PROGRESS (perindopril protection against recurrent stroke study): rationale and design. PROGRESS Management Committee [corrected].
Patients with a history of cerebrovascular disease have a very high risk of stroke, and usual levels of both systolic and diastolic blood pressure are directly and continuously associated with this risk. Trials of blood pressure lowering in patients with transient ischaemic attacks or stroke have been too small to reliably detect the effects on stroke risk of the modest blood pressure reductions achieved. The primary objective of PROGRESS is to determine precisely the effects of blood pressure reduction with an angiotensin converting enzyme (ACE) inhibitor-based regimen on the stroke risk in patients with a history of transient ischaemic attacks or minor stroke. The study is a randomized, double-blind, placebo-controlled clinical trial. Before randomization, there is a 4-week run-in phase on open-label ACE inhibitor treatment. The scheduled duration of treatment and follow-up is 4-5 years. The study will be conducted in collaborating clinical centres in Australia, Belgium, the People's Republic of China, France, Italy, Japan, New Zealand, Sweden and the United Kingdom. The study will involve 6000 patients with a history of transient ischaemic attacks or stroke (ischaemic or haemorrhagic) in the past 5 years. To be eligible patients should have no definite indication for or contra-indication to treatment with an ACE inhibitor and no disability likely to prevent regular attendance at study clinics. Study treatment will comprise perindopril and indapamide or matching placebos for patients without an indication for or contra-indication to treatment with a diuretic, perindopril alone or matching placebo for all other patients. The primary study outcome is total strokes and secondary outcomes include fatal or disabling strokes, total major cardiovascular events, cardiovascular deaths, cognitive function and dementia, and disability and dependency.


Detection of plant virus particles with a capacitive field-effect sensor.
Plant viruses are major contributors to crop losses and induce high economic costs worldwide. For reliable, on-site and early detection of plant viral diseases, portable biosensors are of great interest. In this study, a field-effect SiO2-gate electrolyte-insulator-semiconductor (EIS) sensor was utilized for the label-free electrostatic detection of tobacco mosaic virus (TMV) particles as a model plant pathogen. The capacitive EIS sensor has been characterized regarding its TMV sensitivity by means of constant-capacitance method. The EIS sensor was able to detect biotinylated TMV particles from a solution with a TMV concentration as low as 0.025 nM. A good correlation between the registered EIS sensor signal and the density of adsorbed TMV particles assessed from scanning electron microscopy images of the SiO2-gate chip surface was observed. Additionally, the isoelectric point of the biotinylated TMV particles was determined via zeta potential measurements and the influence of ionic strength of the measurement solution on the TMV-modified EIS sensor signal has been studied.


West Nile virus: a primer for the otolaryngologist.
Since recognition in the United States with a 1999 New York City epidemic, West Nile virus has enduringly migrated westward, leaving few states unaffected. Infection rates are rising at an alarming rate, doubling every year since introduction, with more than 9800 cases in 2003 alone and more than 260 deaths. Patients may present with myriad symptoms including a maculopapular rash that affects the face and trunk and diffuse lymphadenopathy, both of which may result in the initial consultation of the otolaryngologist. We review the clinical history of West Nile virus and its epidemiology, laboratory findings, and variable clinical presentation, with an emphasis on otolaryngologic manifestations. STUDY DESIGN AND SETTING COMPREHENSIVE: review of the literature over the past 50 years with an emphasis on what the present-day otolaryngologist needs to know concerning West Nile virus. Clinical manifestations of the head and neck such as encephalitis, meningitis, maculopapular rash, lymphadenopathy and dysphagia are discussed. To date, there are no articles in the otolaryngology literature discussing West Nile virus. These patients may present initially to multiple providers in diverse specialties because of multifarious initial signs and symptoms. The otolaryngologist must be educated on this quickly growing affliction and practice with a high index of suspicion. In this article we describe the clinical manifestations of West Nile virus, with an emphasis on the otolaryngologic manifestations. The otolaryngologist must become educated about this entity to facilitate preventative measures, adequately treat, and assist other providers in hopeful control and potential eradication of this infectious threat.


Developing a targeting system for bacterial membranes: measuring receptor-phosphatidylglycerol interactions with (1)H NMR, ITC and fluorescence correlation spectroscopy.
An ammonium picket porphyrin that targets bacterial membranes has been prepared and shown to bind to phosphatidylglycerol (PG), a bacterial lipid, when the lipid was in solution, contained within synthetic membrane vesicles, or when in Gram-negative and Gram-positive bacterial membranes. The multifunctional receptor was designed to interact with both the phosphate anion portion and neutral glycerol portion of the lipid headgroup. The receptor's affinity and selectivity for binding to surfactant vesicles or lipid vesicles that contain PG within their membranes was directly measured using fluorescence correlation spectroscopy (FCS). FCS demonstrated that the picket porphyrin's binding pocket was complementary for the lipid headgroup, since simple Coulombic interactions alone did not induce binding. (1)H NMR and isothermal titration calorimetry (ITC) were used to determine the receptor's binding stoichiometry, receptor-lipid complex structure, binding constant, and associated thermodynamic properties of complexation in solution. The lipid-receptor binding motif in solution was shown to mirror the binding motif of membrane-bound PG and receptor. Cell lysis assays with E. coli (Gram-negative) and Bacillus thuringiensis (Gram-positive) probed with UV/Visible spectrophotometry indicated that the receptor was able to penetrate either bacterial cell wall and to bind to the bacterial inner membrane.


A chloroplast phylogeny of Arisaema (Araceae) illustrates Tertiary floristic links between Asia, North America, and East Africa.
The evolution of Arisaema is reconstructed, based on combined sequences (2048 aligned bases) from the chloroplast trnL intron, trnL-trnF spacer, and rpl20-rps12 spacer obtained for species from all 11 sections, including sectional type species and geographically disjunct East African and North American/Mexican species. Analyses were rooted with a representative sample of the closest outgroups, Pinellia and Typhonium, to rigorously test the monophyly of Arisaema. Sections in Arisaema are mostly based on leaf, stem, and inflorescence characters and, with one exception, are not rejected by the molecular data; however, statistical support for sectional relationships in the genus remains poor. Section Tortuosa, which includes eastern North American A. dracontium and Mexican A. macrospathum, is demonstrably polyphyletic. The third New World species, A. triphyllum, also occurs in eastern North America and groups with a different Asian clade than do A. dracontium/A. macrospathum. The genus thus appears to have entered North America twice. Fossil infructescences similar to those of A. triphyllum are known from approximately 18 million-year-old deposits in Washington State and can serve to calibrate a molecular clock. Constraining the age of A. triphyllum to 18 million years (my) and applying either a semiparametric or an ultrametric clock model to the combined data yields an age of approximately 31-49 my for the divergence of A. dracontium/A. macrospathum from their Asian relatives and of 19-32 my for the divergence between African A. schimperianum and a Tibetan/Nepalese relative. The genus thus provides an example of the Oligocene/Miocene floristic links between East Africa, Arabia, the Himalayan region, China, and North America. The phylogeny also suggests secondary loss of the environmental sex determination strategy that characterizes all arisaemas except for two subspecies of A. flavum, which have consistently bisexual spathes. These subspecies are tetraploid and capable of selfing, while a third subspecies of A. flavum is diploid and retains the sex-changing strategy. In the molecular trees, the sex-changing subspecies is sister to the two non-sex-changing ones, and the entire species is not basal in the genus.


Bone loss in the lower leg during 35 days of bed rest is predominantly from the cortical compartment.
Immobilization-induced bone loss is usually greater in the epiphyses than in the diaphyses. The larger fraction of trabecular bone in the epiphyses than in the diaphyses offers an intuitive explanation to account for this phenomenon. However, recent evidence contradicts this notion and suggests that immobilization-induced bone loss from the distal tibia epiphysis is mainly from the cortical compartment. The aim of this study was to establish whether this pattern of bone loss was a general rule during immobilization. We monitored various skeletal sites with different tissue composition during 5 weeks of immobilization. Ten healthy male volunteers with mean age of 24.3 years (SD 2.6 years) underwent strict horizontal bed rest. Bone scans were obtained during baseline data collection, at the end of bed rest and after 14 days of recovery by peripheral Quantitative Computed Tomography (pQCT). Sectional images were obtained from the distal tibia epiphysis (at 4% of the tibia's length), from the diaphysis (at 38%), from the proximal metaphysis (at 93%) and from the proximal epiphysis (at 98%), as well as from the distal femur epiphysis (at 4% of the femur's length) and from the patella. Relative bone losses were largest at the patella, where they amounted to -3.2% (SD 1.8%, p<0.001) of the baseline values, and smallest at the tibia diaphysis, where they amounted to -0.7% (SD 1.0%, p=0.019). The relative losses were generally larger from cortical than from trabecular compartments (p=0.004), and whilst all skeletal sites depicted such cortical losses, substantial trabecular losses were found only from the proximal tibia epiphysis. Results confirm that the differential losses from the various skeletal sites cannot be explained on the basis of trabecular vs. cortical tissue composition differences, but that endocortical circumference can account for the different amounts of bone loss in the tibia. The present study therefore supports the suggestion of the subendocortical layer as a transitional zone, which can readily be transformed into trabecular bone in response to immobilization. The latter will lead to cortical thinning, a factor that has been associated with the risk of fracture and with osteoarthritis.


First Aid and Pre-Hospital Management of Venomous Snakebites.
Antivenom is the definitive treatment for venomous snakebites, but is expensive and not available in many rural and poorly developed regions. Timely transportation to facilities that stock and administer antivenom may not be available in rural areas with poorly developed emergency medical services. These factors have led to consideration of measures to delay onset of toxicity or alternatives to antivenom therapy. PubMed searches were conducted for articles on snakebite treatment, or that contained first aid, emergency medical services, tourniquets, pressure immobilization bandages, suction devices, and lymphatic flow inhibitors. The reviewed articles describe how venoms spread after a venomous snakebite on an extremity, list the proposed first aid measures for delaying the spread of venoms, and evaluate the scientific studies that support or refute methods of snakebite first aid. The recommendations for field treatment of venomous snakebites will be discussed. The evidence suggests that pressure immobilization bandages and related strategies are the best interventions to delay onset of systemic toxicity from venomous snakebites but may increase local toxicity for venoms that destroy tissue at the site of the bite, so their use should be individualized to the circumstances and nature of the venom.


Association between a cell-seeded collagen matrix and cellular cardiomyoplasty for myocardial support and regeneration.
The objective of cellular cardiomyoplasty is to regenerate the myocardium using implantation of living cells. Because the extracellular myocardial matrix is deeply altered in ischemic cardiomyopathies, it could be important to create a procedure aiming at regenerating both myocardial cells and the extracellular matrix. We evaluated the potential of a collagen matrix seeded with cells and grafted onto infarcted ventricles. A myocardial infarction was created in 45 mice using coronary artery ligation. Animals were randomly assigned to 4 local myocardial treatment groups. Group I underwent sham treatment (injection of cell culture medium). Group II underwent injection of human umbilical cord blood mononuclear cells (HUCBCs). Group III underwent injection of HUCBCs and fixation onto the epicardium of a collagen matrix seeded with HUCBCs. Group IV underwent fixation of collagen matrix (without cells) onto the infarct. Echocardiography was performed on postoperative days 7 and 45, followed by histological studies. Echocardiography showed that the association between the cell-loaded matrix and the intrainfarct cell implants was the most efficient approach to limiting postischemic ventricular dilation and remodeling. Ejection fraction improved in both cell-treated groups. The collagen matrix alone did not improve left ventricular (LV) function and remodeling. Histology in Group III showed fragments of the collagen matrix thickening and protecting the infarct scars. Segments of the matrix were consistently aligned along the LV wall, and cells were assembled within the collagen fibers in large populations. Intramyocardial injection of HUCBCs preserves LV function following infarction. The use of a cell-seeded matrix combined with cell injections prevents ventricular wall thinning and limits postischemic remodeling. This tissue engineering approach seems to improve the efficiency of cellular cardiomyoplasty and could emerge as a new therapeutic tool for the prevention of adverse remodeling and progressive heart failure.


KSR1- and ERK-dependent translational regulation of the epithelial-to-mesenchymal transition.
The epithelial-to-mesenchymal transition (EMT) is considered a transcriptional process that induces a switch in cells from a polarized state to a migratory phenotype. Here, we show that KSR1 and ERK promote EMT-like phenotype through the preferential translation of Epithelial-Stromal Interaction 1 (EPSTI1), which is required to induce the switch from E- to N-cadherin and coordinate migratory and invasive behavior. EPSTI1 is overexpressed in human colorectal cancer (CRC) cells. Disruption of KSR1 or EPSTI1 significantly impairs cell migration and invasion in vitro, and reverses EMT-like phenotype, in part, by decreasing the expression of N-cadherin and the transcriptional repressors of E-cadherin expression, ZEB1 and Slug. In CRC cells lacking KSR1, ectopic EPSTI1 expression restored the E- to N-cadherin switch, migration, invasion, and anchorage-independent growth. KSR1-dependent induction of EMT-like phenotype via selective translation of mRNAs reveals its underappreciated role in remodeling the translational landscape of CRC cells to promote their migratory and invasive behavior.


Severity of Victimization and Co-Occurring Mental Health Disorders Among Substance Using Adolescents.
BACKGROUND: Co-occurring mental health disorders are widespread among substance using adolescents. Severity of victimization may be an important factor in explaining co-occurrence of mental health problems among adolescents with substance misuse problems. PURPOSE: The purpose of this study was to evaluate whether severe victimization experiences were shared risk factors for internalizing only, externalizing only, and co-occurring internalizing and externalizing disorders among victimized substance-using adolescents. METHOD: Data for this cross-sectional study were obtained from a multisite research project. Adolescents, ages 11-18, participated in a comprehensive screening program for substance abuse at 106 Substance Abuse and Mental Health Services Administration (SAMHSA) Center for Substance Abuse Treatment (CSAT)-funded grantee sites throughout the United States. RESULTS: Longer duration/frequent victimization, more than one type of victimization, and recent victimization were related to co-occurring internalizing and externalizing disorders. Victimization by a trusted person, however, was only related to internalizing disorders. CONCLUSION: The findings show that some indicators of severe victimization experiences are shared risk factors for internalizing, for externalizing, and for co-occurring internalizing and externalizing problems, thus providing support for the common factors model of co-morbidity. These findings suggest that practitioners in substance abuse treatment must thoroughly assess for severe victimization experiences among adolescents presenting with co-occurring mental health issues. Treatment planning and interventions may focus on helping adolescents cope effectively with their victimization experiences and addressing their MH needs.


'It's like a bag of pick and mix--you don't know what you are going to get': young people's experience of neurofibromatosis Type 1.
To explore the day-to-day experience of young people living with neurofibromatosis type 1 in the UK, focusing on the role that appearance plays in this experience. neurofibromatosis type 1 is a genetic condition, which is highly variable and unpredictable. It can result in varying degrees of visible difference (disfigurement). Both the effect of NF1 on appearance and its uncertainty can prove particularly difficult for those affected. However, very little research to date has investigated the psychosocial impact of neurofibromatosis type 1 on young people or their experiences of managing it. Exploratory qualitative interview study. Nine young people aged 14-24, with a confirmed diagnosis of neurofibromatosis type 1, took part in semi-structured interviews between March-September 2011. Interview transcripts were thematically analysed. Three key themes were identified from the data: (1) 'Different things to different people' reflecting the variability in the condition; (2) 'Relationships and reactions' relating to individuals' social experience; and (3) 'Understanding and misunderstanding' reflecting participants' experiences with organizations and social structures. Findings suggest a need for further research to explore young people's adaptation and management of neurofibromatosis type 1. In particular, raising awareness and understanding of the condition among professionals and in the general public was an important issue for young people. In addition, access to trustworthy information about neurofibromatosis type 1 and practical advice to support adjustment to an altered appearance and managing stigma experiences are highlighted as areas to be considered further.


Data linkage to estimate the extent and distribution of occupational disease: new onset adult asthma in Alberta, Canada.
Although occupational asthma is a well recognized and preventable disease, the numbers of cases presenting for compensation may be far lower than the true incidence. Workers' Compensation Board (WCB) claims for any reason 1995-2004 were linked to physician billing data. New onset adult asthma (NOAA) was defined as a billing for asthma (ICD-9 code of 493) in the 12 months prior to a WCB claim without asthma in the previous 3 years. Incidence was calculated by occupation, industry and, in a case-referent analysis, exposures estimated from an asthma specific job exposure matrix. There were 782,908 WCB eligible claims, with an incidence rate for NOAA of 1.6%: 23 occupations and 21 industries had a significantly increased risk. Isocyanates (OR 1.54: 95% CI 1.01-2.36) and exposure to mixed agricultural allergens (OR = 1.59: 95% CI 1.17-2.18) were related to NOAA overall, as were exposures to cleaning chemicals in men (OR = 1.91:95% CI 1.34-2.73). Estimates of the number of cases of occupational asthma suggested a range of 4% to about half for the proportion compensated. Data linkage of administrative records can demonstrate under-reporting of occupational asthma and indicate areas for prevention.


Innovation network.
Technological progress builds upon itself, with the expansion of invention in one domain propelling future work in linked fields. Our analysis uses 1.8 million US patents and their citation properties to map the innovation network and its strength. Past innovation network structures are calculated using citation patterns across technology classes during 1975-1994. The interaction of this preexisting network structure with patent growth in upstream technology fields has strong predictive power on future innovation after 1995. This pattern is consistent with the idea that when there is more past upstream innovation for a particular technology class to build on, then that technology class innovates more.


Characterization of the resistome in manure, soil and wastewater from dairy and beef production systems.
It has been proposed that livestock production effluents such as wastewater, airborne dust and manure increase the density of antimicrobial resistant bacteria and genes in the environment. The public health risk posed by this proposed outcome has been difficult to quantify using traditional microbiological approaches. We utilized shotgun metagenomics to provide a first description of the resistome of North American dairy and beef production effluents, and identify factors that significantly impact this resistome. We identified 34 mechanisms of antimicrobial drug resistance within 34 soil, manure and wastewater samples from feedlot, ranch and dairy operations. The majority of resistance-associated sequences found in all samples belonged to tetracycline resistance mechanisms. We found that the ranch samples contained significantly fewer resistance mechanisms than dairy and feedlot samples, and that the resistome of dairy operations differed significantly from that of feedlots. The resistome in soil, manure and wastewater differed, suggesting that management of these effluents should be tailored appropriately. By providing a baseline of the cattle production waste resistome, this study represents a solid foundation for future efforts to characterize and quantify the public health risk posed by livestock effluents.


SIRS score reflects clinical features of non-acetaminophen-related acute liver failure with hepatic coma.
In acetaminophen-induced acute liver failure (ALF), the hepatic coma grade worsens and mortality rates increase, as the number of systemic inflammatory response syndrome components fulfilled (SIRS score) increases. This study aimed to investigate the impact of SIRS score on clinical features of non-acetaminophen-related ALF. Ninety-nine patients with non-acetaminophen-related ALF with hepatic coma who did not undergo liver transplantation were investigated. Each patient was given a SIRS score of 0, 1, 2, 3 or 4 at the time of diagnosis. At the diagnosis of ALF with hepatic coma, with the increase of SIRS score, hepatic coma grade and prothrombin activity were deteriorated. After the diagnosis of ALF with hepatic coma, 25 patients (25%) developed acute respiratory distress syndrome (ARDS), 31 patients (31%) developed disseminated intravascular coagulation (DIC), and 21 patients (22%) developed acute renal failure (ARF). Thirty-eight patients (38%) developed MOF. With the increase of SIRS score, frequencies of the development of ARDS, DIC and MOF increased. ARF was more frequently developed in patients with a SIRS score of 2 or higher. Overall, 36 patients (36%) survived. Overall survival rate was 66% in 29 patients with a score of 0, 43% in 21 patients with a score of 1, 17% in 29 patients with a score of 2 and 15% in 20 patients with a score of 3 or 4. SIRS score will be useful for predicting not only the overall survival but also the development of complications such as ARDS, DIC and MOF in non-acetaminophen-related ALF with hepatic coma.


A survey approach for finding cases of epilepsy.
Identify persons with epilepsy by first looking for prescriptions for particular antiseizure drugs. Follow these prescriptions from the pharmacies to the physicians who wrote them for patients. Ask the physicians whether the patients have epilepsy. Finally, contact the patients who do have epilepsy to elicit information about the impact of that condition on their lives. With these steps, it may be possible to carry out successfully a probability survey of epilepsy in the United States population. To learn more about this approach, a field test was funded by the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) of the Public Health Service. From 1978 through 1982, the work was planned, carried out, and evaluated by Research Triangle Institute, Research Triangle Park, NC. Epilepsy is a sensitive topic to ask about in a survey. Also, the condition is sufficiently rare to render ordinary survey approaches inefficient. Even if rarity were not an issue, there would be the problem of response error because a person with epilepsy does not, as a rule, have much clinical information on his or her condition. Better information lies with the physician who provides the care, but many physicians are busy with their practices. Furthermore, their record systems are usually not designed for easy retrieval of information, unless the names of patients are available. In the survey approach considered here, the names of patients are obtained through a random sampling of prescriptions for antiseizure drugs. The field test was divided into three phases with special activities reserved for each. The most important problem confronted was how to safeguard the confidentiality of relationships between pharmacist and patient and between physician and patient.Special guidelines on confidentiality were put into effect for the data collection. These guidelines,however, contributed to serious problems of nonresponse-especially for physicians. This article provides a brief account of the field test, including a rationale for the survey strategy of finding cases of epilepsy through prescriptions for antiseizuredrugs.


Interactive effects of K+, acid, norepinephrine, and ischemia on the heart: implications for exercise.
We tested the hypothesis that cardiac ischemia uncouples the beneficial interaction among hyperkalemia, acidosis, and raised plasma catecholamines when these chemicals are changed to mimic their exercise levels. Potassium chloride, lactic acid, and norepinephrine (NE) were infused intravenously for 2 min into anesthetized, artificially ventilated, thoracotomized rabbits during either occlusion of the left circumflex artery (3 min; n = 10) or after a period of prolonged ischemia (20 min; n = 7) that led to a small infarction. NE (1 microg x kg(-1) x min(-1) iv) offset the negative cardiac effects of hyperkalemia (up to 8.7 +/- 0.7 mM) and acidosis (arterial pH 7.09 +/- 0.03) in normal hearts. Cardiac performance was not significantly depressed by either acute or chronic ischemia before any infusions. However, the protective effect of NE during acute ischemia or after prolonged ischemia with hyperkalemia and acidosis was substantially reduced. These results show that cardiac ischemia attenuates the protective action of NE and increases the depressive effects of hyperkalemia and acidosis. Whether myocardial ischemia amplifies the cardiotoxic effects of hyperkalemia and acidosis during vigorous exercise by attenuating the beneficial effect of catecholamines remains to be determined.


Evaluation of Cladribine treatment in refractory celiac disease type II.
To evaluate cladribine [2-chlorodeoxyadenosine (2-CdA)] therapy in refractory celiac disease (RCD) II. An open-label cohort-study of RCD II patients treated with 2-CdA was performed between 2000 and 2010. Survival rate, enteropathy associated T-cell lymphoma (EATL) occurrence, clinical course, and histological and immunological response rates were evaluated. Overall, 32 patients were included with a median follow-up of 31 mo. Eighteen patients responded well to 2-CdA. Patients responsive to 2-CdA had a statistically significant increased survival compared to those who were unresponsive. The overall 3- and 5-year survival was 83% in the responder and 63% and 22% in the non-responder group, respectively. The overall 2-year clinical, histological and immunological response rates were 81%, 47% and 41%, respectively. Progression into EATL was reported in 16%, all of these patients died. Treatment of RCD II with 2-CdA holds promise, showing excellent clinical and histological response rates, and probably less frequent transition into EATL.


The impact of physical activity level on the short- and long-term pain relief from supervised exercise therapy and education: a study of 12,796 Danish patients with knee osteoarthritis.
It is unknown if people with knee osteoarthritis (OA) who are already physically active benefit from exercise therapy. To study the impact of physical activity level on pain relief, post-intervention and 12 months following exercise therapy and education. The analyses included 12,796 patients with knee OA from the Good Life with osteoArthritis in Denmark (GLA:D®) program. GLA:D® consists of 12 sessions of supervised neuromuscular exercise and two sessions of education delivered by trained physical therapists. The impact of physical activity level on change in knee pain intensity (0-100) immediately post-intervention and at 12 months was estimated using a mixed-effects model adjusted for age, sex, body mass index (BMI), educational level and comorbidity. Physical activity level was assessed using the University of California, Los Angeles (UCLA) activity scale. Physically inactive patients had worse baseline pain compared to patients with low to very high physical activity level (6-15 points worse; P < 0.001). Pain decreased by 13.4 points (95% CI; 9.7 to 17.1) following the treatment program and by 12.8 points (7.7-18.0) at 12 months in the inactive patients, with similar improvements in patients with higher levels of physical activity (P = 0.278 to 0.851). In patients with knee OA, similar and persistent long-term pain relief was found from supervised exercise therapy and education regardless of the initial physical activity level. Patients with high to very high levels of physical activity can expect pain relief from supervised exercise therapy and education similar to that of more physically inactive patients.


Mechanisms of membrane toxicity of hydrocarbons.
Microbial transformations of cyclic hydrocarbons have received much attention during the past three decades. Interest in the degradation of environmental pollutants as well as in applications of microorganisms in the catalysis of chemical reactions has stimulated research in this area. The metabolic pathways of various aromatics, cycloalkanes, and terpenes in different microorganisms have been elucidated, and the genetics of several of these routes have been clarified. The toxicity of these compounds to microorganisms is very important in the microbial degradation of hydrocarbons, but not many researchers have studied the mechanism of this toxic action. In this review, we present general ideas derived from the various reports mentioning toxic effects. Most importantly, lipophilic hydrocarbons accumulate in the membrane lipid bilayer, affecting the structural and functional properties of these membranes. As a result of accumulated hydrocarbon molecules, the membrane loses its integrity, and an increase in permeability to protons and ions has been observed in several instances. Consequently, dissipation of the proton motive force and impairment of intracellular pH homeostasis occur. In addition to the effects of lipophilic compounds on the lipid part of the membrane, proteins embedded in the membrane are affected. The effects on the membrane-embedded proteins probably result to a large extent from changes in the lipid environment; however, direct effects of lipophilic compounds on membrane proteins have also been observed. Finally, the effectiveness of changes in membrane lipid composition, modification of outer membrane lipopolysaccharide, altered cell wall constituents, and active excretion systems in reducing the membrane concentrations of lipophilic compounds is discussed. Also, the adaptations (e.g., increase in lipid ordering, change in lipid/protein ratio) that compensate for the changes in membrane structure are treated.


Characterisation of endoplasmic reticulum and plasma membrane Ca(2+)-ATPases in pancreatic beta-cells and in islets of Langerhans.
We have investigated the plasma membrane (PMCA) and endoplasmic reticulum (SERCA) Ca(2+)-ATPases involved in active transport of Ca2+ in pancreatic beta-cell lines (MIN6, HIT T15, RINm5F) and in islets of Langerhans. Under selective membrane phosphorylation conditions (at low ATP concentration, in the presence of Ca2+ and La3+ and in the absence of Mg2+ at 4 degrees C) the only labelled proteins are the phosphoenzyme intermediates of the Ca(2+)-ATPases. Under these conditions, beta-cell membranes incorporated 32P from [gamma-32P]ATP into two proteins with molecular mass on acidic SDS-polyacrylamide gels of around 115 and 150 kDa. The 150 kDa band was identified as PMCA (i) by reaction with a monoclonal anti-human erythrocyte plasma membrane Ca(2+)-ATPase antibody; (ii) by its typical tryptic cleavage pattern which generated an 80 kDa band; (iii) by lack of inhibition of its autophosphorylation by SERCA-specific inhibitors. The 115 kDa band was identified as SERCA (i) by reaction with a polyclonal anti-rat fast skeletal muscle Ca(2+)-ATPase antibody; (ii) by the concentration-dependent inhibition of its autophosphorylation by thapsigargin and 2,5-di(t-butyl)-1,4-benzohydroquinone (tBHQ), which are specific inhibitors of SERCA. The 115 kDa band was further characterised as the SERCA-2b isoform by reaction with a polyclonal rabbit antibody against the 12 C-terminal amino acids of SERCA-2b.


Neonatal severe hyperparathyroidism secondary to a novel homozygous CASR gene mutation.
Neonatal severe hyperparathyroidism (NSHPT) is a rare autosomal recessive disease. Children present within the first 6 months of life and more commonly in the first few weeks. Common presentation is poor feeding, polyuria, dehydration, lethargy, failure to thrive, hypotonia, gastrointestinal dysmotility, osteopenia and symptoms of respiratory distress due to a poorly developed chest cage. We present a case of a 2-month old girl with severe hypercalcemia and hyperparathyroidism. She was found to have a novel homozygous mutation in the acceptor splicing site of intron 4 (c.1378 -2A>G) of the calcium sensing receptor gene (CASR). This mutation causes frame shift deletion of exon 5 and insensitivity of CASR to calcium. The patient was treated with intravenous fluids, fruosemide, calcitonin, intravenous pamidronate and oral cinacalcet. She did not respond to medical treatment. Parathyroid gland imaging including ultrasound, MRI and sestamibi nuclear scan were not helpful in localizing the glands. Her symptoms resolved following total parathyroidectomy. She is being treated with alfacalcidiol and calcium supplements to maintain normal serum calcium and phosphate. She achieved her normal developmental milestones.


Unique structural and electronic features of perferryl-oxo oxidant in Cytochrome P450.
We have performed hybrid density functional theory (DFT) calculations on the geometric and electronic structures of low-lying doublet and quartet ferryl-oxo [Fe(IV)═O] oxidants and a doublet perferryl-oxo [Fe(V)═O] oxidant in Cytochrome P450. Fully optimized structures of compound I models have been determined, and the proper symmetry of wave functions has been restored by the spin-projection technique. The results show that the perferryl-oxo species is relatively low lying, as compared with the excited state of the ferryl-oxo species, if the iron-oxo bond is properly described as the mixing of several appropriate excited electronic configurations to minimize electron repulsion. This means that the perferryl-oxo species is virtually in a mixed-valent resonance state, ↑Fe(V)═O ↔ ↑Fe(IV)•↑-↓•O, containing a highly reactive pπ atomic oxygen radical. The anionic thiolate ligand acts as a Lewis σ base and functions to achieve the stability of the perferryl-oxo complex and to activate the oxo ligand trans to it by asymmetric bond distortion along the O-Fe-S axis by lengthening the Fe-O bond and shortening the Fe-S bond, prior to the hydrogen-atom abstraction from the substrate.


Pacing and sprint performance in speed skating during a competitive season.
This study assessed the effect of time spent in several race sectors (S) on finishing time and determined the variance in distribution of skating time and in total race time for official 1000-m sprint races conducted during a competitive season. Total race and sector times for the first 200 m (S1) and the following two 400-m laps (S2 and S3) of 34 female and 31 male elite speed skaters performed during a series of World Cup Meetings were analyzed. Overall, skaters started fast, reached their peak in S2, and slowed down in S3, irrespective of race category considered (eg, rank of athlete, number of race, altitude of rink, starting lane). Regression analyses revealed that spending a shorter fraction of time in the last (women in S3: B = 239.1; P < .0001; men in S3: B = 201.5; P < .0001) but not in the first (women in S1: B = -313.1; P < .0001; men in S1: B = -345.6; P < .0001) race sector is associated with a short total race time. Upper- compared with lower-ranked skaters varied less in competition-to-competition sector and total race times (women: 0.02 to 0.33 vs 0.02 to 0.51; men: 0.01 to 0.15 vs 0.02 to 0.57). This study confirmed that skaters adopted a fast start pacing strategy during official 1000-m sprint races. However, analyses indicate that shortening time in the closing but not in the starting sector is beneficial for finishing fast. In addition, findings suggest that lower-ranked skaters should concentrate training on lowering their competition-to-competition variability in sector times.


The diversity of dolichol-linked precursors to Asn-linked glycans likely results from secondary loss of sets of glycosyltransferases.
The vast majority of eukaryotes (fungi, plants, animals, slime mold, and euglena) synthesize Asn-linked glycans (Alg) by means of a lipid-linked precursor dolichol-PP-GlcNAc2Man9Glc3. Knowledge of this pathway is important because defects in the glycosyltransferases (Alg1-Alg12 and others not yet identified), which make dolichol-PP-glycans, lead to numerous congenital disorders of glycosylation. Here we used bioinformatic and experimental methods to characterize Alg glycosyltransferases and dolichol-PP-glycans of diverse protists, including many human pathogens, with the following major conclusions. First, it is demonstrated that common ancestry is a useful method of predicting the Alg glycosyltransferase inventory of each eukaryote. Second, in the vast majority of cases, this inventory accurately predicts the dolichol-PP-glycans observed. Third, Alg glycosyltransferases are missing in sets from each organism (e.g., all of the glycosyltransferases that add glucose and mannose are absent from Giardia and Plasmodium). Fourth, dolichol-PP-GlcNAc2Man5 (present in Entamoeba and Trichomonas) and dolichol-PP- and N-linked GlcNAc2 (present in Giardia) have not been identified previously in wild-type organisms. Finally, the present diversity of protist and fungal dolichol-PP-linked glycans appears to result from secondary loss of glycosyltransferases from a common ancestor that contained the complete set of Alg glycosyltransferases.


Development of chick axial mesoderm: specification of prechordal mesoderm by anterior endoderm-derived TGFbeta family signalling.
Two populations of axial mesoderm cells can be recognised in the chick embryo, posterior notochord and anterior prechordal mesoderm. We have examined the cellular and molecular events that govern the specification of prechordal mesoderm. We report that notochord and prechordal mesoderm cells are intermingled and share expression of many markers as they initially extend out of Hensen's node. In vitro culture studies, together with in vivo grafting experiments, reveal that early extending axial mesoderm cells are labile and that their character may be defined subsequently through signals that derive from anterior endodermal tissues. Anterior endoderm elicits aspects of prechordal mesoderm identity in extending axial mesoderm by repressing notochord characteristics, briefly maintaining gsc expression and inducing BMP7 expression. Together these experiments suggest that, in vivo, signalling by anterior endoderm may determine the extent of prechordal mesoderm. The transforming growth factor (beta) (TGFbeta) superfamily members BMP2, BMP4, BMP7 and activin, all of which are transiently expressed in anterior endoderm mimic distinct aspects of its patterning actions. Together our results suggest that anterior endoderm-derived TGFbetas may specify prechordal mesoderm character in chick axial mesoderm.


Tumor promotion by Mdm2 splice variants unable to bind p53.
The Mdm2 oncoprotein physically associates with p53 and antagonizes its tumor suppressor functions. Previous studies indicate that some tumors express alternatively or aberrantly spliced Mdm2 variants that are unable to bind p53, but whether these actively contribute to carcinogenesis or are a byproduct of cancer progression has been unclear. In this study, we examined the ability of full-length Mdm2 and several tumor-derived splice variants to modulate tumor development in E micro -myc transgenic mice. We report that several tumor-derived Mdm2 splice variants promote tumorigenesis in a manner that is comparable with full-length Mdm2. Our results imply that the current paradigm for understanding Mdm2 action during oncogenesis is incomplete, and its splice variants contribute to human cancer.


Evaluation of Health in All Policies: concept, theory and application.
This article describes some of the crucial theoretical, methodological and practical issues that need to be considered when evaluating Health in All Policies (HiAP) initiatives. The approaches that have been applied to evaluate HiAP in South Australia are drawn upon as case studies, and early findings from this evaluative research are provided. The South Australian evaluation of HiAP is based on a close partnership between researchers and public servants. The article describes the South Australian HiAP research partnership and considers its benefits and drawbacks in terms of the impact on the scope of the research, the types of evidence that can be collected and the implications for knowledge transfer. This partnership evolved from the conduct of process evaluations and is continuing to develop through joint collaboration on an Australian National Health & Medical Research Council grant. The South Australian research is not seeking to establish causality through statistical tests of correlations, but instead by creating a 'burden of evidence' which supports logically coherent chains of relations. These chains emerge through contrasting and comparing findings from many relevant and extant forms of evidence. As such, program logic is being used to attribute policy change to eventual health outcomes. The article presents the preliminary program logic model and describes the early work of applying the program logic approach to HiAP. The article concludes with an assessment of factors that have accounted for HiAP being sustained in South Australia from 2008 to 2013.


Kynurenine plays an immunosuppressive role in 2,4,6-trinitrobenzene sulfate-induced colitis in mice.
Inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, is characterized by chronic intestinal inflammation leading to intestinal mucosal damage. Inflammatory bowel disease causes dysregulation of mucosal T cell responses, especially the responses of CD4+ T cells. Previously, we demonstrated that indoleamine-2,3-dioxygenase plays an immunosuppressive role in 2,4,6-trinitrobenzene sulfate (TNBS)-induced colitis. Although indoleamine-2,3-dioxygenase exerts immunosuppressive effects by altering the local concentration of tryptophan (Trp) and immunomodulatory Trp metabolites, the specific changes in immune regulation during colitis caused by Trp metabolites and its related enzymes remain unclear. To investigate role of kynurenine 3-monooxygenase (KMO) in TNBS-induced colitis and involvement of Trp metabolites in maintenance of intestinal homeostasis. Colitis was induced in eight-week-old male KMO+/+ or KMO-/- mice of C57BL/6N background using TNBS. Three days later, the colon was used for hematoxylin-eosin staining for histological grading, immunohistochemical or immunofluorescence staining for KMO, cytokines, and immune cells. Inflammatory and anti-inflammatory cytokines were measured using quantitative RT-PCR, and kynurenine (Kyn) pathway metabolites were measured by high-performance liquid chromatography. The cell proportions of colonic lamina propria and mesenteric lymph nodes were analyzed by flow cytometry. KMO expression levels in the colonic mononuclear phagocytes, including dendritic cells and macrophages increased upon TNBS induction. Notably, KMO deficiency reduced TNBS-induced colitis, resulting in an increased frequency of Foxp3+ regulatory T cells and increased mRNA and protein levels of anti-inflammatory cytokines, including transforming growth factor-β and interleukin-10. Absence of KMO reduced TNBS-induced colitis via generation of Foxp3+ regulatory T cells by producing Kyn. Thus, Kyn may play a therapeutic role in colon protection during colitis.


Collective Effervescence, Self-Transcendence, and Gender Differences in Social Well-Being During 8 March Demonstrations.
8 March (8M), now known as International Women's Day, is a day for feminist claims where demonstrations are organized in over 150 countries, with the participation of millions of women all around the world. These demonstrations can be viewed as collective rituals and thus focus attention on the processes that facilitate different psychosocial effects. This work aims to explore the mechanisms (i.e., behavioral and attentional synchrony, perceived emotional synchrony, and positive and transcendent emotions) involved in participation in the demonstrations of 8 March 2020, collective and ritualized feminist actions, and their correlates associated with personal well-being (i.e., affective well-being and beliefs of personal growth) and collective well-being (i.e., social integration variables: situated identity, solidarity and fusion), collective efficacy and collective growth, and behavioral intention to support the fight for women's rights. To this end, a cross-cultural study was conducted with the participation of 2,854 people (age 18-79; M = 30.55; SD = 11.66) from countries in Latin America (Mexico, Chile, Argentina, Brazil, Peru, Colombia, and Ecuador) and Europe (Spain and Portugal), with a retrospective correlational cross-sectional design and a convenience sample. Participants were divided between demonstration participants (n = 1,271; 94.0% female) and non-demonstrators or followers who monitored participants through the media and social networks (n = 1,583; 75.87% female). Compared with non-demonstrators and with males, female and non-binary gender respondents had greater scores in mechanisms and criterion variables. Further random-effects model meta-analyses revealed that the perceived emotional synchrony was consistently associated with more proximal mechanisms, as well as with criterion variables. Finally, sequential moderation analyses showed that proposed mechanisms successfully mediated the effects of participation on every criterion variable. These results indicate that participation in 8M marches and demonstrations can be analyzed through the literature on collective rituals. As such, collective participation implies positive outcomes both individually and collectively, which are further reinforced through key psychological mechanisms, in line with a Durkheimian approach to collective rituals.


Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is a genetic disease caused by mutations in desmosomal proteins. The phenotypic hallmark of ARVC is fibroadipocytic replacement of cardiac myocytes, which is a unique phenotype with a yet-to-be-defined molecular mechanism. We established atrial myocyte cell lines expressing siRNA against desmoplakin (DP), responsible for human ARVC. We show suppression of DP expression leads to nuclear localization of the desmosomal protein plakoglobin and a 2-fold reduction in canonical Wnt/beta-catenin signaling through Tcf/Lef1 transcription factors. The ensuing phenotype is increased expression of adipogenic and fibrogenic genes and accumulation of fat droplets. We further show that cardiac-restricted deletion of Dsp, encoding DP, impairs cardiac morphogenesis and leads to high embryonic lethality in the homozygous state. Heterozygous DP-deficient mice exhibited excess adipocytes and fibrosis in the myocardium, increased myocyte apoptosis, cardiac dysfunction, and ventricular arrhythmias, thus recapitulating the phenotype of human ARVC. We believe our results provide for a novel molecular mechanism for the pathogenesis of ARVC and establish cardiac-restricted DP-deficient mice as a model for human ARVC. These findings could provide for the opportunity to identify new diagnostic markers and therapeutic targets in patients with ARVC.


Changes in alcohol-related problems after alcohol policy changes in Denmark, Finland, and Sweden.
European Union travelers' allowances for alcohol import to Denmark, Sweden, and Finland were abolished in 2004. In addition, excise taxes on alcohol were lowered in 2003 and 2005 in Denmark, and in 2004 in Finland. Using northern Sweden as a control site, this study examines whether levels of reported alcohol problems have changed in Denmark, Finland, and southern Sweden as a consequence of these policy changes. Annual cross-sectional surveys were conducted in Denmark, Finland, and Sweden from 2003 to 2006. Five dependency items and seven extrinsic alcohol-related problems were examined. Changes were analyzed within each country/region with logistic regressions and tested for short- and long-term changes. Differential change was also tested between each country and the control site, northern Sweden. Prevalence of alcohol problems decreased over the study period. Only in selected subgroups did problems increase. This mainly occurred in the samples for northern Sweden and Finland, and mostly among older age groups and men. In relation to the control site, however, no increases in problem prevalence were found. Our findings on a decline in reported alcohol problems largely agree with published reports on alcohol consumption over the same period in the study countries. They do not agree, however, with findings on changes in health and social statistics in Finland and Denmark, where some significant increases in alcohol-related harm have been found.


Suture closure of subcutaneous fat and wound disruption after cesarean delivery: a meta-analysis.
To define the role of suture closure of the subcutaneous dead space in preventing wound complications after cesarean delivery. We searched MEDLINE, the Cochrane Database of Systematic Reviews, and the bibliographies of major texts and review articles. Only studies in which patients undergoing cesarean delivery were randomly assigned to closure of the subcutaneous space or to no closure were included. Each study was required to report on at least 1 of the following outcomes: wound infection, hematoma, seroma, or separation. The studies also reported "wound disruption," a combination of these outcomes which either explicitly stated or strongly implied the need for further wound care. Six studies meeting criteria were identified. Three studies included 875 patients with any subcutaneous thickness and noted a decrease in wound disruption with closure (relative risk [RR] 0.56; 95% confidence interval [CI] 0.36, 0.86). Two studies reported results from 181 patients with incision depth of 2 cm or less and noted no difference (RR 1.01; 95% CI 0.46, 2.20). Five studies reported results on 887 patients with wound thickness greater than 2 cm. Although only 1 study had a significant effect by itself, when results were combined, there was a significant decrease in wound disruption (RR 0.66; 95% CI 0.48, 0.91). This reduction seems to be largely a result of decreased wound seromas (4 studies, 852 patients, RR 0.42; 95% CI 0.24, 0.75). In women with wound thickness greater than 2 cm, subcutaneous closure resulted in a risk reduction of 6.2%, and 16.2 women would need subcutaneous closure to prevent 1 wound disruption (number needed to treat). Suture closure of subcutaneous fat during cesarean delivery results in a 34% decrease in risk of wound disruption in women with fat thickness greater than 2 cm.


Barriers and strategies for coordinating care among veterans with traumatic brain injury: a mixed methods study of VA polytrauma care team members.
Veterans who experience traumatic brain injury (TBI) may have long-term needs placing a premium on well-coordinated care. This study aimed to (1) identify barriers to care coordination for Veterans with TBI; and (2) describe strategies used by VA polytrauma care team members to coordinate care for Veterans with TBI. We utilised a mixed method design, including an online survey of VA polytrauma care team members (N = 236) and subsequent semi-structured interviews (N = 25). Analysis of the survey data was descriptive; interview data was analysed using constant comparative techniques. The most common system-related barriers 25 for access to military records (64%) and insufficient time (58%). The most common patient-related barriers were missed appointments/no shows (87%) and the mental health issues (74%). Strategies reported on the survey to promote coordination reflected the centrality of teamwork and communication, and included promoting multidisciplinary team collaboration (32%) and holding 30 regular meetings (23%). Interview findings were consistent, emphasising the effective functioning of multidisciplinary clinics. Polytrauma care team members encounter barriers to care coordination for Veterans with TBI, and have developed strategies in response. Information sharing, provider workload, communication, and patient engagement will be critical to address in future efforts to enhance care coordination in this context.


Degradation of lamin B1 precedes oligonucleosomal DNA fragmentation in apoptotic thymocytes and isolated thymocyte nuclei.
Chromatin condensation and nuclear envelope breakdown are characteristic features of apoptotic cell death, but the mechanisms underlying these phenomena have not been identified. Solubilization of nuclear lamin is responsible for both events in mitosis. In this work, we report that glucocorticoids stimulate rapid degradation of lamin B1 that occurs before oligonucleosomal DNA fragmentation in apoptotic thymocytes. Protease inhibitors and the Ca2+ buffering agent BAPTA-AM block lamin degradation and DNA fragmentation, indicating that the processes are regulated by similar or identical mechanisms. Incubation of isolated thymocyte nuclei with Ca2+ stimulates lamin degradation before the detection of oligonucleosomal DNA fragments. However, in contrast to lamin dissolution during mitosis and some other forms of apoptosis, glucocorticoid-induced degradation of lamin B1 in thymocytes is not accompanied by dephosphorylation-mediated activation of cdc2. Our results demonstrate that lamin degradation is an early feature of apoptosis in thymocytes and suggest that chromatin condensation and breakdown of the nuclear envelope may occur as a result of disruption of nuclear lamina architecture.


The Interaction Between Hematological Cancer Patients and Family Caregivers and Their Life Changes: A Qualitative Dyadic Approach.
Diagnosis of hematological cancer affects patients and caregivers as a unit. Few studies have focused on the relationship between hematological cancer patients and their caregivers. To explore (a) the interaction between patients receiving treatment for hematological cancer in a hematology-oncology clinic and their family caregivers and (b) perceived changes in lives of patients receiving treatment for hematological cancer in a hematology-oncology clinic and their family caregivers. We used a qualitative descriptive design with a dyadic approach. The study sample included 11 patients with hematological cancer and 11 family caregivers selected through purposive sampling. In-depth interviews were conducted using a semistructured interview format. As a result of a content analysis, 3 themes emerged: hidden emotions, companionship, and life changes. Both the patients and the family caregivers described coping by hiding their feelings, thoughts, and needs and reducing communication with each other. Dyad members described commitment to each other and an increase in confidence. In addition, the patients and the family caregivers experienced changes in their roles and perspectives during the diagnosis and treatment process. Patients with hematological cancer and family caregivers need nurses' support. Nurses should be prepared to provide patient-caregiver-based interventions. It is important that nurses take action to strengthen the relationship between patients and their caregivers, particularly with a focus on carrying out interventions to improve communication between them. Nurses can also strengthen dyads' coping by drawing attention to positive developments in their perspectives and relationships.


The cost-effectiveness of identifying and treating malnutrition in hospitals: a systematic review.
Disease-related malnutrition is known to have significant clinical and economic consequences. This systematic review of recent evidence aimed to establish the cost-effectiveness of identifying and treating malnutrition in the hospital setting. A search of four electronic databases and the Internet was conducted for relevant publications from 2003 to 2013. The search strategy considered both nutritional care and healthcare costs. Hospitalised adults with, or at risk of malnutrition, were the focus of the review. Eligibility criteria included publications of original research to identify or treat malnutrition through usual care. Studies with a focus on enteral and parenteral nutrition interventions were beyond the scope of the review. Methodological quality was assessed using the Consensus on Health Economic Criteria checklist. Of the 1174 records identified through database searching, 19 full-text articles were assessed for eligibility. Three studies were included in the final review, highlighting the absence of recent high quality cost-effectiveness studies in this field. One economic modelling study and two prospective clinical trials were included of moderate to high methodological quality. Definite conclusions could not be drawn regarding the cost-effectiveness of individual interventions because of the heterogeneity of treatments, controls and populations. The present review highlights an evidence gap in the care of malnourished hospitalised adults, limiting the ability of clinicians and healthcare managers to make informed, cost-effective treatment decisions. Further economic evaluations are needed and should be considered as a routine component of future research.


[An analog of gonadoliberin in the treatment of prostatic carcinoma].
Twenty-five patients with prostatic carcinoma were involved in a Gehan's oriented phase II trial of D-Trp6-LH-RH in daily doses of 500 mcg for 7 days and 100 mcg for 3 months, this lapse of time being considered optimal for evaluation of the short-term response to treatment in this disease. Serum levels of LH and testosterone decreased rapidly. After 3 months of treatment, pain had disappeared in 14/21 patients; urinary symptoms had completely regressed in 10/22 patients and partially regressed in 9. A more than 50% reduction in prostatic enlargement was detected by ultrasonography in 7/19 patients, and the overall proportion of regression at scintigraphy was 43%. Prostatic acid phosphatases decreased by more than 50% in 10/15 patients. The results obtained with this LH-RH agonist were equivalent to those of orchidectomy and oestrogen therapy. The new drug was well tolerated. Although some of the patients treated are still responding after more than 15 months of treatment, further studies are required to evaluate the duration of response.


Colocalization of fluorescent markers in confocal microscope images of plant cells.
This protocol describes the steps needed to perform quantitative statistical colocalization on two-color confocal images, specifically of plant cells. The procedure includes a calibration test to check the chromatic alignment of the confocal microscope. A software tool is provided to calculate the Pearson and Spearman correlation coefficients ('Pearson-Spearman correlation colocalization' ImageJ plug-in) across regions of interest within the image. Steps are included to help the user practice using the software. The result is a quantitative estimate of the amount of colocalization in the images. Manual masking takes about 1-15 min per image, depending on the detail required, and calculating the correlation coefficients is almost instantaneous. Examples of suitable dyes for such two-color colocalization include Oregon Green or Alexa Fluor 488 dyes in the green range (excited with 488-nm laser line) and Alexa Fluor 555 dye in the red range (excited with 543-nm laser line).


Mindfulness yoga during pregnancy for psychiatrically at-risk women: preliminary results from a pilot feasibility study.
Prenatal psychopathology may have an adverse impact on mother and baby, but few women receive treatment. We offered a 10-week mindfulness yoga (M-Yoga) intervention to psychiatrically high-risk pregnant women as an alternative to pharmacological treatment. Participants (N = 18) were primiparous, 12-26 weeks pregnant, and had elevated scores (>9) on the Edinburgh Postnatal Depression Screen at baseline. In addition to a baseline diagnostic assessment, women completed self-ratings on depression, mindfulness, and maternal-fetal attachment before and after M-Yoga. Findings suggest that M-Yoga was feasible, accepted and effective. Symptoms of depression were significantly reduced (p = 0.025), while mindfulness (p = 0.007) and maternal-fetal attachment (p = 0.000) significantly increased. Overall, this pilot study is the first to demonstrate that M-Yoga may be an effective treatment alternative or augmentation to pharmacotherapy for pregnant women at high risk for psychopathology.


Cost of care for cancer in a health maintenance organization.
The direct costs of medical care for cancer are examined at Kaiser Permanente (KP) in Northern California. Use data from July 1987 through June 1991 were obtained from KP automated files for all 21,977 KP patients in the Bay Area SEER registry with cancer at one of seven cancer sites. Medical charts were reviewed for a stratified sample of 886 patients. Costs were estimated for initial, continuing, and terminal care, and for all person time within 15 years of diagnosis, by stage at diagnosis. From diagnosis until death or 15 years, long-term costs attributable to cancer were as follows: breast, $35,000; colon, $42,000; rectum, $51,000; lung, $33,000; ovarian, $64,000; prostate, $29,000; and Non-Hodgkin's Lymphoma (NHL), $48,000. The utilization and cost results reported here may be useful in assessing the cost-effectiveness of cancer prevention and control programs, in adjusting capitation rates and budgets, and in estimating the aggregate medical care costs attributable to cancer.


Antifungal and antioxidant activities of organic and aqueous extracts of Annona squamosa Linn. leaves.
An increasing demand for natural additives has shifted the attention from synthetic to natural antioxidants and antifungal agents. This study was carried out to evaluate the antifungal and antioxidant activities of methanol, chloroform, and aqueous extracts of Annona squamosa Linn. leaves. The antifungal activities of all extracts of A. squamosa leaves against five different strains of fungi (Alternaria alternata, Candida albicans, Fusarium solani, Microsporum canis, and Aspergillus niger) were evaluated by the agar well diffusion method and the minimum inhibitory concentration of each extract was assessed by antifungal susceptibility using the broth microdilution method. The antioxidant potential of each extract was determined by free radicals (1,1-diphenyl-2-picrylhydrazyl, nitric oxide, and hydrogen peroxide) scavenging activity and reducing power property of A. squamosa leaves. Both organic and aqueous extracts were found to express dose-dependent inhibition against all tested fungi strains in both agar well diffusion and broth dilution methods. The free radical scavenging activity and reducing power property of all extracts were found to be concentration dependent, with the methanol extract exhibiting higher antioxidant activity than the chloroform extract, which was more effective than the aqueous extract of A. squamosa leaves. Results of phytochemical analysis of extracts showed the presence of glycosides, saponins, tannins, flavonoids, phenols, etc. The results obtained from in vitro studies of antifungal and antioxidant activities clearly suggest that the methanol, chloroform, and aqueous extracts of A. squamosa leaves possess antifungal and antioxidant activity.


Effects of methylmercury on approach and avoidance behavior of mallard ducklings.
Mallard ducks were fed a control diet or a diet containing 0.5 or 3 ppm mercury (as methylmercury dicyandiamide) based on the dry feed. These mercury diets are approximately equivalent to 0.1 and 0.6 ppm mercury in a natural succulent diet. I measured for the ducklings the approach behavior in response to a tape-recorded maternal call and the avoidance of a frightening stimulus. There were no significant differences among controls and ducklings from mercury-treated parents in the percentage of ducklings that approached the tape-recorded call. Control ducklings, however, moved back and forth toward the call more than ducklings from mercury-treated parents and also spent more time in the end of the runway near the loudspeaker than ducklings whose parents were fed a diet containing 0.5 ppm mercury. Compared to control ducklings, ducklings from parents fed a diet containing 0.5 or 3 ppm mercruy were hyper-responsive in the test of avoidance of a frightening stimulus. Mallard eggs collected in the wild have been found to contain levels of mercury exceeding the 1 ppm (wet-weight) found in the eggs of hens fed a diet containing 0.5 ppm, but there are no reports of mallard eggs collected in the wild that were found to contain as much mercury (6 to 9 ppm) as eggs from hens fed a diet containing 3 ppm mercury. On a dry-weight basis, the concentration of mercury in the eggs was about 6 times as great as that in the feed for ducks fed the 0.5 ppm mercury diet and about 6 to 9 times as great for ducks fed the 3 ppm mercury diet.


What is cognitive reserve? Theory and research application of the reserve concept.
The idea of reserve against brain damage stems from the repeated observation that there does not appear to be a direct relationship between the degree of brain pathology or brain damage and the clinical manifestation of that damage. This paper attempts to develop a coherent theoretical account of reserve. One convenient subdivision of reserve models revolves around whether they envision reserve as a passive process, such as in brain reserve or threshold, or see the brain as actively attempting to cope with or compensate for pathology, as in cognitive reserve. Cognitive reserve may be based on more efficient utilization of brain networks or of enhanced ability to recruit alternate brain networks as needed. A distinction is suggested between reserve, the ability to optimize or maximize normal performance, and compensation, an attempt to maximize performance in the face of brain damage by using brain structures or networks not engaged when the brain is not damaged. Epidemiologic and imaging data that help to develop and support the concept of reserve are presented.


Acupuncture in the treatment of rheumatic diseases.
Acupuncture has been used for millennia in traditional Chinese medicine as a technique believed to restore the balance of energy in the body caused by disease through the use of needles inserted into specific points or energy channels. This energy is called the de qi. The use of acupuncture for the treatment of pain in musculoskeletal disorders is increasing. Some patients seek alternative therapies because of lack of improvement with conventional treatments. The potential physiological effects of acupuncture on pain relief have been attributed to biochemical processes, such as the release of endorphins into the limbic structures, subcortical areas and brain stem, mechanisms that are also present in placebo-induced analgesia. In addition, pain relief with acupuncture is also associated with patient expectations, beliefs, and interactions with their acupuncturists. In this review, we summarize the latest evidence on the treatment of musculoskeletal conditions including rheumatoid arthritis, fibromyalgia, neck pain, shoulder pain, low back pain, and knee pain with traditional Chinese acupuncture (TCA), electroacupuncture (EA), and the use of moxibustion. Acupuncture is relatively safe, but there are still reports of serious and fatal side effects that must be taken into account when recommending this therapy. Many of the latest trials assessing the benefits of acupuncture in rheumatic diseases found that acupuncture was not better than sham acupuncture, implying that the analgesic effects observed are related to a strong placebo response. While the literature on this topic is extensive, many of the studies lack methodological rigor, and additional large, well-controlled, high quality trials are still needed to determine if acupuncture might be useful in the treatment of chronic rheumatic diseases.


Wood-inhabiting beetles in low stumps, high stumps and logs on boreal clear-cuts: implications for dead wood management.
The increasing demand for biofuels from logging residues require serious attention on the importance of dead wood substrates on clear-cuts for the many forestry-intolerant saproxylic (wood-inhabiting) species. In particular, the emerging harvest of low stumps motivates further study of these substrates. On ten clear-cuts we compared the species richness, abundance and species composition of saproxylic beetles hatching from four to nine year old low stumps, high stumps and logs of Norway spruce. By using emergence traps we collected a total of 2,670 saproxylic beetles among 195 species during the summers of 2006, 2007 and 2009. We found that the species assemblages differed significantly between high stumps and logs all three years. The species assemblages of low stumps, on the other hand, were intermediate to those found in logs and high stumps. There were also significant difference in species richness between the three examined years, and we found significant effect of substrate type on richness of predators and fungivores. As shown in previous studies of low stumps on clear-cuts they can sustain large numbers of different saproxylic beetles, including red-listed species. Our study does, in addition to this fact, highlight a possible problem in creating just one type of substrate as a tool for conservation in forestry. Species assemblages in high stumps did not differ significantly from those found in low stumps. Instead logs, which constitute a scarcer substrate type on clear-cuts, provided habitat for a more distinct assemblage of saproxylic species than high stumps. It can therefore be questioned whether high stumps are an optimal tool for nature conservation in clear-cutting forestry. Our results also indicate that low stumps constitute an equally important substrate as high stumps and logs, and we therefore suggest that stump harvesting is done after carefully evaluating measures to provide habitat for saproxylic organisms.


Insect genomes: progress and challenges.
In the wake of constant improvements in sequencing technologies, numerous insect genomes have been sequenced. Currently, 1219 insect genome-sequencing projects have been registered with the National Center for Biotechnology Information, including 401 that have genome assemblies and 155 with an official gene set of annotated protein-coding genes. Comparative genomics analysis showed that the expansion or contraction of gene families was associated with well-studied physiological traits such as immune system, metabolic detoxification, parasitism and polyphagy in insects. Here, we summarize the progress of insect genome sequencing, with an emphasis on how this impacts research on pest control. We begin with a brief introduction to the basic concepts of genome assembly, annotation and metrics for evaluating the quality of draft assemblies. We then provide an overview of genome information for numerous insect species, highlighting examples from prominent model organisms, agricultural pests and disease vectors. We also introduce the major insect genome databases. The increasing availability of insect genomic resources is beneficial for developing alternative pest control methods. However, many opportunities remain for developing data-mining tools that make maximal use of the available insect genome resources. Although rapid progress has been achieved, many challenges remain in the field of insect genomics.


Multicenter analysis of treatment outcomes in adult patients with lymphoblastic lymphoma who received hyper-CVAD induction followed by hematopoietic stem cell transplantation.
The hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen has been widely used for lymphoblastic lymphoma (LBL) as a primary treatment. However, there is few data about its treatment outcome in Asian patients. Thus, we conducted this study to evaluate the efficacy of hyper-CVAD induction and stem cell transplantation (SCT) consolidation in LBL patients. The treatment responses of 49 patients treated with the hyper-CVAD regimen were retrospectively analyzed in 13 institutions. Given 24 patients who responded to hyper-CVAD underwent consolidation treatment with SCT, overall survival (OS) and progression-free survival (PFS) of patients who received SCT were compared with patients who did not. The overall response rate was 79 %: 73 % (36/49) complete responses, 6 % (3/49) partial responses, and 4 % (2/49) induction deaths. The major limitation for the delivery of the planned hyper-CVAD cycles was hematological toxicity. Among 39 responders, 24 patients underwent autologous (n = 16) and allogeneic SCT (n = 8) consolidation. Their 3-year OS and PFS rates were 76 and 78 %, respectively, and there was no difference in survival outcomes between autologous and allogeneic SCT. However, 15 patients without SCT consolidation showed poorer PFS even though they all achieved complete response. Thus, only seven patients maintained their response at the time of analysis. In conclusion, the hyper-CVAD regimen is effective for remission induction in LBL, and SCT consolidation after hyper-CVAD induction produced better clinical outcomes than did continuation of hyper-CVAD.


Structural basis of the inhibition of class C acid phosphatases by adenosine 5'-phosphorothioate.
The inhibition of phosphatases by adenosine 5'-phosphorothioate (AMPS) was first reported in the late 1960s; however, the structural basis for the inhibition has remained unknown. Here, it is shown that AMPS is a submicromolar inhibitor of class C acid phosphatases, a group of bacterial outer membrane enzymes belonging to the haloacid dehalogenase structural superfamily. Furthermore, the 1.35-Å resolution crystal structure of the inhibited recombinant Haemophilus influenzae class C acid phosphatase was determined; this is the first structure of a phosphatase complexed with AMPS. The conformation of AMPS is identical to that of the substrate 5'-AMP, except that steric factors force a rotation of the thiophosphoryl out of the normal phosphoryl-binding pocket. This conformation is catalytically nonproductive, because the P atom is not positioned optimally for nucleophilic attack by Asp64, and the O atom of the scissile O-P bond is too far from the Asp (Asp66) that protonates the leaving group. The structure of 5'-AMP complexed with the Asp64→Asn mutant enzyme was also determined at 1.35-Å resolution. This mutation induces the substrate to adopt the same nonproductive binding mode that is observed in the AMPS complex. In this case, electrostatic considerations, rather than steric factors, underlie the movement of the phosphoryl. The structures not only provide an explanation for the inhibition by AMPS, but also highlight the precise steric and electrostatic requirements of phosphoryl recognition by class C acid phosphatases. Moreover, the structure of the Asp64→Asn mutant illustrates how a seemingly innocuous mutation can cause an unexpected structural change.


The Deferasirox-AmBisome Therapy for Mucormycosis (DEFEAT Mucor) study: a randomized, double-blinded, placebo-controlled trial.
Host iron availability is fundamental to mucormycosis pathogenesis. The combination of liposomal amphotericin B (LAmB) and deferasirox iron chelation therapy synergistically improved survival in diabetic mice with mucormycosis. To determine the safety of combination deferasirox plus LAmB therapy for mucormycosis, a multicentred, placebo-controlled, double-blinded clinical trial was conducted. Twenty patients with proven or probable mucormycosis were randomized to receive treatment with LAmB plus deferasirox (20 mg/kg/day for 14 days) or LAmB plus placebo (NCT00419770, clinicaltrials.gov). The primary analyses were for safety and exploratory efficacy. Patients in the deferasirox arm (n=11) were more likely than those in the placebo arm (n=9) to have active malignancy, neutropenia and corticosteroid therapy, and were less likely to receive concurrent non-study antifungal therapy. Reported adverse events and serious adverse events were similar between the groups. However, death was more frequent in the deferasirox than in the placebo arm at 30 days (45% versus 11%, P=0.1) and 90 days (82% versus 22%, P=0.01). Global success (alive, clinically stable, radiographically improved) for the deferasirox arm versus the placebo arm at 30 and 90 days, respectively, was 18% (2/11) versus 67% (6/9) (P=0.06) and 18% (2/11) versus 56% (5/9) (P=0.2). Patients with mucormycosis treated with deferasirox had a higher mortality rate at 90 days. Population imbalances in this small Phase II study make generalizable conclusions difficult. Nevertheless, these data do not support a role for initial, adjunctive deferasirox therapy for mucormycosis.


What is the conformation of physiologically-active dinucleoside polyphosphates in solution? Conformational analysis of free dinucleoside polyphosphates by NMR and molecular dynamics simulations.
Dinucleoside polyphosphates, or dinucleotides (Np(n)N'; N, N' = A, U, G, C; n = 2-7), are naturally occurring ubiquitous physiologically active compounds. Despite the interest in dinucleotides, and the relevance of their conformation to their biological function, the conformation of dinucleotides has been insufficiently studied. Therefore, here we performed conformational analysis of a series of Np(n)N' Na(+) salts (N = A, G, U, C; N' = A, G, U, C; n = 2-5) by various NMR techniques. All studied dinucleotides, except for Up(4/5)U, formed intramolecular base stacking interactions in aqueous solutions as indicated by NMR. The conformation around the glycosidic angle in Np(n)N's was found to be anti/high anti and the preferred conformation around the C4'-C5', C5'-O5' bonds was found to be gauche-gauche (gg). The ribose moiety in Np(n)N's showed a small preference for the S conformation, but when attached to cytosine the ribose ring preferred the N conformation. However, no predominant conformation was observed for the ribose moiety in any of the dinucleotides. Molecular dynamics simulations of Ap(2)A and Ap(4)A Na(+) salts supported the experimental results. In addition, three modes of base-stacking were found for Ap(2/4)A: α-α, β-β and α-β, which exist in equilibrium, while none is dominant. We conclude that natural, free Np(n)N's (n = 2-5) at physiological pH exist mostly in a folded (stacked), rather than extended conformation, in several interconverting stacking modes. Intramolecular base stacking of Np(n)N's does not alter the conformation of each of the nucleotide moieties, which remains the same as that of the mononucleotides in solution.


A high-throughput screen for the engineered production of β-lactam antibiotics.
High-throughput screens and selections have had profound impact on our ability to engineer proteins possessing new, desired properties. These methods are especially useful when applied to the modification of existing enzymes to create natural and unnatural products. In an advance upon existing methods we developed a high-throughput, genetically regulated screen for the in vivo production of β-lactam antibiotics using a green fluorescent protein (gfp) reporter. This assay proved reliable and sensitive and presents a dynamic range under which a wide array of β-lactam architectural subclasses can be detected. Moreover, the graded response elicited in this assay can be used to rank mutant activity. The utility of this development was demonstrated in vivo and then applied to the first experimental investigation of a putative catalytic residue in carbapenem synthase (CarC). Information gained about the mutability of this residue defines one parameter for enzymatic activity and sets boundaries for future mechanistic and engineering efforts.


Congenital stridor with feeding difficulty as a presenting symptom of Dok7 congenital myasthenic syndrome.
The congenital myasthenic syndromes (CMS) are a group of genetic disorders of neuromuscular transmission causing fatigable weakness. Symptoms may be present from birth, but diagnosis is often delayed for several years, notably in post-synaptic CMS due to mutations in the DOK7 gene. Recently, we noted a subgroup of children with CMS in whom congenital stridor and bilateral vocal cord palsy predated other symptoms. All had mutations in the DOK7 gene. The purpose of this study was to review our population of DOK7 CMS patients with congenital stridor and assess whether there were other phenotypic features which might raise suspicion of a diagnosis of CMS in the neonatal period, in the absence of limb weakness and ptosis and prompt earlier referral for neurophysiological investigation, genetic diagnosis and appropriate treatment. A retrospective case review of 11 DOK7 CMS patients at a tertiary referral centre. Six patients were identified with DOK7 mutations and congenital stridor, four requiring intubation soon after birth. Four patients had a diagnosis of bilateral vocal cord palsy and three required tracheostomy, successfully decannulated in one after 3 years. All six patients had difficulty with feeding, with weak suck and swallow necessitating nasogastric feeding in five, two of whom required gastrostomy. Despite all six children having had neonatal symptoms, the mean age at CMS diagnosis was 5 years and 9 months. CMS, particularly caused by mutations in the DOK7 gene, is a rare but treatable cause of congenital stridor in the neonate. A combination of congenital stridor, especially with an apparently idiopathic bilateral vocal cord palsy and weak suck and swallow should alert the clinician to the possibility of CMS and prompt early referral for neurophysiology and genetic investigations. Confirmation of a CMS diagnosis enables treatment to be initiated, informed management of the VCP and anticipation of myasthenic symptoms, particularly life-threatening respiratory decompensation. Treatment may allow early decannulation or possible avoidance of tracheostomy. At least 12 genes are known to cause CMS; the presence of congenital stridor may help target genetic diagnosis.


Activity of broadly neutralizing antibodies, including PG9, PG16, and VRC01, against recently transmitted subtype B HIV-1 variants from early and late in the epidemic.
For the development of a neutralizing antibody-based human immunodeficiency virus type 1 (HIV-1) vaccine, it is important to characterize which antibody specificities are most effective against currently circulating HIV-1 variants. We recently reported that HIV-1 has become more resistant to antibody neutralization over the course of the epidemic, and we here explore whether this increased neutralization resistance is also observed for the newly identified broadly neutralizing antibodies (BrNAbs) PG9, PG16, and VRC01. Furthermore, we performed a comprehensive analysis of the neutralizing sensitivity of currently circulating recently transmitted subtype B viruses to the currently most known BrNAbs. Virus variants isolated less than 6 months after seroconversion from individuals who seroconverted between 2003 and 2006 (n = 21) were significantly more resistant to neutralization by VRC01 than viruses from individuals who seroconverted between 1985 and 1989 (n = 14). In addition, viruses from contemporary seroconverters tended to be more resistant to neutralization by PG16, which coincided with the presence of more mutations at positions in the viral envelope that may potentially influence neutralization by this antibody. Despite this increased neutralization resistance, all recently transmitted viruses from contemporary seroconverters were sensitive to at least one BrNAb at concentrations of ≤5 μg/ml, with PG9, PG16, and VRC01 showing the greatest breadth of neutralization at lower concentrations. These results suggest that a vaccine capable of eliciting multiple BrNAb specificities will be necessary for protection of the population against HIV-1 infection.


Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome.
The disturbance of the central nervous system and immunological abnormalities have been suggested in patients with chronic fatigue syndrome (CFS). We focused on immunological abnormalities against neurotransmitter receptors in CFS. Using a sensitive radioligand assay, we examined serum autoantibodies to recombinant human muscarinic cholinergic receptor 1 (CHRM1), mu-opioid receptor (OPRM1), 5-hydroxytryptamine receptor 1A (HTR1A), and dopamine receptor D2 (DRD2) in patients with CFS (n=60) and results were compared with those in patients with autoimmune disease (n=33) and in healthy controls (n=30). The mean anti-CHRM1 antibody index was significantly higher in patients with CFS (p<0.0001) and autoimmune disease (p<0.05) than that in healthy controls, and positive reaction was found in 53.3% of patients with CFS. Anti-OPRM1 antibodies, anti-HTR1A antibodies, and anti-DRD2 antibodies were found in 15.2, 1.7, and 5.0% of patients with CFS, respectively. Anti-nuclear antibodies were found in 56.7% (34/60) of patients with CFS, but anti-nuclear antibody titers did not correlate with the activities of the above four autoantibodies. The patients with positive autoantibodies to CHRM1 had a significantly higher mean score (1.81) of 'feeling of muscle weakness' than negative patients (1.18) among CFS patients (p<0.01). Higher scores on 'painful node', 'forgetfulness', and 'difficulty thinking' were also found in CFS patients with anti-CHRM1 antibodies but did not reach statistical significance. In conclusion, autoantibodies to CHRM1 were detected in a large number of CFS patients and were related to CFS symptoms. Our findings suggested that subgroups of CFS are associated with autoimmune abnormalities of CHRM1.


Battery operated preconcentration-assisted lateral flow assay.
Paper-based analytical devices (e.g. lateral flow assays) are highly advantageous as portable diagnostic systems owing to their low costs and ease of use. Because of their low sensitivity and detection limits for biomolecules, these devices have several limitations in applications for real-field diagnosis. Here, we demonstrate a paper-based preconcentration enhanced lateral flow assay using a commercial β-hCG-based test. Utilizing a simple 9 V battery operation with a low power consumption of approximately 81 μW, we acquire a 25-fold preconcentration factor, demonstrating a clear sensitivity enhancement in the colorimetric lateral flow assay; consequently, clear colors are observed in a rapid kit test line, which cannot be monitored without preconcentration. This device can also facilitate a semi-quantitative platform using the saturation value and/or color intensity in both paper-based colorimetric assays and smartphone-based diagnostics.


Australian occupational therapy driver assessors' opinions on improving on-road driver assessment procedures.
We collected practitioner opinions to improve the validity and reliability of the on-road driver assessment procedures used in Australia. We used focus groups to document the views of experienced occupational therapy driver assessors using a purposive sampling method. Eight focus groups were conducted with 55 clinicians practicing in urban and rural regions. There was strong support for greater standardization of procedures for all tests. For drivers seeking unrestricted (open) licenses, use of standard routes with predetermined assessment points was important where practicable. Where use of a nonstandard route for this purpose was unavoidable, it was important to specify a minimum set of requirements related to route characteristics and assessment items. Australian occupational therapy driver assessors support greater standardization of test routes and procedures to improve reliability and validity. However, the extent to which standardization can be achieved is limited by variable road traffic environments where assessments are conducted.


Dietary advice interventions in pregnancy for preventing gestational diabetes mellitus.
Gestational diabetes mellitus (GDM) is a form of diabetes occurring during pregnancy which can result in short- and long-term adverse outcomes for women and babies. With an increasing prevalence worldwide, there is a need to assess strategies, including dietary advice interventions, that might prevent GDM. To assess the effects of dietary advice interventions for preventing GDM and associated adverse health outcomes for women and their babies. We searched Cochrane Pregnancy and Childbirth's Trials Register (3 January 2016) and reference lists of retrieved studies. Randomised controlled trials (RCTs) and quasi-RCTs assessing the effects of dietary advice interventions compared with no intervention (standard care), or to different dietary advice interventions. Cluster-RCTs were eligible for inclusion but none were identified. Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of the included studies. Data were checked for accuracy. The quality of the evidence was assessed using the GRADE approach. We included 11 trials involving 2786 women and their babies, with an overall unclear to moderate risk of bias. Six trials compared dietary advice interventions with standard care; four compared low glycaemic index (GI) with moderate- to high-GI dietary advice; one compared specific (high-fibre focused) with standard dietary advice. Dietary advice interventions versus standard care (six trials) Considering primary outcomes, a trend towards a reduction in GDM was observed for women receiving dietary advice compared with standard care (average risk ratio (RR) 0.60, 95% confidence interval (CI) 0.35 to 1.04; five trials, 1279 women; Tau² = 0.20; I² = 56%; P = 0.07; GRADE: very low-quality evidence); subgroup analysis suggested a greater treatment effect for overweight and obese women receiving dietary advice. While no clear difference was observed for pre-eclampsia (RR 0.61, 95% CI 0.25 to 1.46; two trials, 282 women; GRADE: low-quality evidence) a reduction in pregnancy-induced hypertension was observed for women receiving dietary advice (RR 0.30, 95% CI 0.10 to 0.88; two trials, 282 women; GRADE: low-quality evidence). One trial reported on perinatal mortality, and no deaths were observed (GRADE: very low-quality evidence). None of the trials reported on large-for-gestational age or neonatal mortality and morbidity.For secondary outcomes, no clear differences were seen for caesarean section (average RR 0.98, 95% CI 0.78 to 1.24; four trials, 1194 women; Tau² = 0.02; I² = 36%; GRADE: low-quality evidence) or perineal trauma (RR 0.83, 95% CI 0.23 to 3.08; one trial, 759 women; GRADE: very low-quality evidence). Women who received dietary advice gained less weight during pregnancy (mean difference (MD) -4.70 kg, 95% CI -8.07 to -1.34; five trials, 1336 women; Tau² = 13.64; I² = 96%; GRADE: low-quality evidence); the result should be interpreted with some caution due to considerable heterogeneity. No clear differences were seen for the majority of secondary outcomes reported, including childhood/adulthood adiposity (skin-fold thickness at six months) (MD -0.10 mm, 95% CI -0.71 to 0.51; one trial, 132 children; GRADE: low-quality evidence). Women receiving dietary advice had a lower well-being score between 14 and 28 weeks, more weight loss at three months, and were less likely to have glucose intolerance (one trial).The trials did not report on other secondary outcomes, particularly those related to long-term health and health service use and costs. We were not able to assess the following outcomes using GRADE: postnatal depression; maternal type 2 diabetes; neonatal hypoglycaemia; childhood/adulthood type 2 diabetes; and neurosensory disability. Low-GI dietary advice versus moderate- to high-GI dietary advice (four trials) Considering primary outcomes, no clear differences were shown in the risks of GDM (RR 0.91, 95% CI 0.63 to 1.31; four trials, 912 women; GRADE: low-quality evidence) or large-for-gestational age (average RR 0.60, 95% CI 0.19 to 1.86; three trials, 777 babies; Tau² = 0.61; P = 0.07; I² = 62%; GRADE: very low-quality evidence) between the low-GI and moderate- to high-GI dietary advice groups. The trials did not report on: hypertensive disorders of pregnancy; perinatal mortality; neonatal mortality and morbidity.No clear differences were shown for caesarean birth (RR 1.27, 95% CI 0.79 to 2.04; two trials, 201 women; GRADE: very low-quality evidence) and gestational weight gain (MD -1.23 kg, 95% CI -4.08 to 1.61; four trials, 787 women; Tau² = 7.31; I² = 90%; GRADE: very low-quality evidence), or for other reported secondary outcomes.The trials did not report the majority of secondary outcomes including those related to long-term health and health service use and costs. We were not able to assess the following outcomes using GRADE: perineal trauma; postnatal depression; maternal type 2 diabetes; neonatal hypoglycaemia; childhood/adulthood adiposity; type 2 diabetes; and neurosensory disability. High-fibre dietary advice versus standard dietary advice (one trial) The one trial in this comparison reported on two secondary outcomes. No clear difference between the high-fibre and standard dietary advice groups observed for mean blood glucose (following an oral glucose tolerance test at 35 weeks), and birthweight. Very low-quality evidence from five trials suggests a possible reduction in GDM risk for women receiving dietary advice versus standard care, and low-quality evidence from four trials suggests no clear difference for women receiving low- versus moderate- to high-GI dietary advice. A possible reduction in pregnancy-induced hypertension for women receiving dietary advice was observed and no clear differences were seen for other reported primary outcomes. There were few outcome data for secondary outcomes.For outcomes assessed using GRADE, evidence was considered to be low to very low quality, with downgrading based on study limitations (risk of bias), imprecision, and inconsistency.More high-quality evidence is needed to determine the effects of dietary advice interventions in pregnancy. Future trials should be designed to monitor adherence, women's views and preferences, and powered to evaluate effects on short- and long-term outcomes; there is a need for such trials to collect and report on core outcomes for GDM research. We have identified five ongoing studies and four are awaiting classification. We will consider these in the next review update.