Honduras (n = 25) or El Salvador (n = 23). The mean age was 28.7 years, the mean CD4+ lymphocyte count at presentation was 173 cells/mm3, and 36 (64%) had acquired immunodeficiency syndrome (AIDS) at presentation. The 13 women (23% versus 22% for all locally treated HIV patients) were disproportionately Honduran (10 of 25 Hondurans versus 3 of 31 other Central Americans; P = 0.011). The HIV risk factors included heterosexuality in 46%, homosexuality in 29%. and a history of injection drug use in 7% (versus 10%, 57%, and 34%, respectively, for all locally treated HIV patients). The 76 diagnosed opportunistic infections (OIs) included a disproportionately greater number of patients with tuberculosis (n = 14, 33% versus 6% of all locally treated AIDS patients), toxoplasmosis (n = 10, 24% versus 7%), and cryptococcal meningitis (n = 9, 21% versus 7%), and a lower number of patients with pneumocystosis (n = 12, 29% versus 43%) and candida esophagitis (n = 2, 5% versus 16%). Central American immigrants infected with HIV present with relatively advanced disease, and the most frequent OIs are diseases for which effective prophylaxis exists. Targeted HIV screening and early intervention in this group are warranted.


Testosterone and explosive aggression in autism spectrum disorders.
Autism spectrum disorders (ASD) are a set of heterogeneous neurodevelopmental conditions, characterized by early-onset difficulties in social communication and unusually restricted, repetitive behavior and interests. Children with ASD have a high rate of irritability and aggressive symptoms which have significant impact on their lives, families and society. The etiology of aggression in humans is likely complex and includes both biological and behavioral causes. Biological approaches have focused on hormones and neurotransmitters that are hypothesized to contribute to the etiology and clinical manifestation of aggressive behavior in humans. Testosterone is a male sex hormone and some studies suggest that it can play a role in the complex etiology of aggressive behavior. Two specific subtypes of aggression have been identified: explosive and non-explosive. Explosive aggression is accompanied by a raged affect and is usually more dangerous and not immediately responsive to behavioral treatment. In our review we would like to provide current findings and discuss potential limitation of research in this area. We propose to determine bio-behavioral model of explosive aggression in children with ASD which will predict which children will be most responsive to potential antiandrogen therapy and behavioral therapy.


Effect of prior receipt of antibiotics on the pathogen distribution and antibiotic resistance profile of key Gram-negative pathogens among patients with hospital-onset urinary tract infections.
This retrospective cohort study characterized the impact of prior antibiotic exposure on distribution and nonsusceptibility profiles of Gram-negative pathogens causing hospital-onset urinary tract infections (UTI). Hospital patients with positive urine culture for Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and other Enterobacteriaceae ≥3 days after hospital admission were included. Assessment outcomes included the distribution of bacteria in urine cultures, antibiotic susceptibility patterns, and the effect of prior antibiotic exposure, defined as 0, 1, or ≥2 prior antibiotics, on the distribution and antibiotic susceptibility profiles of the Gram-negative organisms. The most commonly isolated pathogens from 5574 unique UTI episodes (2027 with and 3547 without prior antibiotic exposure) were E. coli (49.5%), K. pneumoniae (17.1%), and P. aeruginosa (8.2%). P. aeruginosa was significantly more commonly isolated in patients with ≥2 prior antibiotic exposures (12.6%) compared with no exposure (8.2%; p = 0.036) or 1 prior exposure (7.9%; p = 0.025). Two or more prior antibiotic exposures were associated with slightly higher incidences of fluoroquinolone nonsusceptibility, multidrug resistance, and extended-spectrum β-lactamase phenotype compared with 0 or 1 exposure, suggesting an increased risk for resistant Gram-negative pathogens among hospital patients with urinary tract infections occurring ≥3 days after admission. Clinicians should critically assess prior antibiotic exposure when selecting empirical therapy for patients with hospital-onset urinary tract infections caused by Gram-negative pathogens.


Recovery, responsiveness and interpretability of patient-reported outcome measures after surgery for Dupuytren's disease.
This prospective cohort study investigated the responsiveness and interpretability of the Disabilities of the Arm, Shoulder and Hand (DASH) and Unité Rhumatologique des Affections de la Main (URAM) outcome measures for assessing recovery after fasciectomy and dermofasciectomy for Dupuytren's disease. DASH outcome scores at 1 year were significantly better than at 6 weeks, suggesting that recovery is not complete by 6 weeks. Of the 101 patients recruited to the DASH cohort, 71 completed preoperative, 6 week and 1 year postoperative DASH scores; 68 of them completed preoperative and 1 year postoperative DASH scores and an external anchor question. In the URAM cohort, 30/44 completed the preoperative and the 1 year postoperative URAM scores and the anchor question. The DASH score exhibited moderate responsiveness but poor interpretability on receiver operating characteristic curve analysis, such that a minimal important change could not be estimated. The URAM score showed acceptable responsiveness, and an MIC of 10.5 on receiver operating characteristic analysis. II.


The effects of a supervised toothbrushing programme on the caries increment of primary school children, initially aged 5-6 years.
Children in the London Boroughs of Kensington, Chelsea and Westminster have one of the highest levels of caries in England and Wales. In 1997/98, the mean dmft for 5-year-old children was 2.83 with only 45.9% of the children being caries free. The aim of this study was to determine whether teacher-supervised toothbrushing, once a day, at school, during term time, with commercial toothpaste containing 1,450 ppm fluoride, could reduce dental caries in primary school children when compared with children from the same community who did not receive this intervention. A total of 517 children (mean age 5.63 years) were recruited for the study. Class teachers were trained individually by the same dental hygienist in an appropriate toothbrushing technique for young children. Children in the intervention group brushed once a day at school. All examinations were by visual assessment only. All teeth present were assessed using the BASCD criteria. For children in the intervention group, the overall caries increment (2.60) was significantly less (10.9%; p < 0.001) than for children in the non-intervention group (2.92). Among different tooth surfaces, the difference in caries increment between the intervention group (0.78) and the non-intervention group (1.03) was greatest for the proximal surfaces (21.4%; p < 0.01). In conclusion, this study suggests that a programme of daily teacher-supervised toothbrushing with fluoride toothpaste can be effectively targeted into socially deprived communities and a significant reduction in dental caries can thereby be achieved especially among caries-susceptible children.


Defining the methodological challenges and opportunities for an effective science of sociotechnical systems and safety.
An important part of the application of sociotechnical systems theory (STS) is the development of methods, tools and techniques to assess human factors and ergonomics workplace requirements. We focus in this paper on describing and evaluating current STS methods for workplace safety, as well as outlining a set of six case studies covering the application of these methods to a range of safety contexts. We also describe an evaluation of the methods in terms of ratings of their ability to address a set of theoretical and practical questions (e.g. the degree to which methods capture static/dynamic aspects of tasks and interactions between system levels). The outcomes from the evaluation highlight a set of gaps relating to the coverage and applicability of current methods for STS and safety (e.g. coverage of external influences on system functioning; method usability). The final sections of the paper describe a set of future challenges, as well as some practical suggestions for tackling these. We provide an up-to-date review of STS methods, a set of case studies illustrating their use and an evaluation of their strengths and weaknesses. The paper concludes with a 'roadmap' for future work.


Antioxidant and immuno-enhancing effects of Echinacea purpurea.
We studied the protective effects of Echinacea purpurea against radiation by evaluating changes in the peripheral blood cell count and peripheral blood antioxidant activity. E. purpurea administration had a suppressive effect on radiation-induced leukopenia, especially on lymphocytes and monocytes, and resulted in a faster recovery of blood cell counts. Mouse peripheral blood antioxidant activity was increased by E. purpurea, and a relationship between the suppressive effect on radiation-induced leukopenia and the antioxidant effect was suggested. Furthermore, we reviewed the evidence of augmentation of found in this study humoral immunity. The effects of immune activation by E. purpurea were investigated by measuring total immunoglobulin (IgG, IgM). The radioprotective effects of immune activation by E. purpurea were investigated by measuring T lymphocyte subsets in the peripheral blood of mice following whole-body irradiation. E. purpurea activates macrophages to stimulate IFN-gamma production in association with the secondary activation of T lymphocytes, resulting in a decrease in IgG and IgM production. Cytokines released from macrophages in mouse peripheral blood after E. purpurea administration activated helper T cells to proliferate. In addition, it is reported that activated macrophages in association with the secondary T lymphocyte activation increases IFN-gamma production and stimulates proliferation of cytotoxic T cells and suppressor T cells. We think that CD 4 and CD 8 subsets were more immunologically enhanced by E. purpurea than helper T cells and suppressor T cell these results reflect activation. In addition, we think that these results reflect cell-mediated immune responses.


The neural correlates of impaired inhibitory control in anxiety.
According to Attentional Control Theory (Eysenck et al., 2007) anxiety impairs the inhibition function of working memory by increasing the influence of stimulus-driven processes over efficient top-down control. We investigated the neural correlates of impaired inhibitory control in anxiety using an antisaccade task. Low- and high-anxious participants performed anti- and prosaccade tasks and electrophysiological activity was recorded. Consistent with previous research high-anxious individuals had longer antisaccade latencies in response to the to-be-inhibited target, compared with low-anxious individuals. Central to our predictions, high-anxious individuals showed lower ERP activity, at frontocentral and central recording sites, than low anxious individuals, in the period immediately prior to onset of the to-be-inhibited target on correct antisaccade trials. Our findings indicate that anxiety interferes with the efficient recruitment of top-down mechanisms required for the suppression of prepotent responses. Implications are discussed within current models of attentional control in anxiety (Bishop, 2009; Eysenck et al., 2007).


Impacts on practitioners of using research-based carer assessment tools: experiences from the UK, Canada and Sweden, with insights from Australia.
Researchers and practitioners in several Western countries have recently developed tools for assessing the situation of the carers of adults who are ill, elderly or have disabilities. The present article describes the impact of three such assessment tools, from Canada, the UK and Sweden, on the professional practice of assessors. All tools were tested in agency-based studies. Focus groups, workshops and interviews with assessors were employed to understand the impact on professionals and their practice. An Australian researcher and case manager comments on these experiences from her unique perspective. The results reveal that the use of carer assessments can lead to changes in the appropriateness of intervention by informing practitioners of issues which are given little attention, but which impact on the adequacy of interventions to the service user. Across the projects, most workers found that the tools facilitated a more comprehensive, in-depth and carer-focused assessment. Experience across all the projects suggests that, used sensitively, such tools and approaches can play a key role in transforming the relationship between carers, and the health and social care system. Giving carers a legitimate voice, acknowledging their perspective and expertise, and making them central to assessment processes accords them status both as active partners, and as individuals with their own needs and aspirations, rather than seeing them primarily as resources. As a result of their experiences, many workers and administrators concluded that home-care programmes must change their mandate to include carers among their clients, raising the issue of available monetary and human resources to meet the needs of this group. In addition, as our Australian colleague points out, time, efficiency, relevance, benefit and minimal intrusiveness are important factors for practitioners which influence their use of assessment tools.


RFID analysis of the complexity of cellular pathology workflow-An opportunity for digital pathology.
Digital pathology (DP) offers potential for time efficiency gains over an analog workflow however, to date, evidence supporting this claim is relatively lacking. Studies available concentrate on specific workflow points such as diagnostic reporting time, rather than overall efficiencies in slide logistics that might be expected. This is in part a result of the complexity and variation in analog working, and the challenge therefore in capturing this. We have utilized RFID technology to conduct a novel study capturing the movement of diagnostic cases within the analog pathway in a large teaching hospital setting, thus providing benchmark data for potential efficiency gains with DP. This technology overcomes the need to manually record data items and has facilitated the capture of both the physical journey of a case and the time associated with relevant components of the analog pathway predicted to be redundant in the digital setting. RFID tracking of 1,173 surgical pathology cases and over 30 staff in an analog cellular pathology workflow illustrates the complexity of the physical movement of slides within the department, which impacts on case traceability within the system. Detailed analysis of over 400 case journeys highlights redundant periods created by batching of slides at workflow points, including potentially 2-3 h for a case to become available for reporting after release from the lab, and variable lag-times prior to collection for reporting, and provides an illustration of patterns of lab and pathologist working within the analog setting. This study supports the challenge in evidencing efficiency gains to be anticipated with DP in the context of the variation and complexity of the analog pathway, but also evidences the efficiency gains that may be expected through a greater understanding of patterns of working and movement of cases. Such data may benefit other departments building a business case for DP.


Crisis discharges and readmission risk in acute psychiatric male inpatients.
Severe pressures on beds in psychiatric services have led to the implementation of an early ("crisis") discharge policy in the Western Cape, South Africa. The study examined the effect of this policy and length of hospital stay (LOS) on readmission rates in one psychiatric hospital in South Africa. Discharge summaries of adult male patients (n = 438) admitted to Stikland Psychiatric Hospital during 2004 were retrospectively examined. Each patient's clinical course was then analysed for the period between January 1st, 2004, and August 31st, 2006. Although shorter LOS was associated with decreased readmission rates, the effect of crisis discharges was far more powerful. Patients discharged as usual had a far lower risk of readmission than those discharged due to bed pressures (i.e. crisis discharge). Increased risks associated with the early discharge policy necessitate the urgent review of the current management of bed shortages in this inpatient facility. The strengthening of community initiatives, particularly assertive outreach could be a way forward.


Human papillomavirus 1a complete DNA sequence: a novel type of genome organization among papovaviridae.
The complete nucleotide sequence of human papillomavirus type 1a (7811 nucleotides) has been established. The overall organization of the viral genome is different from that of other related papovaviruses (SV40, BKV, polyoma). Firstly, genetic information seems to be coded by one strand. Secondly, no significant homology is found with SV40 or polyoma coding sequence for either DNA or deducted protein sequences. The relatedness of human and bovine papillomaviruses is revealed by a conserved coding sequence in the two species. Two regions can be defined on the viral genome: the putative early region contains two large open reading frames of 1446 and 966 nucleotides, together with several split ones, and corresponds to the transforming part of the bovine papillomavirus type 1 genome, and the remaining sequences, which include two open reading frames likely to encode structural polypeptide(s). The DNA sequence is analysed and putative signals for regulation of gene expression, and homologies with the Alu family of human ubiquitous repeats and the SV40 72-bp repeat are outlines.


Improved method for the routine identification of toxigenic Escherichia coli by DNA amplification of a conserved region of the heat-labile toxin A subunit.
This report describes a DNA amplification procedure for routine identification of heat-labile-toxin-producing Escherichia coli. Two oligonucleotide primers were used in a polymerase chain reaction procedure to amplify a highly conserved region of the A subunit of the heat-labile enterotoxin gene. Amplifications were done directly on E. coli colonies from plates when Salmonella, Shigella, or parasite infections were excluded as agents of the severe diarrhea in the patients. The conditions for the polymerase chain reaction method were empirically determined, and the procedure is inexpensive, sensitive, and specific. Positive results can be obtained over a wide variation in bacterial numbers, with no inhibition of Thermus aquaticus DNA polymerase. Detection of the amplified product can be done by agarose gel electrophoresis, which is specific and sensitive enough for routine diagnosis of this pathogen in clinical isolates. If greater sensitivity and specificity are required, hybridization with 32P- or alkaline phosphatase-labeled oligonucleotide probes can be used. Our results suggest that heat-labile-toxin-producing E. coli is responsible for about 9% of nondiagnosed diarrhea cases in Tygerberg Hospital, Tygerberg, Republic of South Africa.


Use of resuscitative endovascular balloon occlusion of the aorta in a highly lethal model of noncompressible torso hemorrhage.
Noncompressible torso hemorrhage is a leading cause of death in trauma, with many patients dying before definitive hemorrhage control. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an adjunct than can be used to expand the window of salvage in patients with end-stage hemorrhagic shock. The aim of this study was to evaluate the effect of continuous and intermittent REBOA (iREBOA) on mortality using a highly lethal porcine model of noncompressible torso hemorrhage. Male splenectomized pigs (70-90 kg) underwent a laparoscopic liver injury (80% resection of left lobe) followed by a 10-min free-bleed period. Animals were then divided into three groups (n = 8) for a 60-min intervention phase (n = 8): continuous occlusion (cREBOA), iREBOA, or no occlusion (nREBOA). Groups then underwent whole blood resuscitation, damage control surgery, and further critical care. Endpoints were mortality and hemodynamic and circulating measures of shock and resuscitation. Systolic blood pressure (in mmHg) at the end of the free-bleed period for cREBOA, iREBOA, and nREBOA was 31 ± 14, 48 ± 28, and 28 ± 17, respectively (P = 0.125). Following the start of the intervention phase, systolic blood pressure was higher in the iREBOA and cREBOA groups compared with the nREBOA (85 ± 37 and 96 ± 20 vs. 42 ± 4; P < 0.001). Overall mortality for the cREBOA, iREBOA, and nREBOA groups was 25.0%, 37.5%, and 100.0% (P = 0.001). Resuscitative endovascular balloon occlusion of the aorta can temporize exsanguinating hemorrhage and restore life-sustaining perfusion, bridging critical physiology to definitive hemorrhage control. Prospective observational studies of REBOA as a hemorrhage control adjunct should be undertaken in appropriate groups of human trauma patients.


Outcome Measures Used in Ocular Gene Therapy Trials: A Scoping Review of Current Practice.
Multiple gene therapy trials are occurring for a variety of ophthalmic diseases around the world. The safety of gene therapy in the eye has been established, and the next step is to reliably assess efficacy. This is primarily done through the use of imaging techniques and visual function measures. Standardized visual function assessments, however, were originally developed for a clinical setting and may not be suitable for detecting and quantifying therapeutic changes. This scoping review takes a comprehensive look at current practice in terms of the outcome measures defined at trial registration. These were compared to the outcome measures reported in the literature. All published trials reported the pre-registered primary outcome measure. A range of additional secondary outcomes were reported that were not originally planned. Gaps in gene therapy assessment exist and further discussion are required to find a way forward, particularly as more conditions progress to phase 2 and 3 trials. Several factors impacting on trial design and outcome measure choice are discussed.


[Quality of life of patients with venous thromboses in different variants of anticoagulant therapy].
The CIVIQ questionnaire was used to evaluate quality of life of patients presenting with deep vein thrombosis of lower limbs in different variants of anticoagulant therapy. The study included a total of 170 patients who were depending on the variant of anticoagulant therapy subdivided into 3 groups: Group One (comprising 48 patients) taking rivaroxaban as monotherapy; Group Two (consisting of 73 subjects) receiving low molecular weight heparin (enoxaparin sodium) followed by adjusting the warfarin dose, and Group Three (including 49 patients) receiving low molecular weight heparin (enoxaparin sodium) followed by rivaroxaban. The total value of the level of quality of life in all groups showed a tendency towards restoration. However, patients taking warfarin during the follow-up period were found to have negative dynamics by the 6th month of treatment. It was revealed that quality of life on all parameters was higher in patients taking rivaroxaban and lower in those taking warfarin. The parameters of the physical component of health turned out to depend upon the degree of recanalization of the thrombus. After 6 months of anticoagulant therapy patients taking rivaroxaban (Groups One and Three) were found to have good recanalization in 87.5 and 87.7% of cases, respectively, while in Group Two being observed in 54.8% of patients only. Taking an anticoagulant at a fixed dose not requiring laboratory control (rivaroxaban) increases patient compliance, thus leading to improvement of both mental and social wellbeing.


The long and winding road: Effects of exercise intensity and type upon sustained attention.
Aerobic exercise enhances the ability to sustain attention (peaking at moderate intensities) by stimulating noradrenergic activity, which affects the fronto-parietal attention network. Prior exercise studies examining attention have focused on the influence of exercise intensity, yet few studies have examined the influence of the type of exercise protocol administered. Here, we propose that sustained attention is greater during (a) moderate compared to low intensity exercise, and (b) moderate intensity exercise administered at a varied-load compared to a constant-load but the same overall intensity. To test this hypothesis, we recorded attentional focus in twelve male cyclists during a sustained attention to response task (SART) in four conditions; at rest, and during exercise at a low constant-, moderate constant- and moderate varied-load intensity. The change in α-amylase (indicative of the noradrenergic response) from saliva samples and activation of the right prefrontal and parietal cortices using near-infrared spectroscopy were recorded. The findings revealed that moderate intensity exercise at a constant-load leads to faster responses and less accuracy in the SART than rest and low intensity exercise. Moderate intensity exercise at a variable-load leads to even faster responses but with no loss of accuracy in the SART. This pattern of results is explained by a larger increase in salivary α-amylase during moderate (constant and varied) intensity cycling and higher activation in the dorso-lateral prefrontal cortex during the varied, but not the constant-load condition. In conclusion, we show that, in addition to exercise intensity, the type of exercise also has important implications upon attentional focus. While moderate intensity exercise generally enhances attentional focus, monotonous exercise at a constant-load may mask such benefits.


Alien species as a driver of recent extinctions.
We assessed the prevalence of alien species as a driver of recent extinctions in five major taxa (plants, amphibians, reptiles, birds and mammals), using data from the IUCN Red List. Our results show that alien species are the second most common threat associated with species that have gone completely extinct from these taxa since AD 1500. Aliens are the most common threat associated with extinctions in three of the five taxa analysed, and for vertebrate extinctions overall.


Design of the oxygen and substrate pathways. IV. Partitioning energy provision from fatty acids.
This paper quantifies the fluxes of fatty acids through the pathways supplying muscle mitochondria with oxidative fuel in exercising dogs and goats. We used continuous infusions of 1-[14C]palmitate and indirect calorimetry to measure fatty acid supply from two sources: the circulation and the triglyceride stores within the muscle cells. Our goal was to determine maximal flux through these two branches of the lipid pathway as key functional parameters for testing the principle of symmorphosis, i.e. that structural capacity is quantitatively matched to functional demand in the oxidative substrate pathways. It is under these rate-limiting conditions that we predict that all of the structural capacity will be used. Maximal rates of fatty acid oxidation were reached at low exercise intensities of 40% Mo2max. Fatty acids from the circulation supplied only a small fraction (15-25%) of the total fat oxidized under these conditions. Although dogs were able to oxidize circulatory fatty acids faster than goats, maximal rates were not in proportion to the 2.2-fold difference in aerobic capacity between the two species. Dogs compensated for their relatively lower use of circulatory fatty acids by oxidizing more triglycerides from lipid droplets in their muscle cells. We conclude that fatty acids from intramuscular triglyceride stores are a major source of fuel during maximal rates of lipid oxidation. Furthermore, it is this branch of the fatty acid pathway that is adapted to the large difference in aerobic capacity between dogs and goats.


Transcatheter implantation of self-expandable valved prosthesis in outlet right ventricle an experimental study in pigs.
Patients with congenital heart disease who underwent pulmonary valvotomy or surgery to open the pulmonary valve ring are prone to develop residual pulmonary insufficiency or stenosis that may lead to right heart failure with clinical deterioration. These children require multiple interventions throughout their lives, which impose a high rate of morbidity and mortality. To develop a less invasive technique for implantation of a valved prosthesis through the right ventricle. The valved prosthesis consists of an auto expanding metal stent built with nitinol, surrounded with polyester, where the three leaflets of bovine pericardium were mounted. Twelve pigs were used to perform the implants. Echocardiographic control was performed immediately after implantation and one, four, eight and 12 weeks. One animal showed reflux of moderate to severe and three mild reflux. Transvalvular gradients measured before implantation ranged from 3 to 6 mmHg and that soon after the implant was increased, ranging from 7 to 45 mmHg. There was a decrease in these gradients during follow up and in only four of the twelve animals the gradients were above 20 mmHg. Thrombus formation occurred in the prosthesis of six animals, and this was the most frequent complication. These findings highlight the need for studies with the use of anticoagulants and antiplatelet, an attempt to reduce this event. The study aims to contribute for the start of the use of prosthetic heart valves that could be implanted through minimally invasive techniques without the use of cardiopulmonary bypass.


Effects of low level pulsed radio frequency fields on induced osteoporosis in rat bone.
Effect of modulated pulsed electromagnetic fields (PEMFs; carrier frequency, 14 MHz. modulated at 16 Hz of amplitude 10 V peak to peak) on sciatic neurectomy induced osteoporosis in rat femur and tibia resulted in statistically significant increase in bone mineral density, and deceleration in bone resorption process and consequently further osteoporosis in rat bone. These results suggest that such an effective window of pulsed radio frequency fields may be used therapeutically for the treatment of osteoporosis.


Effects of dietary L-carnitine and coenzyme Q10 supplementation on performance and ascites mortality of broilers.
The study was conducted to determine the effects of dietary L-carnitine and coenzyme Q10 (CoQ10) supplementation on growth performance and ascites mortality of broilers. A 3 x 3 factorial arrangement was employed with three levels (0, 75 and 150 mg/kg) of L-carnitine and three levels of CoQ10 (0, 20 and 40 mg/kg) supplementation during the experiment. Five hundred and forty one-day-old Arbor Acre male broiler chicks were randomly allocated into nine groups with six replicates each. All birds were fed with the basal diets from day 1 to 7 and changed to the experimental diets from day 8. During day 15 to 21 all the birds were exposed to low ambient temperature (15-18 degrees C) to induce ascites. The results showed that under this condition, growth performance of broilers were not significantly affected by CoQ10 or L-carnitine + CoQ10 supplementation during week 0-3 and 0-6, but body weight gain (BWG) of broilers was significantly reduced by 150 mg/ kg L-carnitine during week 0-6. Packed cell volume (PCV) of broilers was significantly decreased by L-carnitine and L-carnitine + CoQ10 supplementation (P < 0.05). Erythrocyte osmotic fragility (EOF), ascites heart index (AHI) and ascites mortality of broilers were significantly decreased by L-carnitine, CoQ10 and L-carnitine + CoQ10 supplementation. Though no significant changes were observed in total antioxidative capability (T-AOC), total superoxide dismutase (T-SOD) was increased by L-carnitine, CoQ10 and L-carnitine + CoQ10 supplementation (P < 0.05). Malonaldehyde (MDA) content was significantly decreased by CoQ10 and L-carnitine + CoQ10 supplementation. The results indicate that dietary L-carnitine and CoQ10 supplementation reduce ascites mortality of broilers; the reason may be partially associated with their antioxidative effects.


Evaluation of job satisfaction and working atmosphere of dental nurses in Germany.
The purpose of the study was to assess the level of job satisfaction of dental nurses in ambulatory care and to explore the impact of aspects of working atmosphere on and their association with job satisfaction. This cross-sectional study was based on a job satisfaction survey. Data were collected from 612 dental nurses working in 106 dental care practices. Job satisfaction was measured with the 10-item Warr-Cook-Wall job satisfaction scale. Working atmosphere was measured with five items. Linear regression analyses were performed in which each item of the job satisfaction scale was handled as dependent variables. A stepwise linear regression analysis was performed with overall job satisfaction and the five items of working atmosphere, job satisfaction, and individual characteristics. The response rate was 88.3%. Dental nurses were satisfied with 'colleagues' and least satisfied with 'income.' Different aspects of job satisfaction were mostly associated with the following working atmosphere issues: 'responsibilities within the practice team are clear,' 'suggestions for improvement are taken seriously,' 'working atmosphere in the practice team is good,' and 'made easier to admit own mistakes.' Within the stepwise linear regression analysis, the aspect 'physical working condition' (β = 0.304) showed the highest association with overall job satisfaction. The total explained variance of the 14 associated variables was 0.722 with overall job satisfaction. Working atmosphere within this discrete sample of dental care practice seemed to be an important influence on reported working condition and job satisfaction for dental nurses. Because of the high association of job satisfaction with physical working condition, the importance of paying more attention to an ergonomic working position for dental nurses to ensure optimal quality of care is highlighted.


Insulin protects against hepatic damage postburn.
Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway, leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes.


The variance and the quantity 2Dt in capillary zone electrophoresis.
The variance is generally used as a measure of dispersion of zones in capillary zone electrophoresis (CZE). It is a quantitative measure of the separation power of a system and different causes of dispersion can be rated by their partial variances, which can be summed up to total variance. However, the additivity is only valid for independent dispersion sources, a fact that often seems to be ignored. The ubiquitous dispersion source diffusion is taken into consideration by the Einstein term 2Dt. Other sources of dispersion are, e.g., injection, detection, thermal gradients, adsorption, and hydrodynamic flow. For each of these sources various variance expressions have been derived. The origin of the term 2Dt and its relation to the variance is explained and the calculation of variance in general is discussed. The equivalence of the diffusion variance and the term 2Dt is verified with some simple initial forms of sample zone and the additivity of variances in ideal zone electrophoresis is demonstrated. The change of conductivity in zones results in asymmetrical zone forms which is an indication of nonideality of a system. It is shown that in such cases the term 2Dt is no longer valid and its use as an additive variance component leads to an erroneous total variance. Because in zone electrophoresis conductivity in a zone always changes more or less, the additivity of variances is never perfectly valid. However, in many cases the nonideality may be so small that the additivity in practice is still applicable.(ABSTRACT TRUNCATED AT 250 WORDS)


Evaluation of vitrification for cryopreservation of teeth.
The aim of this study was to investigate whether vitrification in the cryopreservation of periodontal ligament (PDL) cells could be useful for tooth banking. In step 1, primary cultured human PDL cells were cryopreserved in 100% conventional cryopreservation media and 100% vitrification media (ESF40 media) in different temperatures for 2 weeks. In step 2, a series of modified vitrification formulae named T1 (75% vitrification media + 25% F-media), T2 (50% vitrification media + 50% F-media) and T3 (25% vitrification media + 75% F-media) were used to store PDL cells for 2 weeks and 4 weeks in liquid nitrogen. MTT assay was performed to examine the viability of PDL cells. Maximum cell viability was achieved in cells stored in 100% conventional cryopreservation media at -196 (positive control group) in step 1. Compared to the positive control group, viability of the cells stored in 100% vitrification media was very low as 10% in all test conditions. In step 2, as the percentage of vitrification media decreased, the cell viability increased in cells stored for 2 weeks. In 4-week storage of cells in step 2, higher cell viability was observed in the T2 group than the other vitrification formulae while the positive control group had the highest viability. There was no statistically significant difference in the cell viability of 2-week and 4-week stored cells in the T2 group. These observations indicate 100% vitrification media is not successful in PDL cell cryopreservation. Conventional cryopreservation media is currently the most appropriate media type for this purpose while T2 media would be interesting to test for long-term storage of PDL cells.


Gonadotropin-releasing hormone and protein kinase C signaling to ERK: spatiotemporal regulation of ERK by docking domains and dual-specificity phosphatases.
Activated ERK translocates to the nucleus to regulate transcription. Spatiotemporal aspects of this response dictate biological consequences and are influenced by dual-specificity phosphatases (DUSPs) that can scaffold and dephosphorylate ERK. In HeLa cells, GnRH causes transient and protein kinase C (PKC)-dependent ERK activation, but termination mechanisms are unknown. We now explore DUSP roles using short inhibitory RNA to knock down endogenous ERK, adenoviruses to express GnRH receptors and add-back ERK2-GFP, and automated microscopy to monitor ERK location and activation. GnRH caused rapid and transient increases in dual phosphorylated ERK2 (ppERK2) and nuclear to cytoplasmic ERK2-green fluorescent protein (GFP) ratio, whereas responses to a PKC-activating phorbol ester were more sustained. In cells expressing D319N ERK2-GFP (D319N mutation impairs docking-domain-dependent binding to DUSPs), GnRH caused more sustained increases in ppERK2 and nuclear to cytoplasmic ERK2-GFP ratio and also had more pronounced effects on Egr-1 luciferase (a transcriptional reporter for ERK activation). Cycloheximide caused more sustained effects of GnRH and phorbol ester on ppERK, suggesting termination by nuclear-inducible DUSPs. GnRH also increased expression of nuclear-inducible DUSP1 and -4, but their knockdown did not alter GnRH-mediated ERK signaling. Screening a short inhibitory RNA library targeting 16 DUSPs (nuclear-inducible DUSPs, cytoplasmic ERK MAPK phosphatases, c-Jun N-terminal kinase/p38 MAPK phosphatases, and atypical DUSPs) revealed GnRH effects to be influenced by DUSPs 5, 9, 10, 16, and 3 (i.e. by each DUSP class). Thus, GnRH-mediated ERK responses (like PKC-mediated ERK responses) are dependent on protein neosynthesis and docking-domain-dependent binding, but for GnRH activation (unlike PKC activation), this does not reflect dependence on nuclear-inducible DUSPs. Termination of these GnRH effects is apparently dependent upon a preexisting rapid turnover protein.


Global Perspective on the Impact of the COVID-19 Pandemic on Rheumatology and Health Equity.
Although the public health emergency associated with the COVID-19 pandemic has ended, challenges remain, especially for individuals with rheumatic diseases. We aimed to assess the historical and ongoing effects of COVID-19 on individuals with rheumatic diseases and rheumatology practices globally, with specific attention to vulnerable communities and lessons learned. We reviewed literature from several countries and regions, including Africa, Australia and New Zealand, China, Europe, Latin America, and the US. In this review, we summarize literature that not only examines the impact of the pandemic on individuals with rheumatic diseases, but also research that reports the lasting changes to rheumatology patient care and practice, and health service use. Across countries, challenges faced by individuals with rheumatic diseases during the pandemic included disruptions in health care and medication supply shortages. These challenges were associated with worse disease and mental health outcomes in some studies, particularly among those who had social vulnerabilities defined by socioeconomic, race, or rurality. Moreover, rheumatology practice was impacted in all regions, with the uptake of telemedicine and changes in health care utilization. While many regions developed rapid guidelines to disseminate scientific information, misinformation and disinformation remained widespread. Finally, vaccine uptake among individuals with rheumatic diseases has been uneven across the world. As the acute phase of the pandemic wanes, ongoing efforts are needed to improve health care access, stabilize rheumatology drug supplies, improve public health communication, and implement evidence-based vaccination practices to reduce COVID-19 morbidity and mortality among individuals with rheumatic diseases.


Hybridization alters spontaneous mutation rates in a parent-of-origin-dependent fashion in Arabidopsis.
Over 70 years ago, increased spontaneous mutation rates were observed in Drosophila spp. hybrids, but the genetic basis of this phenomenon is not well understood. The model plant Arabidopsis (Arabidopsis thaliana) offers unique opportunities to study the types of mutations induced upon hybridization and the frequency of their occurrence. Understanding the mutational effects of hybridization is important, as many crop plants are grown as hybrids. Besides, hybridization is important for speciation and its effects on genome integrity could be critical, as chromosomal rearrangements can lead to reproductive isolation. We examined the rates of hybridization-induced point and frameshift mutations as well as homologous recombination events in intraspecific Arabidopsis hybrids using a set of transgenic mutation detector lines that carry mutated or truncated versions of a reporter gene. We found that hybridization alters the frequency of different kinds of mutations. In general, Columbia (Col)×Cape Verde Islands and Col×C24 hybrid progeny had decreased T→G and T→A transversion rates but an increased C→T transition rate. Significant changes in frameshift mutation rates were also observed in some hybrids. In Col×C24 hybrids, there is a trend for increased homologous recombination rates, except for the hybrids from one line, while in Col×Cape Verde Islands hybrids, this rate is decreased. The overall genetic distance of the parents had no influence on mutation rates in the progeny, as closely related accessions on occasion displayed higher mutation rates than accessions that are separated farther apart. However, reciprocal hybrids had significantly different mutation rates, suggesting parent-of-origin-dependent effects on the mutation frequency.


Macrophage and T cell produced IL-10 promotes viral chronicity.
Chronic viral infections lead to CD8(+) T cell exhaustion, characterized by impaired cytokine secretion. Presence of the immune-regulatory cytokine IL-10 promotes chronicity of Lymphocytic Choriomeningitis Virus (LCMV) Clone 13 infection, while absence of IL-10/IL-10R signaling early during infection results in viral clearance and higher percentages and numbers of antiviral, cytokine producing T cells. IL-10 is produced by several cell types during LCMV infection but it is currently unclear which cellular sources are responsible for induction of viral chronicity. Here, we demonstrate that although dendritic cells produce IL-10 and overall IL-10 mRNA levels decrease significantly in absence of CD11c(+) cells, absence of IL-10 produced by CD11c(+) cells failed to improve the LCMV-specific T cell response and control of LCMV infection. Similarly, NK cell specific IL-10 deficiency had no positive impact on the LCMV-specific T cell response or viral control, even though high percentages of NK cells produced IL-10 at early time points after infection. Interestingly, we found markedly improved T cell responses and clearance of normally chronic LCMV Clone 13 infection when either myeloid cells or T cells lacked IL-10 production and mice depleted of monocytes/macrophages or CD4(+) T cells exhibited reduced overall levels of IL-10 mRNA. These data suggest that the decision whether LCMV infection becomes chronic or can be cleared critically depends on early CD4(+) T cell and monocyte/macrophage produced IL-10.


Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema.
Lymphedema is a dreaded complication of cancer treatment. However, despite the fact that >5 million Americans are affected by this disorder, the development of effective treatments is limited by the fact that the pathology of lymphedema remains unknown. The purpose of these studies was to determine the role of inflammatory responses in lymphedema pathology. Using mouse models of lymphedema, as well as clinical lymphedema specimens, we show that lymphatic stasis results in a CD4 T-cell inflammation and T-helper 2 (Th2) differentiation. Using mice deficient in T cells or CD4 cells, we show that this inflammatory response is necessary for the pathological changes of lymphedema, including fibrosis, adipose deposition, and lymphatic dysfunction. Further, we show that inhibition of Th2 differentiation using interleukin-4 (IL-4) or IL-13 blockade prevents initiation and progression of lymphedema by decreasing tissue fibrosis and significantly improving lymphatic function, independent of lymphangiogenic growth factors. We show that CD4 inflammation is a critical regulator of tissue fibrosis and lymphatic dysfunction in lymphedema and that inhibition of Th2 differentiation markedly improves lymphatic function independent of lymphangiogenic cytokine expression. Notably, preventing and/or reversing the development of pathological tissue changes that occur in lymphedema may be a viable treatment strategy for this disorder.


First Latin American clinical practice guidelines for the treatment of systemic lupus erythematosus: Latin American Group for the Study of Lupus (GLADEL, Grupo Latino Americano de Estudio del Lupus)-Pan-American League of Associations of Rheumatology (PANLAR).
Systemic lupus erythematosus (SLE), a complex and heterogeneous autoimmune disease, represents a significant challenge for both diagnosis and treatment. Patients with SLE in Latin America face special problems that should be considered when therapeutic guidelines are developed. The objective of the study is to develop clinical practice guidelines for Latin American patients with lupus. Two independent teams (rheumatologists with experience in lupus management and methodologists) had an initial meeting in Panama City, Panama, in April 2016. They selected a list of questions for the clinical problems most commonly seen in Latin American patients with SLE. These were addressed with the best available evidence and summarised in a standardised format following the Grading of Recommendations Assessment, Development and Evaluation approach. All preliminary findings were discussed in a second face-to-face meeting in Washington, DC, in November 2016. As a result, nine organ/system sections are presented with the main findings; an 'overarching' treatment approach was added. Special emphasis was made on regional implementation issues. Best pharmacologic options were examined for musculoskeletal, mucocutaneous, kidney, cardiac, pulmonary, neuropsychiatric, haematological manifestations and the antiphospholipid syndrome. The roles of main therapeutic options (ie, glucocorticoids, antimalarials, immunosuppressant agents, therapeutic plasma exchange, belimumab, rituximab, abatacept, low-dose aspirin and anticoagulants) were summarised in each section. In all cases, benefits and harms, certainty of the evidence, values and preferences, feasibility, acceptability and equity issues were considered to produce a recommendation with special focus on ethnic and socioeconomic aspects. Guidelines for Latin American patients with lupus have been developed and could be used in similar settings.


A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain.
Between 40% and 60% of Americans use complementary and alternative medicine to manage medical conditions, prevent disease, and promote health and well-being. Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) have been used to treat joint pain associated with several inflammatory conditions. We conducted a meta-analysis of 17 randomized, controlled trials assessing the pain relieving effects of omega-3 PUFAs in patients with rheumatoid arthritis or joint pain secondary to inflammatory bowel disease and dysmenorrhea. Meta-analysis was conducted with Cochrane Review Manager 4.2.8. for six separate outcomes using standardized mean differences (SMDs) as a measure of effect size: (1) patient assessed pain, (2) physician assessed pain, (3) duration of morning stiffness, (4) number of painful and/or tender joints, (5) Ritchie articular index, and (6) nonselective nonsteroidal anti-inflammatory drug consumption. Supplementation with omega-3 PUFAs for 3-4 months reduces patient reported joint pain intensity (SMD: -0.26; 95% CI: -0.49 to -0.03, p=0.03), minutes of morning stiffness (SMD: -0.43; 95% CI: -0.72 to -0.15, p=0.003), number of painful and/or tender joints (SMD: -0.29; 95% CI: -0.48 to -0.10, p=0.003), and NSAID consumption (SMD: -0.40; 95% CI: -0.72 to -0.08, p=0.01). Significant effects were not detected for physician assessed pain (SMD: -0.14; 95% CI: -0.49 to 0.22, p=0.45) or Ritchie articular index (SMD: 0.15; 95% CI: -0.19 to 0.49, p=0.40) at 3-4 months. The results suggest that omega-3 PUFAs are an attractive adjunctive treatment for joint pain associated with rheumatoid arthritis, inflammatory bowel disease, and dysmenorrhea.


The 'Own Children' fertility estimation procedure: a reappraisal.
The Full Birth History has become the dominant source of estimates of fertility levels and trends for countries lacking complete birth registration. An alternative, the 'Own Children' method, derives fertility estimates from household age distributions, but is now rarely used, partly because of concerns about its accuracy. We compared the estimates from these two procedures by applying them to 56 recent Demographic and Health Surveys. On average, 'Own Children' estimates of recent total fertility rates are 3 per cent lower than birth-history estimates. Much of this difference stems from selection bias in the collection of birth histories: women with more children are more likely to be interviewed. We conclude that full birth histories overestimate total fertility, and that the 'Own Children' method gives estimates of total fertility that may better reflect overall national fertility. We recommend the routine application of the 'Own Children' method to census and household survey data to estimate fertility levels and trends.


Shared decision making and consent post-Montgomery, UK Supreme Court judgement supporting best practice.
The UK Supreme Court Montgomery judgement marks a decisive shift in the legal test of duty of care in the context of consent to treatment from the perspective of the clinician (as represented by Bolam rules) to that of the patient. This has important implications in the surgical field worldwide, where informed consent is critical. This paper aims to explain the ruling and how it impacts the consent process. The case and ruling are outlined and summarised as pertaining to consent and requirements for validity; a shift from the clinician's interpretation about what would be best for patients to the values of the particular patient concerned in the decision in question. A sample of recent commentaries is reviewed. Four examples illustrate some of the practical applications of the Montgomery ruling on consent and how the ruling can empower doctors and patients to make mutually beneficial shared decisions. Future consent should be obtained using a Montgomery compliant strategy in accordance with the principles of shared decision making.


Name that percussive tune: Associative memory and amplitude envelope.
A series of experiments demonstrated novel effects of amplitude envelope on associative memory, with tones exhibiting naturally decaying amplitude envelopes (e.g., those made by two wine glasses clinking) better associated with target objects than amplitude-invariant tones. In Experiment 1 participants learned associations between household objects and 4-note tone sequences constructed of spectrally matched pure tones with either "flat" or "percussive" amplitude envelopes. Those hearing percussive tones correctly recalled significantly more sequence-object associations. Experiment 2 demonstrated that participants hearing percussive tones learned the associations more quickly. Experiment 3 used "reverse percussive" tones (percussive tones played backwards) to test whether differences in overall energy might account for this effect, finding they did not lead to the same level of performance as percussive tones. Experiment 4 varied the envelope at encoding and retrieval to determine which stage of the task was most affected by the envelope manipulation. Participants hearing percussive tones at both encoding and retrieval performed significantly better than the other three groups (i.e., flat at encoding/percussive at retrieval, etc.). We conclude that amplitude envelope plays an important role in learning and memory, a finding with relevance to psychological research on audition and associative memory, as well as practical relevance for improving human-computer interface design.


Genome-wide linkage analysis of 1,233 prostate cancer pedigrees from the International Consortium for Prostate Cancer Genetics using novel sumLINK and sumLOD analyses.
Prostate cancer (PC) is generally believed to have a strong inherited component, but the search for susceptibility genes has been hindered by the effects of genetic heterogeneity. The recently developed sumLINK and sumLOD statistics are powerful tools for linkage analysis in the presence of heterogeneity. We performed a secondary analysis of 1,233 PC pedigrees from the International Consortium for Prostate Cancer Genetics (ICPCG) using two novel statistics, the sumLINK and sumLOD. For both statistics, dominant and recessive genetic models were considered. False discovery rate (FDR) analysis was conducted to assess the effects of multiple testing. Our analysis identified significant linkage evidence at chromosome 22q12, confirming previous findings by the initial conventional analyses of the same ICPCG data. Twelve other regions were identified with genome-wide suggestive evidence for linkage. Seven regions (1q23, 5q11, 5q35, 6p21, 8q12, 11q13, 20p11-q11) are near loci previously identified in the initial ICPCG pooled data analysis or the subset of aggressive PC pedigrees. Three other regions (1p12, 8p23, 19q13) confirm loci reported by others, and two (2p24, 6q27) are novel susceptibility loci. FDR testing indicates that over 70% of these results are likely true positive findings. Statistical recombinant mapping narrowed regions to an average of 9 cM. Our results represent genomic regions with the greatest consistency of positive linkage evidence across a very large collection of high-risk PC pedigrees using new statistical tests that deal powerfully with heterogeneity. These regions are excellent candidates for further study to identify PC predisposition genes.


Congenital epidermolysis bullosa acquisita: vertical transfer of maternal autoantibody from mother to infant.
Epidermolysis bullosa acquisita (EBA) is a rare, chronic, autoimmune bullous dermatosis that is caused by autoantibodies against the noncollagenous terminus of the α chain of type VII collagen, resulting in decreased anchoring fibrils in the lamina densa. It classically presents with skin fragility and trauma-induced blisters that are particularly extensive over the distal aspect of the extremities and that heal with milia, dyspigmentation, and scarring, similar in presentation to dystrophic epidermolysis bullosa. Disease onset is typically in adulthood, although rare cases of childhood disease occur. To our knowledge, a case involving a neonate with congenital EBA has not yet been reported in the literature. We describe a newborn with transient EBA due to the passive transfer of maternal autoantibodies. A 2-day-old girl was evaluated for tense blisters and areas of denuded skin that had been present since birth. Her mother carried the diagnosis of EBA. The results of histopathologic analysis, immunofluorescence studies, and enzyme-linked immunosorbent assay confirmed the diagnosis of neonatal EBA. The patient improved with supportive therapy and has not required systemic intervention. Autoimmune neonatal bullous skin disease caused by placental transfer of maternal IgG autoantibodies is rare. It has been reported in neonates born to mothers with pemphigus vulgaris, pemphigus foliaceus, and gestational pemphigoid. To our knowledge, congenital EBA has not been previously reported. Vertically acquired congenital autoimmune blistering disorders appear to be self-limited and resolve with supportive therapy, concomitant with the presumed clearance of maternal autoantibodies from the neonate's circulation.


Novel Neural Network Approach to Predict Drug-Target Interactions Based on Drug Side Effects and Genome-Wide Association Studies.
We propose a novel machine learning approach to expand the knowledge about drug-target interactions. Our method may help to develop effective, less harmful treatment strategies and to enable the detection of novel indications for existing drugs. We developed a novel machine learning strategy to predict drug-target interactions based on drug side effects and traits from genome-wide association studies. We integrated data from the databases SIDER and GWASdb and utilized them in a unique way by a neural network approach. We validate our method using drug-target interactions from the STITCH database. In addition, we compare the chemical similarity of the predicted target to known targets of the drug under consideration and present literature-based evidence for predicted interactions. We find drug combination warnings for drugs we predict to target the same protein, hinting to synergistic effects aggravating harmful events. This substantiates the translational value of our approach, because we are able to detect drugs that should be taken together with care due to common mechanisms of action. Taken together, we conclude that our approach is able to generate a novel and clinically applicable insight into the molecular determinants of drug action.


Adverse effects of α-ketoglutarate/malate in a rat model of acute kidney injury.
Acute kidney injury (AKI) is the most common kidney disease in hospitalized patients with high mortality. Ischemia and reperfusion (I/R) is one of the major causes of AKI. The combination of α-ketoglutarate+malate (αKG/MAL) showed the ability to reduce hypoxia-induced damage to isolated proximal tubules. The present study utilizes a rat model of I/R-induced AKI accompanied by intensive biomonitoring to examine whether αKG/MAL provides protection in vivo. AKI was induced in male Sprague-Dawley rats by bilateral renal clamping (40 min) followed by reperfusion (240 min). αKG/MAL was infused continuously for 60 min before and 45 min after ischemia. Normoxic and I/R control groups received 0.9% NaCl solution. The effect of αKG/MAL was evaluated by biomonitoring, blood and plasma parameters, histopathology, and immunohistochemical staining for kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), as well as by determination of tissue ATP and nonesterified fatty acid concentrations. Intravenous infusion of αKG/MAL at a cumulative dose of 1 mmol/kg each (146 mg/kg αKG and 134 mg/kg MAL) did not prevent I/R-induced increases in plasma creatinine, histopathological alterations, or cortical ATP depletion. On the contrary, the most notable adverse affect in animals receiving αKG/MAL was the decrease in mean arterial blood pressure, which was also accompanied by a reduction in heart rate. Supplementation with αKG/MAL, which is very protective against hypoxia-induced injury in isolated proximal tubules, does not protect against I/R-induced renal injury in vivo, possibly due to cardiovascular depressive effects.


What determines the success and failure of environmental crowdfunding?
Online crowdfunding can help address the perennial financial shortfalls in environmental conservation and management. Although many online crowdfunding campaigns fail to collect any funds due to not achieving their targets, little is known about what drives success. To address this knowledge gap, we applied a mixed-methods approach to data from 473 successful and failed campaigns hosted on the online crowdfunding platform Readyfor. We found that fundraising performance varied by topic, with campaigns on pet animal management outperforming those focussed on landscape management and sustainable use. We also found that marketing strategies associated with online findability and increased reach through social networks, increased fundraising success. However, the existence of other environmental campaigns running simultaneously, reduced the chance of success, which implies that the selecting popular topics does not always increase the likelihood of success due to increased competition. Wider applications of marketing could enhance the ability of environmental crowdfunding campaigns to raise funds.


Bottled water versus tap water: understanding consumers' preferences.
The consumption of bottled water has been increasing consistently over the last decade, even in countries where tap water quality is considered excellent. This paper discusses some of the reasons why people decide for an option that is often more expensive and less comfortable than tap water. Consumer surveys usually stress two main factors: dissatisfaction with tap water organoleptics (especially taste) and health/risk concerns. However, many other factors are involved, including demographic variables and the perceived quality of the water source. Trust in tap water companies also seems to influence public behaviour. A clearer picture of bottled water consumption can be achieved when different aspects are considered.


Hoxb-13: a new Hox gene in a distant region of the HOXB cluster maintains colinearity.
The Hox genes are involved in patterning along the A/P axes of animals. The clustered organization of Hox genes is conserved from nematodes to vertebrates. During evolution, the number of Hox genes within the ancestral complex increased, exemplified by the five-fold amplification of the AbdB-related genes, leading to a total number of thirteen paralogs. This was followed by successive duplications of the cluster to give rise to the four vertebrate HOX clusters. A specific subset of paralogs was subsequently lost from each cluster, yet the composition of each cluster was likely conserved during tetrapod evolution. While the HOXA, HOXC and HOXD clusters contain four to five AbdB-related genes, only one gene (Hoxb-9) is found in the HOXB complex. We have identified a new member of paralog group 13 in human and mouse, and shown that it is in fact Hoxb-13. A combination of genetic and physical mapping demonstrates that the new gene is found approx. 70 kb upstream of Hoxb-9 in the same transcriptional orientation as the rest of the cluster. Despite its relatively large distance from the HOX complex, Hoxb-13 exhibits temporal and spatial colinearity in the main body axis of the mouse embryo. The onset of transcription occurs at E9.0 in the tailbud region. At later stages of development, Hoxb-13 is expressed in the tailbud and posterior domains in the spinal cord, digestive tract and urogenital system. However, it is not expressed in the secondary axes such as the limbs and genital tubercle. These results indicate that the 5' end of the HOXB cluster has not been lost and that at least one member exists and is highly conserved among different vertebrate species. Because of its separation from the complex, Hoxb-13 may provide an important system to dissect the mechanism(s) responsible for the maintenance of colinearity.


Relationship of fast- and slow-timescale neuronal dynamics in human MEG and SEEG.
A growing body of evidence suggests that the neuronal dynamics are poised at criticality. Neuronal avalanches and long-range temporal correlations (LRTCs) are hallmarks of such critical dynamics in neuronal activity and occur at fast (subsecond) and slow (seconds to hours) timescales, respectively. The critical dynamics at different timescales can be characterized by their power-law scaling exponents. However, insight into the avalanche dynamics and LRTCs in the human brain has been largely obtained with sensor-level MEG and EEG recordings, which yield only limited anatomical insight and results confounded by signal mixing. We investigated here the relationship between the human neuronal dynamics at fast and slow timescales using both source-reconstructed MEG and intracranial stereotactical electroencephalography (SEEG). Both MEG and SEEG revealed avalanche dynamics that were characterized parameter-dependently by power-law or truncated-power-law size distributions. Both methods also revealed robust LRTCs throughout the neocortex with distinct scaling exponents in different functional brain systems and frequency bands. The exponents of power-law regimen neuronal avalanches and LRTCs were strongly correlated across subjects. Qualitatively similar power-law correlations were also observed in surrogate data without spatial correlations but with scaling exponents distinct from those of original data. Furthermore, we found that LRTCs in the autonomous nervous system, as indexed by heart-rate variability, were correlated in a complex manner with cortical neuronal avalanches and LRTCs in MEG but not SEEG. These scalp and intracranial data hence show that power-law scaling behavior is a pervasive but neuroanatomically inhomogeneous property of neuronal dynamics in central and autonomous nervous systems.


Re-utilization outcomes and costs of minor acute illness treated at family physician offices, walk-in clinics, and emergency departments.
To examine factors associated with re-utilization of health services and to estimate and compare costs of treatment for minor acute illnesses in family physicians' offices (FPOs), walk-in clinics (WICs), and emergency departments (EDs). Prospective cohort study using questionnaires, telephone follow up, medical chart data, and costs according to Ontario Health Insurance Plan (OHIP) schedules. 16 FPOs, 12 WICs, and 13 EDs in three Ontario cities. Consecutive patients with one of eight predefined minor acute illnesses found in all three settings (upper respiratory infection, pharyngitis, acute bronchitis, acute otitis media, serous otitis media, low back pain, gastroenteritis, and urinary tract infection). "Early" (< 3 days) versus "later" (3 days to 2 weeks) re-utilization of health services after initial encounter and direct cost to OHIP. The overall rate of re-utilization of health services for the same episode of illness was 11.3% for early and 20.6% for later re-utilization. Factors associated with early re-utilization were initial evaluation in ED setting (odds ratio [OR] = 6.5, confidence interval [CI] = 2.2-19.2) and, regardless of setting, less satisfaction with patient-centred care (OR = 1.7 for each one-point decrease on a four-point scale; CI = 1.1-2.7). Factors associated with later re-utilization were ED setting (OR = 4.9; CI = 2.4-9.9) and diagnosis of urinary tract infection (OR = 2.4; CI = 1.1-5.2). Factors tested and found not signifcantly associated with rate of re-utilization were patients' age, sex, responses to a variety of questions assessing psychosocial factors (stress, social support, independence), and opinions on health care. Cost of care was similar for FPOs and WICs and higher for EDs for all diagnoses. The initial visit was the largest component of cost in all settings, and this component (as well as total cost) was consistently higher in EDs. Both re-utilization rates and costs are higher for those seeking care in EDs for minor acute illness. Patient-centred care, an important feature of health care encounters regardless of setting, can reduce re-utilization rates.


Localized adenocarcinoma of the lung: oncogene expression of erbB-2 and p53 in 150 patients.
Historical information and pathological material from 150 consecutive patients with localized adenocarcinoma of the lung was collected to evaluate oncogene expression of erbB-2 and p53, and erbB-2 gene amplification. Pathological material after resection was reviewed to verify histological staging, and patient follow-up was complete in all cases for at least 68 months. Immunohistochemistry of erbB-2 (HER-2/neu) and p53 oncogene expression was performed on two separate paraffin tumor blocks for each patient with normal lung as control. Gene amplification of erbB-2 was measured after DNA extraction from 20-micrometer sections of erbB-2-positive and -negative tumors. All analyses were blinded and included Kaplan-Meier survival estimates with Cox proportional hazards regression modeling. Two adequate blocks of tumor and normal lung were available for 138 (92%) patients. Immunohistochemical identification of expression of p53 was observed in 49 (37%) patients and erbB-2 in 17 (13%) patients. DNA dot blot analyses were performed on 17 erbB-2-positive and 13 randomly selected erbB-2-negative tumors. There was 1 (6%) of 17 erbB-2-positve tumors with 4-fold erbB-2 gene amplification. Actual 5-year survival was 63% and actuarial 10-year survival was 59% for the entire population of 150 patients. Significant univariate predictors (P < 0.05) of cancer death were the presence of symptoms, tumor size >3 cm, poor differentiation, visceral pleural invasion, and p53 expression. Multivariate analysis associated symptoms and p53 expression as independent factors with decreased survival. Thus, this project examined p53 and erbB-2 expression in patients with localized adenocarcinoma and associated p53 status with survival. Multicenter collection of data should allow the development of a model of cancer recurrence in this most common lung cancer.


Blogging as a viable research methodology for young people with arthritis: a qualitative study.
The development of services that are responsive to the needs of users is a health policy priority. Finding ways of engaging young people in research to gain insights into their particular experiences, perspectives, and needs is vital but challenging. These data are critical to improving services in ways that meet the needs of young people. Our aim was to evaluate Web-based blogging as a viable method for understanding the daily experiences and condition management strategies of young people with juvenile arthritis. To meet the objectives of the study, a qualitative approach was required to gather information on the experiences and perspectives of young people regarding the management of their condition and its daily impact. In collaboration with a group of young people with arthritis, a custom website was developed. This website provided the opportunity for young people (aged 11-19) with arthritis from a United Kingdom pediatric hospital to contribute blogs. It was designed so that young people were free to write about whatever was important to them, but the site also included some structure and prompts to facilitate the writing of blogs. Qualitative analytical procedures were employed, supported by NVivo software. Engagement in the study by young people was variable in terms of their participation rates, frequency of website visits, and the length of their blogs. Young people used the site in different ways, some responding to the website categories and prompts that the team created, while others used it as a diary to record their experiences and thoughts. In line with principles of qualitative inquiry, the data collection was participant-led. Young people were in control of what, how much, and how often they wrote. However, some young people expressed difficulty regarding knowing what they should blog about. For a number of reasons, discussed here, the blogs may also not be fully reflective of experiences and perspectives of the participants. However, the data obtained provided insights into young people's experiences of living with arthritis and their use of medicines in the context of their daily lives. Web-based research with young people presents opportunities and challenges for researchers. Web-based blogging methodology has the potential to give young people and parents the space and empowerment to express their own ideas and concerns. However, this project suggests that it might not be the best way to engage a large diverse group of young people and might most effectively be combined with other approaches. Despite these limitations, the study provided valuable data about the experience and impact of living with a long-term condition from the perspectives of young people with arthritis.


[Tobacco use among secondary school students in Argentina].
To evaluate the prevalence of smoking among Argentine adolescents and describe its usage, factors related to taking up the habit, and exposure to second-hand smoke in the home. A cross-sectional study conducted through an anonymous survey of students 12-18 years of age in either the 8th grade of basic education or in the second course of high school or polytechnic school. The study took place in 2002 at 239 school within five urban centers of Argentina (Ciudad Autónoma de Buenos Aires, Partidos del Gran Buenos Aires, Gran Córdoba, Gran Mendoza, and Santa Fe). The random sample was stratified by socioeconomic level and rates were calculated according to an expanded sample composed of samplings from each stage. The survey was completed by 11 734 students (50.5% males; 44.1% were 12-14 years of age and 56.7% were 15-18 years). In all, 30.0% of the males and 35.0% of the females were smokers at the time of the survey (22.5% in the 12-14 year age group and 40.1% in the 15-18 group). The main reason given for taking up smoking was "to see what it was like" (43.7%); 44.3% of the students who smoked did so when they felt anxious. In all, 64.5% claimed they wanted to stop and 72.5% had attempted to quit, although fewer than 8% of the smokers had gotten any professional help to do so. The overwhelming majority considered it unhealthy to smoke tobacco (93.5%) and be around second-hand smoke (89.6%). Only 30.4% felt they had not received enough information on detrimental effects of smoking. More than 70% of the adolescents were living with a smoker. There is a high rate of smoking among Argentine students, especially females. Policies must be established that will prevent smoking initiation in secondary school. Recommendations are to prohibit tobacco-product advertising and to require stronger health warnings labels.


The NeuroAiD II (MLC901) in vascular cognitive impairment study (NEURITES).
A substantial proportion of patients after nondisabling stroke are cognitively impaired compared to age- and education-matched community-dwelling controls. Moreover, poststroke patients who have 'vascular cognitive impairment no dementia' (VCIND) of moderate severity have a high risk of incident dementia, dependency and death. Further studies are urgently needed to demonstrate effective cognition-enhancing therapies in VCIND given the scarcity of evidence-based treatment options. NeuroAiD is a traditional Chinese medicine that has been shown to induce neuroplasticity, promote cell proliferation and stimulate the development of dense axonal and dendritic networks in animal stroke models. NeuroAiD may improve cerebral blood flow and functional recovery after stroke in patients. To investigate the effects and tolerability of NeuroAiD II in patients with VCIND. The NeuroAiD II (MLC901) in Vascular Cognitive Impairment Study (NEURITES) is a 24-week, double-blind, randomized, placebo-controlled phase II study of NeuroAiD II in patients with VCIND. The primary outcome is executive function as measured by the Verbal Fluency test. Secondary outcomes include cognitive assessments such as the ADAS-Cog, MoCA, MMSE and Cognitive Battery: activities of daily living as measured by the Alzhei-mer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scale for mild cognitive impairment, behavior as measured by the Neuropsychiatric Inventory, and depression as measured by the Geriatric Depression Scale and the Beck Depression Scale. In addition, there will be novel exploratory outcomes: (a) magnetic resonance imaging of lesion location (structural imaging), structural integrity of white matter pathways (diffusion tensor imaging), neuronal function (resting studies) and perfusion (arterial spin labeling and MR angiography), and (b) retinal and optic nerve imaging. Safety and tolerability will be assessed using adverse events, laboratory tests and vital signs. NEURITES has the potential to set new standards for the systematic evaluation of Asian traditional medicine for integration into standard medicine practice and establishing a novel therapeutic approach for improving cognition after stroke.


Genes that act before conjugation to prepare the Saccharomyces cerevisiae nucleus for caryogamy.
Mutations in four nuclear genes, kar1 cdc4, 28, and 37, block or impair nuclear fusion during conjugation of Saccharomyces cerevisiae. Mutations in all four genes are recessive for the caryogamy defect; in matings between diploid cells both of which are heterozygous for any one of the four mutations (-/+ X -/+), caryogamy occurs with normal proficiency. However, mutations in all four genes are "nuclear dominant"; that is, both parent nuclei must contribute one wild-type allele of each gene for successful caryogamy. In order to discriminate between two possible models to explain nuclear dominance, we have examined the caryogamy proficiency of mutant nuclei after they had passed through a heterocaryotic cytoplasm. The kar1, cdc28, and cdc37 caryogamy defects are all phenotypically suppressed in this experiment (cdc4 could not be tested). We conclude from our results that the KAR1, CDC28, and CDC37 gene products can diffuse between nuclei in a heterocaryon and that they probably perform their function for caryogamy prior to cell fusion. One simple model consistent with the roles of CDC28 and CDC37 in mitosis as well as in caryogamy is that these gene products are structural components of the nucleus that must be built into it during one cell cycle in order to permit successful caryogamy at the next G1.


The role of Artemisia turanica extract on renal oxidative and biochemical markers in STZ-induced diabetes in rat.
The aim of the current study was to investigate the protective effect of Artemisia turanica (AT) against diabetes- induced renal oxidative stress in rats. Fifty male Wistar rats were randomly divided into five groups: control, STZ-induced diabetic rats, diabetic rats+ metformin, diabetic rats + AT extract, diabetic rats+ metformin+ AT extract. In the present study, diabetes was induced by a single-dose (55 mg/kg, ip) injection of streptozotocin (STZ). Diabetic rats were daily treated with metformin (300 mg/kg), AT extract (70 mg/kg) and metformin+ AT extract for 4 consecutive weeks. Tissue activities of superoxide dismutase (SOD) and catalase and the levels of malondialdehyde (MDA) and total thiol content were measured in kidney tissue. Serum concentrations of glucose, creatinine, and urea, as well as, lipid profile were also measured. STZ significantly increased the levels of glucose, triglyceride, urea and MDA compared to the control group. Total thiol content, as well as, catalase and SOD activities showed significant decreases in diabetic group when compared with the control animals. Serum glucose, triglyceride, cholesterol and renal MDA showed a significant decrease and renal total thiol and the activities of antioxidant enzymes showed significant increases in AT+STZ group compared with the diabetic group. In diabetic rats received AT+ metformin, serum LDL and HDL, renal MDA and SOD and catalase activities significantly improved compared with the diabetic rats. These findings suggested that AT extract has therapeutic effects on renal oxidative damage and lipid profile in diabetes, that possibly may be due to its antioxidant and hypolipidemic effects.


Statistical measures for workload capacity analysis.
A critical component of how we understand a mental process is given by measuring the effect of varying the workload. The capacity coefficient (Townsend & Nozawa, 1995; Townsend & Wenger, 2004) is a measure on response times for quantifying changes in performance due to workload. Despite its precise mathematical foundation, until now rigorous statistical tests have been lacking. In this paper, we demonstrate statistical properties of the components of the capacity measure and propose a significance test for comparing the capacity coefficient to a baseline measure or two capacity coefficients to each other.


Frequency analysis of cytolytic T lymphocyte precursors (CTL-P) generated in vivo during lethal rabies infection of mice. II. Rabies virus genus specificity of CTL-P.
Cytolytic T lymphocyte precursors (CTL-P) were sensitized in vivo by intraplantar infection of C57BL/6 mice with a lethal dose of rabies virus, strain ERA (ERA). As a result of sensitization CTL-P matured to interleukin-receptive CTL-P (IL-CTL-P) that could be expanded in vitro to Thy-1+, Lyt-2+ CTL clones in the presence of IL without subjection to antigen-driven selection. After infection with ERA, IL-CTL-P-derived CTL lysed fibroblasts infected with rabies virus but not those infected with another rhabdovirus, the vesicular stomatitis virus. These CTL, however, did not discriminate between fibroblasts infected with the serologically closely related laboratory strains of classic rabies virus, ERA and HEP-Flury, and the serologically distinct rabies-related African isolate Mokola. This finding implies that in vivo sensitized IL-CTL-P recognize common genus-specific determinants expressed on cells infected with members of the lyssavirus genus.


Views of doctors in training on the importance and availability of career advice in UK medicine.
To determine whether doctors in their first year after qualification wanted career advice, and, if so, whether they thought they had been able to obtain useful advice, and whether older doctors thought that adequate career advice had been available to them. We carried out a postal questionnaire survey of all UK medical graduates of 1988, 1993, 1996, 1999 and 2002, and a 25% random sample of the graduates of 2000. The response rate was 67.4% (24 261/35 976 mailed questionnaires). Of doctors in the first postgraduate year, 95% agreed that: 'It is important to be given career advice at this stage of training.' A total of 38% disagreed with the statement: 'I have been able to obtain useful career advice since graduation.' Of more experienced doctors surveyed between 3 and 11 years after graduation, 34% agreed that: 'Making career choices has been made more difficult by inadequate career advice.' The great majority of junior doctors want career advice after qualification. It cannot be assumed that they are able to seek it out for themselves satisfactorily. Career advice needs to be planned into postgraduate work and training.


Overview of cancer time-trend studies in relation to changes in cigarette manufacture.
The chief purpose of the present chapter is not to review lung cancer trends in general, but merely to consider the extent to which trends in national lung cancer rates can help assess any differences between the carcinogenic effects of different types of cigarette. For this limited purpose, the British data are uniquely informative, for British male lung cancer rates were already high but stable before the cigarette tar levels were halved, and British male cigarette consumption remained stable for some years thereafter. Against this apparently stable background, an otherwise unexplained decrease of about one-half in British male lung cancer mortality in early middle age has followed the decrease in cigarette tar deliveries, which is consistent with Stellman's conclusion (this volume), based on review of the case-control and prospective studies, that cigarette-induced lung cancer risks are approximately proportional to machine-measured tar deliveries. Lung cancer trends are also reviewed for males from the USA (where cigarette tar deliveries have been greatly reduced) and from the USSR (where they have not).


Injury prevalence across sports: a descriptive analysis on a representative sample of the Danish population.
Physical activity plays an important role in public health, owing to a range of health-related benefits that it provides. Sports-related injuries are known to be an important barrier to continued physical activity. Still, the prevalence of injuries on a general population level has not yet been explored in a descriptive epidemiological investigation. The purpose of the questionnaire-based study, therefore, was to describe the prevalence of injury in a representative sample of the Danish population. Two samples of 10,000 adults (> 15 years) and 6500 children and adolescents (7-15 years) were invited to respond to a web-based questionnaire. Of these, 3498 adults (35.0%) and 3221 children (49.6%) responded successfully. The definition of sports injury was time-loss and medical attention-based, inhibiting participants from sports activity for at least 7 days, and/or involved contact with a healthcare professional, respectively. Amongst adults, 642 (18.4% [95%CI: 17.1%; 19.6%]) reported to have had an injury within the past 12 months. Males reported significantly more injuries than females (difference in prevalence proportion: 9.2%-points [95%CI: 6.7%-points; 11.8%-points]). The prevalence of injuries was greatest in running (ninj = 198), football (ninj = 94) and strength training (ninj = 89). Amongst children, 621 (19.3% [95%CI: 17.9%; 20.6%]) had been injured. No difference in injury prevalence proportion existed between boys and girls. The prevalence of injuries was greatest in football (ninj = 235), handball (ninj = 86) and gymnastics (ninj = 66). Sports injuries seem to be very frequent in Denmark, since a total of 18.4% of the adults and 19.3% of the children reported having had one or more injuries within the past 12 months, equal to either time lost with physical activity and/or contact to the health care system.


Measuring Disease Damage and Its Severity in Childhood-Onset Systemic Lupus Erythematosus.
To describe the frequency and types of disease damage occurring with childhood-onset systemic lupus erythematosus (SLE) as measured by the 41-item Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), and to assess the SDI's ability to reflect damage severity. Information for the SDI was prospectively collected from 1,048 childhood-onset SLE patients. For a subset of 559 patients, physician-rated damage severity measured by visual analog scale (MD VAS damage) was also available. Frequency of SDI items and the association between SDI summary scores and MD VAS damage were estimated. Finally, an international consensus conference, using nominal group technique, considered the SDI's capture of childhood-onset SLE-associated damage and its severity. After a mean disease duration of 3.8 years, 44.2% of patients (463 of 1,048) already had an SDI summary score >0 (maximum 14). The most common SDI items scored were proteinuria, scarring alopecia, and cognitive impairment. Although there was a moderately strong association between SDI summary scores and MD VAS damage (Spearman's r = 0.49, P < 0.0001) in patients with damage (SDI summary score >0), mixed-effects analysis showed that only 4 SDI items, each occurring in <2% of patients overall, were significantly associated with MD VAS damage. There was consensus among childhood-onset SLE experts that the SDI in its current form is inadequate for estimating the severity of childhood-onset SLE-associated damage. Disease damage as measured by the SDI is common in childhood-onset SLE, even with relatively short disease durations. Given the shortcomings of the SDI, there is a need to develop new tools to estimate the impact of childhood-onset SLE-associated damage.


The conservation value of degraded forests for agile gibbons Hylobates agilis.
All gibbon species are globally threatened with extinction yet conservation efforts are undermined by a lack of population and ecological data. Agile gibbons (Hylobates agilis) occur in Sumatra, Indonesia and adjacent mainland Southeast Asia. Population densities are known from four sites (three in Sumatra) while little is known about their ability to tolerate habitat degradation. We conducted a survey of agile gibbons in Harapan Rainforest, a lowland forest site in Sumatra. The area has been severely degraded by selective logging and encroachment but is now managed for ecosystem restoration. We used two survey methods: an established point count method for gibbons with some modifications, and straight line transects using auditory detections. Surveys were conducted in the three main forest types prevalent at the site: high, medium, and low canopy cover secondary forests. Mean group density estimates were higher from point counts than from line transects, and tended to be higher in less degraded forests within the study site. We consider points more time efficient and reliable than transects since detectability of gibbons was higher from points per unit effort. We recommend the additional use of Distance sampling methods to account for imperfect detection and provide other recommendations to improve surveys of gibbons. We estimate that the site holds at least 6,070 and as many as 11,360 gibbons. Our results demonstrate that degraded forests can be extremely important for the conservation of agile gibbons and that efforts to protect and restore such sites could contribute significantly to the conservation of the species.