Effect of nitrogenase components from mutant and wild-type strains of Azotobacter on the dilution effect of nitrogenase.
Nitrogenase activity exhibits a dilution effect. Evidence is presented that the reason for the dilution effect is that one of the component proteins of nitrogenase is limiting in preparations of this enzyme. The limiting component appears to be the non-haem-iron-containing protein (also called fraction II, iron protein, azoferredoxin), which is equivalent to the enhancement factor for nitrogenase activity present in extracts of nitrogenaseless mutant 22R1. A mathematical function of specific activity is described that is useful in describing nitrogenase. It takes into account the dilution effect and the exponential nature of the relationship between nitrogenase activity and enzyme protein concentration.


Human papilloma virus vaccine and primary ovarian failure: another facet of the autoimmune/inflammatory syndrome induced by adjuvants.
Post-vaccination autoimmune phenomena are a major facet of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) and different vaccines, including HPV, have been identified as possible causes. The medical history of three young women who presented with secondary amenorrhea following HPV vaccination was collected. Data regarding type of vaccine, number of vaccination, personal, clinical and serological features, as well as response to treatments were analyzed. All three patients developed secondary amenorrhea following HPV vaccinations, which did not resolve upon treatment with hormone replacement therapies. In all three cases sexual development was normal and genetic screen revealed no pertinent abnormalities (i.e., Turner's syndrome, Fragile X test were all negative). Serological evaluations showed low levels of estradiol and increased FSH and LH and in two cases, specific auto-antibodies were detected (antiovarian and anti thyroid), suggesting that the HPV vaccine triggered an autoimmune response. Pelvic ultrasound did not reveal any abnormalities in any of the three cases. All three patients experienced a range of common non-specific post-vaccine symptoms including nausea, headache, sleep disturbances, arthralgia and a range of cognitive and psychiatric disturbances. According to these clinical features, a diagnosis of primary ovarian failure (POF) was determined which also fulfilled the required criteria for the ASIA syndrome. We documented here the evidence of the potential of the HPV vaccine to trigger a life-disabling autoimmune condition. The increasing number of similar reports of post HPV vaccine-linked autoimmunity and the uncertainty of long-term clinical benefits of HPV vaccination are a matter of public health that warrants further rigorous inquiry.


Perceived Dentist and Dental Hygienist Task Distribution After Dental and Dental Hygiene Students' Team Intervention.
Attitudes of dental students regarding the provision of treatment tend to be dentist-centered; however, facilitating mixed student group formation could change such perceptions. The aim of this study was to investigate the perceived scope of practice of dental and dental hygiene students and whether their perceptions of task distribution between dentists and dental hygienists would change following an educational intervention consisting of feedback, intergroup comparison, and competition between mixed-group teams. The study employed a pretest-posttest single group design. Third-year dental students and second-year dental hygiene students at a university in The Netherlands were randomly assigned to intraprofessional teams (four or five members) and received team-based performance feedback and comparison. The intervention was finalized with an award ceremony for the best intraprofessional team. Before and after the intervention, students completed a questionnaire measuring their perceived distribution of ten tasks between dentists and dental hygienists. A total of 38 dental students and 32 dental hygiene students participated in the intervention-all 70 of those eligible. Questionnaires were completed by a total 88.4% (n=61) of the participants: 34 dental (89.5%) and 27 dental hygiene students (84.4%). Dental and dental hygiene students had similar perceptions regarding teeth cleaning (prophylaxis) (p=0.372, p=0.404) and, after the intervention, preventive tasks (p=0.078). Following the intervention, dental students considered four out of ten tasks as less dentist-centered: radiograph for periodontal diagnosis (p=0.003), local anesthesia (p=0.037), teeth cleaning (p=0.037), and periodontal treatment (p=0.045). Dental hygiene students perceived one task as being less dentist-centered after the intervention: radiograph for cariologic diagnosis (p=0.041). This study found that these dental and dental hygiene students had different opinions regarding the scope of practice for dentistry and dental hygiene. The number of redistributed tasks after the intervention was especially substantial among the dental students, although the amount of change per task was minimal. Half of all tasks were perceived as less dentist-centered as a result of the intervention.


Conventional mechanical ventilation in pediatrics.
To review the various challenges of providing mechanical ventilation to pediatric patients with diseases of increased airway resistance, diseases of abnormal lung compliance or normal lungs. Original data from our pediatric intensive care unit and animal research laboratory. Relevant articles included in the MEDLINE electronic database during the last 10 years. Also included were book chapters and definitive studies, as judged by the authors, in the fields of asthma, acute respiratory distress syndrome, mechanical ventilation, ventilator-induced lung injury and permissive hypercapnia. Mechanical ventilation of patients with diseases of increased airway resistance should center on avoidance of dynamic hyperinflation, allowing complete exhalation prior to the initiation of a subsequent breath and permissive hypercapnia. Positive end-expiratory pressure should be used sparingly to prevent atelectasis and facilitate synchrony in spontaneously breathing patients. Mechanical ventilation of patients with diseases of abnormal lung compliance should take into consideration the inhomogeneous distribution of lung disease. Focus should be on avoidance of volutrauma and atelectrauma that could result in ventilator-associated lung injury. The last decade was marked by significant advances in the management of pediatric respiratory failure. The choice of mechanical ventilation strategy can significantly influence the subsequent course of lung injury. Mechanical ventilation can no longer be viewed simply as a harmless support modality that is employed to keep patients alive while disease-specific treatments are used to ameliorate the underlying pathology.


Universal behavior in the mesoscale properties of amyloid fibrils.
Amyloid fibrils are ubiquitous proteinaceous aggregates occurring in vivo and in vitro, with an invariant structural fingerprint at the molecular length scale. However, interpretation of their mesoscopic architectures is complicated by diverse observable polymorphic states. We here present a constitutive model for amyloid fibrils based on the minimization of the total energy per fibril. The model is benchmarked on real amyloid fibrils studied by atomic force microscopy. We use multistranded β-lactoglobulin amyloid fibrils as a model system exhibiting a rich polymorphism. The constitutive model quantitatively recapitulates the main mesoscopic topological features of amyloid fibrils, that is, the evolution of fibril periodicity as a function of the ionic strength of the solution and of the fibril width. A universal mesoscopic structural signature of the fibrils emerges from this picture, predicting a general, parameter-free law for the periodicity of the fibrils, that depends solely on the number of protofilaments per fibril. These predictions are validated experimentally and conclusively highlight the role of competing electrostatic and elastic contributions as the main players in the establishment of amyloid fibrils structure.


Hyperglycemia in pregnancy and developmental outcomes in children at 18-60 months of age: the PANDORA Wave 1 study.
This study aimed to explore the association between hyperglycemia in pregnancy (type 2 diabetes (T2D) and gestational diabetes mellitus (GDM)) and child developmental risk in Europid and Aboriginal women.PANDORA is a longitudinal birth cohort recruited from a hyperglycemia in pregnancy register, and from normoglycemic women in antenatal clinics. The Wave 1 substudy included 308 children who completed developmental and behavioral screening between age 18 and 60 months. Developmental risk was assessed using the Ages and Stages Questionnaire (ASQ) or equivalent modified ASQ for use with Aboriginal children. Emotional and behavioral risk was assessed using the Strengths and Difficulties Questionnaire. Multivariable logistic regression was used to assess the association between developmental scores and explanatory variables, including maternal T2D in pregnancy or GDM.After adjustment for ethnicity, maternal and child variables, and socioeconomic measures, maternal hyperglycemia was associated with increased developmental "concern" (defined as score ≥1 SD below mean) in the fine motor (T2D odds ratio (OR) 5.30, 95% CI 1.77-15.80; GDM OR 3.96, 95% CI 1.55-10.11) and problem-solving (T2D OR 2.71, 95% CI 1.05-6.98; GDM OR 2.54, 95% CI 1.17-5.54) domains, as well as increased "risk" (score ≥2 SD below mean) in at least one domain (T2D OR 5.33, 95% CI 1.85-15.39; GDM OR 4.86, 95% CI 1.95-12.10). Higher maternal education was associated with reduced concern in the problem-solving domain (OR 0.27, 95% CI 0.11-0.69) after adjustment for maternal hyperglycemia.Maternal hyperglycemia is associated with increased developmental concern and may be a potential target for intervention so as to optimize developmental trajectories.


Dutch juvenile idiopathic arthritis patients, carers and clinicians create a research agenda together following the James Lind Alliance method: a study protocol.
Research on Juvenile Idiopathic Arthritis (JIA) should support patients, caregivers/parents (carers) and clinicians to make important decisions in the consulting room and eventually to improve the lives of patients with JIA. Thus far these end-users of JIA-research have rarely been involved in the prioritisation of future research. Dutch organisations of patients, carers and clinicians will collaboratively develop a research agenda for JIA, following the James Lind Alliance (JLA) methodology. In a 'Priority Setting Partnership' (PSP), they will gradually establish a top 10 list of the most important unanswered research questions for JIA. In this process the input from clinicians, patients and their carers will be equally valued. Additionally, focus groups will be organised to involve young people with JIA. The involvement of all contributors will be monitored and evaluated. In this manner, the project will contribute to the growing body of literature on how to involve young people in agenda setting in a meaningful way. A JIA research agenda established through the JLA method and thus co-created by patients, carers and clinicians will inform researchers and research funders about the most important research questions for JIA. This will lead to research that really matters.


Effect of losartan on proteinuria and urinary angiotensinogen excretion in non-diabetic patients with chronic kidney disease.
Activation of the rennin-angiotensin system (RAS) is thought to contribute to hypertension and proteinuria, and eventually to the progression of chronic kidney disease (CKD). Recent evidence suggests that urinary angiotensinogen (UAGT) excretion reflects activation of the intrarenal RAS. This study was performed to determine the effect of losartan on proteinuria and UAGT excretion in non-diabetic patients with CKD with non-nephrotic-range proteinuria. Thirty-two patients with non-nephrotic-range proteinuria (0.045-0.23 g/mmol creatinine) and normal renal function between April 2005 and April 2006 were randomised to a losartan (n=17) or a control (n=15) group. Patients in the losartan group received losartan 50 mg/day, and the doses were titrated up to 100 mg/day after 6 weeks. Serum and urinary angiotensinogen concentrations were measured by sandwich ELISA. The primary end point was the percentage change in proteinuria. The secondary end points were changes in estimated glomerular filtration rate and UAGT excretion. The follow-up period was 24 months. Baseline characteristics in the two groups were similar. After 24 months, losartan had reduced urinary protein excretion by 43% (from mean±SD 0.13±0.04 to 0.073±0.03 g/mmol, p<0.0001), but proteinuria had not changed in the control group. The percentage change in mean arterial pressure did not differ between the groups. Losartan decreased logarithmically converted UAGT excretion (from 1.58±0.47 to 1.00±0.52, p=0.001). Estimated glomerular filtration rate decreased significantly only in the control group. Losartan significantly decreased proteinuria and UAGT excretion, and preserved renal function in non-diabetic patients with CKD.


Eye and airway symptoms in low occupational exposure to toluene diisocyanate.
Exposure to diisocyanates is a well known occupational hazard. The objective of this study was to determine the possibility of an association between low exposure to toluene diisocyanate (TDI) (airborne isocyanates and biomarkers of isocyanates in plasma and urine) and symptoms of the eyes and upper and lower airways. Altogether 136 workers occupationally exposed to TDI and 118 unexposed employees were studied. A physician compiled thorough medical and occupational histories and registered symptoms, total and work-related, of the eyes, nose, and lower airways. The exposure was assessed with personal air measurements and with biomarkers of exposure in plasma and urine. The average exposure in the ambient air at the workplace of the exposed participants was below 1 ppb. Compared with the unexposed group, the exposed workers reported more total symptoms of the eyes and lower airways, as well as nose bleeding. A similar pattern, with even higher odds ratios, was observed for work-related symptoms. However, only eye symptoms proved to be significantly associated with the exposure, notably with all of the exposure measures. The risk was more pronounced for exposure to 2,4-TDI than for exposure to 2,6-TDI. Even very low exposure to TDI is related to negative health effects on exposed workers. Clear dose-response relationships were observed between three different measures of exposure and symptoms of the eyes.


A comparison of sample size and power in case-only association studies of gene-environment interaction.
Assuming continuous, normally distributed environmental and categorical genotype variables, the authors compare 6 case-only designs for tests of association in gene-environment interaction. Novel tests modeling the environmental variable as either the response or the predictor and allowing a genetic variable with multiallelic variants are included. The authors show that tests imposing the same genotypic pattern of inheritance perform similarly regardless of whether genotype is the response variable or the predictor variable. The novel tests using the genetic variable as the response variable are advantageous because they are robust to non-normally distributed environmental exposures. Dominance deviance-deviation from additivity in the main or interaction effects-is key to test performance: When it is zero or modest, tests searching for a trend with increasing risk alleles are optimal; when it is large, tests for genotypic effects are optimal. However, the authors show that dominance deviance is attenuated when it is observed at a proxy locus, which is common in genome-wide association studies, so large dominance deviance is likely to be rare. The authors conclude that the trend test is the appropriate tool for large-scale association scans where the true gene-environment interaction model is unknown. The common practice of assuming a dominant pattern of inheritance can cause serious losses of power in the presence of any recessive, or modest dominant, effects.


Management of Malignant Pleural Mesothelioma in the Elderly Population.
The median age at diagnosis for malignant pleural mesothelioma (MPM) is approximately 72 years. Elderly patients pose unique management challenges because of the increased risk of therapy-related toxicities and mortality. Because there are no high-volume retrospective studies, prospective trials, or dedicated treatment recommendations for this population, this investigation addresses a major knowledge gap by examining national practice patterns and postoperative/survival outcomes in elderly MPM patients. The National Cancer Database was queried for patients aged ≥ 80 years with newly diagnosed nonmetastatic MPM. Multivariable logistic regression ascertained factors associated with observation and surgery. Kaplan-Meier analysis assessed overall survival (OS), and multivariable Cox proportional hazards modeling examined factors associated with OS. Survival was also calculated following propensity matching. Additionally, postoperative outcomes were evaluated in surgical patients. Of 4526 patients, 2% received surgery and chemotherapy, 22% underwent chemotherapy alone, and 63% were observed. Respective median OS was 12.2, 9.5, and 4.1 months (p < 0.001). Differences between all groups persisted following propensity matching (all comparisons p < 0.05). For the 8% of patients who underwent specified definitive surgery (95% of whom received pleurectomy/decortication), 30- and 90-day mortality rates were 11.0% and 28.5%, respectively. The median length of postoperative hospitalization was 6 days, with 30-day readmission occurring in 7.5% of patients. The majority of elderly MPM patients in the US are observed, which was associated with poorer OS than chemotherapy and/or surgery. Although highly selected surgery/chemotherapy patients were associated with the longest OS, given the high biases in database studies and high perioperative mortality rates, careful patient selection for combined modality approaches in this population is imperative.


The properties of the visual system in the Australian desert ant Melophorus bagoti.
The Australian desert ant Melophorus bagoti shows remarkable visual navigational skills relying on visual rather than on chemical cues during their foraging trips. M. bagoti ants travel individually through a visually cluttered environment guided by landmarks as well as by path integration. An examination of their visual system is hence of special interest and we address this here. Workers exhibit distinct size polymorphism and their eye and ocelli size increases with head size. The ants possess typical apposition eyes with about 420-590 ommatidia per eye, a horizontal visual field of approximately 150° and facet lens diameters between 8 and 19 μm, depending on body size, with frontal facets being largest. The average interommatidial angle Δϕ is 3.7°, the average acceptance angle of the rhabdom Δρ(rh) is 2.9°, with average rhabdom diameter of 1.6 μm and the average lens blur at half-width Δρ(l) is 2.3°. With a Δρ(rh)/Δϕ ratio of much less than 2, the eyes undersample the visual scene but provide high contrast, and surprising detail of the landmark panorama that has been shown to be used for navigation.


IGF, type I IGF receptor and IGF-binding protein mRNA expression in the developing mouse lung.
The IGFs are important mitogens involved in lung growth and development. The regulation of IGF action depends not only on the expression of IGFs and IGF receptors, but also on the modulation of IGF activity by IGF-binding proteins (IGFBPs). In this study, we describe the mRNA expression of IGF-I, IGF-II, type I IGF receptor, IGFBP-2, IGFBP-4 and IGFBP-5 during mouse lung development as studied by in situ hybridization techniques. The IGF, type I IGF receptor and IGFBP-2, -4 and -5 genes were expressed in developing lung as early as embryonal day 12.5. Expression of IGFBPs-1, -3 and -6 was below detection. IGF and IGFBP-2 mRNAs were expressed both in mesenchymal and epithelial cells. Type I IGF receptor transcripts were also observed throughout the developing lung, with the exception of the epithelial cells of the bronchi after embryonal day 15. Furthermore, mRNA expression of IGFBPs-4 and -5 was noted in neighbouring cell types, and after embryonal day 15, co-expression of the type I IGF receptor and IGFBP-4 transcripts was detected. The observed expression patterns imply that the IGFBP-2, -4 and -5 genes are differentially regulated during embryonic development and suggest that each may have a discrete function. A possible role for IGFBPs-2, -4 and -5 is to participate in the regulation of cell-specific IGF responses during mouse lung development.


A gamma-tocopherol-rich mixture of tocopherols inhibits chemically induced lung tumorigenesis in A/J mice and xenograft tumor growth.
The present study investigated the effects of a preparation of a gamma-tocopherol-rich mixture of tocopherols (gamma-TmT) on chemically induced lung tumorigenesis in female A/J mice and the growth of H1299 human lung cancer cell xenograft tumors. In the A/J mouse model, the lung tumors were induced by either 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; intraperitoneal injections with 100 and 75 mg/kg on Week 1 and 2, respectively) or NNK plus benzo[a]pyrene (B[a]P) (8 weekly gavages of 2 mumole each from Week 1 to 8). The NNK plus B[a]P treatment induced 21 tumors per lung on Week 19; dietary 0.3% gamma-TmT treatment during the entire experimental period significantly lowered tumor multiplicity, tumor volume and tumor burden (by 30, 50 and 55%, respectively; P < 0.05). For three groups of mice treated with NNK alone, the gamma-TmT diet was given during the initiation stage (Week 0 to 3), post-initiation stage (Week 3 to 19) or the entire experimental period, and the tumor multiplicity was reduced by 17.8, 19.7 or 29.3%, respectively (P < 0.05). gamma-TmT treatment during the tumor initiation stage or throughout the entire period of the experiment also significantly reduced tumor burden (by 36 or 43%, respectively). In the xenograft tumor model of human lung cancer H1299 cells in NCr-nu/nu mice, 0.3% dietary gamma-TmT treatment significantly reduced tumor volume and tumor weight by 56 and 47%, respectively (P < 0.05). In both the carcinogenesis and tumor growth models, the inhibitory action of gamma-TmT was associated with enhanced apoptosis and lowered levels of 8-hydroxydeoxyguanine, gamma-H2AX and nitrotyrosine in the tumors of the gamma-TmT-treated mice. In cell culture, the growth of H1299 cells was inhibited by tocopherols with their effectiveness following the order of delta-T > gamma-TmT > gamma-T, whereas alpha-T was not effective. These results demonstrate the inhibitory effect of gamma-TmT against lung tumorigenesis and the growth of xenograft tumors of human lung cancer cells. The inhibitory activity may be due mainly to the actions of delta-T and gamma-T.


Litomosoides carinii: mode of action in vitro of benzothiazole and amoscanate derivatives with antifilarial activity.
It is suggested that the recently developed benzothiazole and amoscanate derivatives with antifilarial activity exert their action in vitro by an inhibition of mitochondrial-derived respiration. It was confirmed that the drugs CGP 20376, 21835, 20308, 21306, and 6140 cause a rapid immobilization in vitro of the adult filarial worm, Litomosoides carinii, the time required being similar to rotenone at the same concentration. The other drugs investigated, CGPs 20309, 21833, 24589, 23518, and 13231, were also effective; however, they required much longer incubation times. Submitochondrial particles (SMP) were prepared from Ascaris muscle and rat liver. The concentration of drug causing 50% inhibition of respiration (IC50) was calculated. It was found that the drugs most rapidly inhibiting respiration have IC50s for NADH oxidase of less than 25 microM in both Ascaris and rat liver SMP. This effect on SMP respiration could be overcome by using succinate as a substrate, indicating the site of inhibition to be within complex I of the mitochondrial respiratory chain. Further experiments showed that whereas the respiratory chain's NADH:ferricyanide reductase was unaffected by these drugs, there were pronounced effects on both Ascaris and rat liver NADH:quinone reductase activity. This suggests that the inhibition within complex I occurs after the flavoprotein dehydrogenase, but before the site of the quinone reduction. The other compounds examined, which had a slower effect on motility, also showed inhibition of the NADH oxidase, but not to as great an extent as the aforementioned compounds. The compounds most active against motility were also most effective at inhibiting respiration in intact adult L. carinii. Analysis of the aerobic end products produced by L. carinii showed that acetate production was greatly reduced even in the presence of low concentrations of the drugs. There was also a slight decrease in lactate production. However, a direct effect on the glycolytic pathway was ruled out by two observations. One, that the production of lactate from cell-free extracts of L. carinii is unaffected by the presence of the drugs, and secondly, that a protozoan, Giardia lamblia, reliant on glycolysis for energy production, can survive for long periods of time in the presence of high concentrations of the drugs. A correlation can be observed between the time for immobilization of the filarial worm and the strength of inhibition of mitochondrial respiration. Therefore, it is suggested that, at least in vitro, the mechanism of toxicity of these antifilarials in L. carinii is due to the blocking of the respiratory chain at a site similar to that of rotenone.


Heart rate variability in healthy subjects: effect of age and the derivation of normal ranges for tests of autonomic function.
The diagnosis of autonomic neuropathy frequently depends on results of tests which elicit reflex changes in heart rate. Few well-documented normal ranges are available for these tests. The present study was designed to investigate the effect of age upon heart rate variability at rest and in response to a single deep breath, the Valsalva manoeuvre, and standing. A computerised method of measurement of R-R interval variation was used to study heart rate responses in 310 healthy subjects aged 18-85 years. Heart rate variation during each procedure showed a skewed distribution and a statistically significant negative correlation with age. Normal ranges (90% and 95% confidence limits) for subjects aged 20-75 years were calculated for heart rate difference (max-min) and ratio (max/min) and standard deviation (SD). Heart rate responses were less than the 95th centile in at least one of the four procedures in 39 (12.6%) out of the 310 subjects, and were below this limit in two or more tests in five (1.6%) subjects. In view of the decline in heart rate variation with increasing age, normal ranges for tests of autonomic function must be related to the age of the subject.


Successful field performance in warm and dry environments of soybean expressing the sunflower transcription factor HB4.
Soybean yield is limited primarily by abiotic constraints. No transgenic soybean with improved abiotic stress tolerance is commercially available. We transformed soybean plants with genetic constructs able to express the sunflower transcription factor HaHB4, which confers drought tolerance to Arabidopsis and wheat. One line (b10H) carrying the sunflower promoter was chosen among three independent lines because it exhibited the best performance in seed yield, and was evaluated in the greenhouse and in 27 field trials in different environments in Argentina. In greenhouse experiments, transgenic plants showed increased seed yield under stress conditions together with greater epicotyl diameter, larger xylem area, and increased water use efficiency compared with controls. They also exhibited enhanced seed yield in warm and dry field conditions. This response was accompanied by an increase in seed number that was not compensated by a decrease in individual seed weight. Transcriptome analysis of plants from a field trial with maximum difference in seed yield between genotypes indicated the induction of genes encoding redox and heat shock proteins in b10H. Collectively, our results indicate that soybeans transformed with HaHB4 are expected to have a reduced seed yield penalty when cultivated in warm and dry conditions, which constitute the best target environments for this technology.


The REmote Patient Education in a Telemedicine Environment Architecture (REPETE).
The objective of the study was to develop and implement an architecture for remote training that can be used in the narrowband home telemedicine environment. A remote training architecture, the REmote Patient Education in a Telemedicine Environment (REPETE) architecture, using a remote control protocol (RCP) was developed. A set of design criteria was specified. The developed architecture was integrated into the IDEATel home telemedicine unit (HTU) and evaluated against these design criteria using a combination of technical and expert evaluations. Technical evaluation of the architecture demonstrated that remote cursor movements and positioning displayed on the HTU were smooth and effectively real-time. The trainers were able to observe within approximately 2 seconds lag what the patient sees on their HTU screen. Evaluation of the architecture by experts was favorable. Responses to a Likert scale questionnaire regarding audio quality and remote control performance indicated that the expert evaluators thought that the audio quality and remote control performance were adequate for remote training. All evaluators strongly agreed that the system would be useful for training patients. The REPETE architecture supports basic training needs over a narrowband dial-up connection. We were able to maintain an audio chat simultaneously with performing a remote training session, while maintaining both acceptable audio quality and remote control performance. The RCP provides a mechanism to provide training without requiring a trainer to go to the patient's home and effectively supports deictic referencing to on screen objects.


The enteric nervous system and the musculature of the colon are altered in patients with spina bifida and spinal cord injury.
Neurogenic bowel dysfunction occurs in a large percentage of adult patients with spina bifida (SB) and spinal cord injury (SCI), significantly affecting their quality of life. Although bowel motility is autonomously regulated by the enteric nervous system (ENS), disruption of the modulation of the ENS by extrinsic innervation as present in many patients with SB and SCI might lead to motility disorders. In order to gain insight in the pathophysiology, we studied histological changes of the neuromuscular structures in the colon of SB and SCI patients. Archival colon tissue blocks from SB (n = 13) and SCI (n = 34) patients were collected nationwide in The Netherlands and compared with control samples (n = 16). Histological (semiquantitative) evaluation of the ENS, the network of interstitial cells of Cajal (ICC), and the muscularis propria was performed using hematoxylin and eosin, periodic acid Schiff, and elastic von Gieson staining, and immunohistochemistry with antibodies against HuC/D, calretinin, S100, CD117, α-smooth muscle actin, and desmin. Compared to controls, SB and SCI patients showed neuronal loss and decreased nerve fiber density in the myenteric plexus. Lower nerve fiber density was significantly more often found in patients with severe bowel dysfunction. Other major findings were loss of ICCs around the myenteric plexus and fibrosis in the longitudinal muscle layer. Altered histology of the ENS may explain abnormal intestinal motility in SB and SCI patients. Furthermore, loss of myenteric nerve fibers (including enteric glial cells) may play a major role in the development of severe motility complaints.


Intrahepatic hepatitis C virus RNA quantification in microdissected hepatocytes.
Debate continues on whether serum and intrahepatic HCV viral loads are correlated and if HCV viral load correlates with the severity of liver disease. These difficulties may at least in part be linked to liver cell heterogeneity, when total liver extracts from HCV-infected individuals are tested for HCV RNA quantification. We have therefore investigated the feasibility of quantifying HCV replication using a laser-based microdissection technique. We compared the results with those obtained for serum HCV RNA quantification and immunochemistry in the case of HCV antigen detection in the liver. Twenty-one HCV-positive patients with chronic active hepatitis (n=10) or cirrhosis (n=11) were analyzed. A positive correlation (P=0.0019) was observed between HCV RNA quantifications in sera and microdissected cells. Immunohistochemistry demonstrated that HCV antigen hepatocytes were randomly distributed within liver lobules. Their percentage varied in different patients (0-40%), but did not correlate with the HCV viral load. We have designed a sensitive methodology to evaluate the intrahepatic HCV viral load by combining a standardized RNA quantification method with microdissected hepatocytes from frozen liver needle biopsies. Our results directly demonstrate a positive correlation between serum and intrahepatic viral loads, which therefore provides a reliable reflection of intrahepatic HCV replication.


Selenium supplementation modulates zinc levels and antioxidant values in blood and tissues of diabetic rats fed zinc-deficient diet.
Diabetes mellitus is associated to a reduction of antioxidant defenses that leads to oxidative stress and complications in diabetic individuals. The present study was undertaken to investigate the effect of selenium on blood biochemical parameters, antioxidant enzyme activities, and tissue zinc levels in alloxan-induced diabetic rats fed a zinc-deficient diet. The rats were divided into two groups; the first group was fed a zinc-sufficient diet, while the second group was fed a zinc-deficient diet. Half of each group was treated orally with 0.5 mg/kg sodium selenite. Tissue and blood samples were taken from all animals after 28 days of treatment. At the end of the experiment, the body weight gain and food intake of the zinc-deficient diabetic animals were lower than that of zinc-adequate diabetic animals. Inadequate dietary zinc intake increased glucose, lipids, triglycerides, urea, and liver lipid peroxidation levels. In contrast, serum protein, reduced glutathione, plasma zinc and tissue levels were decreased. A zinc-deficient diet led also to an increase in serum glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, and liver glutathione-S-transferase and to a decrease in serum alkaline phosphatase activity and glutathione peroxidase. Selenium treatment ameliorated all the values approximately to their normal levels. In conclusion, selenium supplementation presumably acting as an antioxidant led to an improvement of insulin activity, significantly reducing the severity of zinc deficiency in diabetes.


Efficacy of the valsalva maneuver on needle projection pain and hemodynamic responses during spinal puncture.
This study evaluated the efficacy of the valsalva maneuver that can induce baroreceptor activation and nociception, on needle projection pain and hemodynamic responses associated with spinal puncture. Ninety adults, ASA physical status I and II undergoing elective surgeries were included. Patients were randomized into three equal groups. Group I (C): control; Group II (B): ball; pressed a rubber ball (attention-diverting method); Group III (V): valsalva; blew into sphygmomanometer tubing and hold the mercury column up to 30 mm Hg for a period of at least 20s. Spinal needle projection pain was graded using numeric rating scale (NRS): 1-10, where scales of 1-3 were rated as mild, 4-6 as moderate, and >6 as severe. Blood pressure and heart rate, five minutes before the procedure, during the spinal puncture and first and third minutes after that, were also recorded. Significant reduction in NRS was observed in the valsalva group compared with the control and the ball groups (p=0.001). There were statistical but no significant clinical differences in mean arterial blood pressure and heart rates between the study groups (P=0.008 and P=0.016 respectively). In conclusion valsalva maneuver can decrease the skin puncture pain associated with spinal needle projection while observing hemodynamic changes.


Change in body mass can overrule the effects of maternal testosterone on primary offspring sex ratio of first eggs in homing pigeons.
The phenomenon of primary offspring sex ratio adjustment is being extensively studied, yet knowledge of the underlying proximate mechanism is still mainly hypothetical. Female birds are the heterogametic sex, thus potentially controlling the sex of the gamete to be fertilized. In several bird species, independent studies showed effects of maternal plasma testosterone, corticosterone, or condition on primary offspring sex ratio. Our objective was to investigate the causal relation between these two maternal hormones, body condition, and offspring sex ratio in homing pigeons (Columba livia domestica). Following our earlier study, we again implanted females with testosterone and determined embryo sex of first eggs. To identify the pathway of sex ratio adjustment, we repeatedly measured not only maternal plasma testosterone and mass but also plasma corticosterone, cholesterol, and glucose, all indicators of body condition. We also calculated the temporal change in these parameters, which has been proposed to be a more accurate predictor of offspring sex ratio compared with the absolute values. Furthermore, we analyzed testosterone concentrations in outer yolk layers, which potentially influence the first meiotic division of the gamete. We found no relation between plasma parameter and embryo sex of first eggs; testosterone treatment did not affect any of the measured parameters. However, females that increased in mass produced more male embryos, irrespective of treatment group. Outer yolk layer testosterone concentrations did not differ between treatment groups or between male and female eggs. We propose that not only the absolute values but also the complex interactions between maternal hormones and body condition ultimately affect the mechanism of primary offspring sex manipulation.


The mutational consequences of plant transformation.
Plant transformation is a genetic engineering tool for introducing transgenes into plant genomes. It is now being used for the breeding of commercial crops. A central feature of transformation is insertion of the transgene into plant chromosomal DNA. Transgene insertion is infrequently, if ever, a precise event. Mutations found at transgene insertion sites include deletions and rearrangements of host chromosomal DNA and introduction of superfluous DNA. Insertion sites introduced using Agrobacterium tumefaciens tend to have simpler structures but can be associated with extensive chromosomal rearrangements, while those of particle bombardment appear invariably to be associated with deletion and extensive scrambling of inserted and chromosomal DNA. Ancillary procedures associated with plant transformation, including tissue culture and infection with A tumefaciens, can also introduce mutations. These genome-wide mutations can number from hundreds to many thousands per diploid genome. Despite the fact that confidence in the safety and dependability of crop species rests significantly on their genetic integrity, the frequency of transformation-induced mutations and their importance as potential biosafety hazards are poorly understood.


Detection of Mycobacterium avium subspecies paratuberculosis in Swiss dairy cattle by real-time PCR and culture: a comparison of the two assays.
To compare the two different diagnostic assays for the detection of Mycobacterium avium ssp. paratuberculosis, the aetiological agent of paratuberculosis. Faecal samples were derived from 310 cows, representing 13 commercial dairy herds in various locations in Switzerland with expected increased risk because of a past history of disease. Detection assays for M. avium ssp. paratuberculosis were culture (gold standard) and a newly designed real-time PCR. Real-time PCR identified 31 of 310 animals as positive within this risk population whereas culture identified 20 positive animals. The specificity of real-time PCR was confirmed by DNA sequencing of the PCR product. Depending on the test used, the paratuberculosis prevalence in our tested risk population ranged from 6.5 to 10%. Real-time PCR and culture data were in good agreement, and real-time PCR generates data in a short time in contrast to culture. We consider real-time PCR as a suitable alternative method to culture for the detection of M. avium ssp. paratuberculosis in a national surveillance programme.


Targeting cytokine expression in glial cells by cellular delivery of an NF-kappaB decoy.
Inhibition of nuclear factor (NF)-kappaB has emerged as an important strategy for design of anti-inflammatory therapies. In neurodegenerative disorders like Alzheimer's disease, inflammatory reactions mediated by glial cells are believed to promote disease progression. Here, we report that uptake of a double-stranded oligonucleotide NF-kappaB decoy in rat primary glial cells is clearly facilitated by noncovalent binding to a cell-penetrating peptide, transportan 10, via a complementary peptide nucleic acid (PNA) sequence. Fluorescently labeled oligonucleotide decoy was detected in the cells within 1 h only when cells were incubated with the decoy in the presence of cell-penetrating peptide. Cellular delivery of the decoy also inhibited effects induced by a neurotoxic fragment of the Alzheimer beta-amyloid peptide in the presence of the inflammatory cytokine interleukin (IL)-1beta. Pretreatment of the cells with the complex formed by the decoy and the cell-penetrating peptide-PNA resulted in 80% and 50% inhibition of the NF-kappaB binding activity and IL-6 mRNA expression, respectively.


The holozoan Capsaspora owczarzaki possesses a diverse complement of active transposable element families.
Capsaspora owczarzaki, a protistan symbiont of the pulmonate snail Biomphalaria glabrata, is the centre of much interest in evolutionary biology due to its close relationship to Metazoa. The whole genome sequence of this protist has revealed new insights into the ancestral genome composition of Metazoa, in particular with regard to gene families involved in the evolution of multicellularity. The draft genome revealed the presence of 23 families of transposable element, made up from DNA transposon as well as long terminal repeat (LTR) and non-LTR retrotransposon families. The phylogenetic analyses presented here show that all of the transposable elements identified in the C. owczarzaki genome have orthologous families in Metazoa, indicating that the ancestral metazoan also had a rich diversity of elements. Molecular evolutionary analyses also show that the majority of families has recently been active within the Capsaspora genome. One family now appears to be inactive and a further five families show no evidence of current transposition. Most individual element copies are evolutionarily young; however, a small proportion of inserts appear to have persisted for longer in the genome. The families present in the genome show contrasting population histories and appear to be in different stages of their life cycles. Transcriptome data have been analyzed from multiple stages in the C. owczarzaki life cycle. Expression levels vary greatly both between families and between different stages of the life cycle, suggesting an unexpectedly complex level of transposable element regulation in a single celled organism.


10-20 Joules as a neuromolecular quantum in medicinal chemistry: an alternative approach to myriad molecular pathways?
The myriads of molecular pathways that have been measured to understand the physical bases of neuronal and other cellular functions have exceeded classical comprehension. In the tradition of Bohr and Schrodinger, the hypothesis is developed that molecular pathways are simply epiphenomenal transports of quanta with increments in the order of 10(-20) J. Experimental measurements of photon emissions from cell cultures and the serial steps of phosphorylation in general molecular pathways and transformations in chromophores supported this contention. This discrete value is also associated with action potentials, intersynaptic events, the biophysical bases of membrane potentials, the numbers of action potentials per cell from magnetic energy potential, and the interionic distances around membranes. Consideration of information as discrete increments of energy may allow greater experimental control and external intervention of pathways relevant to medicinal chemistry.


Detection of Bordetella pertussis associated with the alveolar macrophages of children with human immunodeficiency virus infection.
In humans, infection with Bordetella pertussis is considered to be localized to an epithelial surface. However, an intracellular state in cultured cells and in the macrophages of infected animals has been shown. By using indirect immunofluorescence with a monoclonal antibody, it was found that 3 of 20 bronchoalveolar lavage specimens from children with human immunodeficiency virus infection had B. pertussis associated with pulmonary alveolar macrophages. None of the cultures from the patients grew B. pertussis. The B. pertussis appeared to be intracellular.


Repositioning error in low back pain. Comparing trunk repositioning error in subjects with chronic low back pain and control subjects.
Repositioning error of the trunk was tested in 20 subjects with chronic low back pain and in 20 control subjects. The 3Space Tracker (Polhemus, Colchester, VT), a device that measures three-dimensional position in space, was used to determine the subject's trunk position. To determine whether repositioning error is different in subjects with chronic low back pain than in control subjects. Proprioception allows the body to maintain proper orientation during static and dynamic activities. In peripheral joint injuries, researchers have demonstrated a loss of some aspects of proprioception and improvement in outcome with retraining. Although the components of proprioception in subjects with low back pain have not been well studied, it is thought that these persons lose some elements of proprioception that can be measured in a quantifiable way. If so, then rehabilitation to improve these deficits is important. In this pilot study, one aspect of proprioception, repositioning error, was examined. The subjects attempted to replicate target positions of the trunk in flexion, extension, lateral bending, and lateral rotation. Repositioning error was calculated as the absolute difference between the actual and the subject-replicated target positions. No significant difference was found in repositioning error between the control subjects and the persons with chronic low back pain. Because proprioception is complex and entails the use of many afferent receptors, it is difficult to measure any one afferent deficiency discretely. The authors believe that this study, in which one aspect of proprioception was measured in an indirect manner, provides important background information on low back position sense. Further studies analyzing aspects of proprioception in subjects with low back pain are recommended.


Absence of high-risk stigmata predicts good prognosis even in severely anemic patients with suspected acute upper gastrointestinal bleeding.
The need for a blood transfusion, defined as hemoglobin < 70 g/L, is the measure for assessing the risk levels in patients with upper gastrointestinal bleeding (UGIB). However, not all patients with a low hemoglobin level have a poor prognosis. We assessed the clinical predictive factors associated with poor short-term prognosis in patients with a low hemoglobin level. In this prospective cohort study, all consecutive patients with suspected acute UGIB at Tokyo Metropolitan Tama Medical Center were enrolled between 2008 and 2015. Then, we extracted those who needed a blood transfusion (hemoglobin < 70 g/L) and explored the variables associated with all-cause mortality within 28 days after presentation. Among 1307 patients, 311 needed a blood transfusion and 13 (4.2%) died from all causes. The presence of high-risk stigmata requiring endoscopic treatment (peptic ulcers; Forrest scores Ia, Ib and IIa; varices with current bleeding or signs of recent bleeding; and spurting or gushing bleeding or visible vessel in other diseases), diagnosed by emergency endoscopy, was a unique factor affecting mortality (odds ratio: 8.47, 95% confidence interval: 1.45-160, P = 0.01). Patients without high-risk stigmata neither died from UGIB nor had rebleeding, irrespective of the hemoglobin levels. Patients without high-risk stigmata showed a good prognosis even if they needed a blood transfusion. This result could facilitate triage of patients with suspected acute UGIB who only need a blood transfusion.


Adjuvant radiation therapy in locally advanced non-small cell lung cancer: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based clinical practice guideline.
To provide guidance to physicians and patients with regard to the use of adjuvant external beam radiation therapy (RT) in locally advanced non-small cell lung cancer (LA NSCLC) based on available medical evidence complemented by consensus-based expert opinion. A panel authorized by the American Society for Radiation Oncology (ASTRO) Board of Directors and Guidelines Subcommittee conducted 2 systematic reviews on the following topics: (1) indications for postoperative adjuvant RT and (2) indications for preoperative neoadjuvant RT. Practice guideline recommendations were approved using an a priori-defined consensus-building methodology supported by ASTRO and approved tools for the grading of evidence quality and the strength of guideline recommendations. For patients who have undergone surgical resection, high-level evidence suggests that use of postoperative RT does not influence survival, but optimizes local control for patients with N2 involvement, and its use in the setting of positive margins or gross primary/nodal residual disease is recommended. No high-level evidence exists for the routine use of preoperative induction chemoradiation therapy; however, modern surgical series and a post-hoc Intergroup 0139 clinical trial analysis suggest that a survival benefit may exist if patients are properly selected and surgical techniques/postoperative care is optimized. A consensus and evidence-based clinical practice guideline for the adjuvant radiotherapeutic management of LA NSCLC has been created addressing 2 important questions.


Association between shift work and periodontal health in a representative sample of an Asian population.
The association of shift work with periodontal disease is not well known. We studied the relationship between shift work and periodontitis in a representative sample of an Asian population. Participants were 4597 full-time employees from the Fourth Korean National Health and Nutrition Examination Survey (KNHANES IV). Shifting patterns were categorized into five shifts: daytime (N=3768), evening (N=121), night (N=59), rotating (N=206), and irregular (N=443). Periodontitis was measured with the Community Periodontal Index (CPI). Confounders included age, gender, income, and education. Mediators were frequency of daily tooth brushing, regular dental check-up, smoking, alcohol consumption, diabetes, obesity, and white blood cell count. Multiple logistic regression analyses were performed to evaluate the relationship. The prevalence of periodontitis in the study population was 32.3%. Shift workers had an elevated odds ratio (OR) of periodontitis [OR 1.22, 95% confidence interval (95% CI) 1.01-1.48] after controlling for confounders. The magnitude of the association between shift work and periodontitis attenuated with adjustment of mediators (smoking and a marker of inflammation). In subgroup analyses, the association was significant (OR 1.42, 95% CI 1.03-1.95) among those ≥45 years. Irregular shift among those ≥45 years showed a significant association (OR 1.79, 95% CI 1.15-2.78). Findings of this cross-sectional study suggest that shift work may be associated with periodontitis. Shift workers aged ≥45 years and irregular shift workers aged ≥45 years were risk groups for periodontitis.


Alterations in Glucose Metabolism on Cognition: A Possible Link Between Diabetes and Dementia.
The use of the carbohydrate glucose as an energetic source is essential for an adequate function of the human body. The complex regulation of this molecule involves the coordinated action of various organs such as pancreas, liver and brain. Any disruption of this physiological balance may result in a dangerous compromise of general metabolic activities increasing the possibility of developing T1DM, T2DM and possibly AD. Astrocytes convert glucose into lactate and transfer it to neurons. This lactate is essential for neuronal metabolism and for various processes including the formation of synapses, dendrites and the expression of genes involved in memory. The brain is highly susceptible to variations in glucose blood levels, and both hypoglycemia and hyperglycemia can be dangerous. Pathological hyperglycemia induces changes in plasmatic osmotic pressure, mitochondrial production of free radicals, oxidative stress and activation of neuronal apoptosis, among others. Both AD and diabetes are chronic diseases having age as an important risk factor. As the brain ages, it seems to become much more susceptible to cellular damage induced by excess of circulating glucose and this could explain the appearance of cognitive changes observed in some patients with diabetes. Excessive circulation of pro-inflammatory agents has been observed in insulin resistance and is likely that some of these mediators may cross the bloodbrain barrier and induce abnormal neuroinflammation. GSK-3 is overexpressed in diabetes and also has been reported to regulate tau phosphorylation and production of Aβ peptides in the brain. Currently, diabetes (hyperglycemia) is considered as a risk factor for the development of AD. A novel therapeutic approach, using intranasal insulin and anti-diabetic medications in patients suffering from AD is being explored and is discussed in this review.


Large-scale Circulating microRNA Profiling for the Liquid Biopsy of Prostate Cancer.
The high false-positive rate of prostate-specific antigen (PSA) may lead to unnecessary prostate biopsies. Therefore, the United States Preventive Services Task Force recommends that decisions regarding PSA-based screening of prostate cancer should be made with caution in men ages 55-69 years, and that men ≥70 years should not undergo PSA screening. Here, we investigated the potential of serum miRNAs as an accurate diagnostic method in patients with suspected prostate cancer. Serum samples of 809 patients with prostate cancer, 241 negative prostate biopsies, and 500 patients with other cancer types were obtained from the National Cancer Center, Japan. Forty-one healthy control samples were obtained from two other hospitals in Japan. Comprehensive microarray analysis was performed for all samples. Samples were divided into three sets. Candidate miRNAs for prostate cancer detection were identified in the discovery set (n = 123). A diagnostic model was constructed using combinations of candidate miRNAs in the training set (n = 484). The performance of the diagnostic model was evaluated in the validation set (n = 484). In the discovery set, 18 candidate miRNAs were identified. A robust diagnostic model was constructed using the combination of two miRNAs (miR-17-3p and miR-1185-2-3p) in the training set. High diagnostic performance with a sensitivity of 90% and a specificity of 90% was achieved in the validation set regardless of the Gleason score and clinical tumor-node-metastasis stage. The model developed in this study may help improve the diagnosis of prostate cancer and reduce the number of unnecessary prostate biopsies.


Chain-breaking antioxidant activity of hydroxylated and methoxylated magnolol derivatives: the role of H-bonds.
Chemical modification of magnolol, an uncommon dimeric neolignan contained in Magnolia genus trees, provides a unique array of polyphenols having interesting biological activity potentially related to radical scavenging. The chain-breaking antioxidant activity of four new hydroxylated and methoxylated magnolol derivatives was explored by experimental and computational methods. The measurement of the rate constant of the reaction with ROO˙ radicals (kinh) in an apolar solvent showed that the introduction of hydroxyl groups ortho to the phenolic OH in magnolol increased the kinh value, being 2.4 × 105 M-1 s-1 and 3.3 × 105 M-1 s-1 for the mono and the dihydroxy derivatives respectively (kinh of magnolol is 6.1 × 104 M-1 s-1). The di-methoxylated derivative is less reactive than magnolol (kinh = 1.1 × 104 M-1 s-1), while the insertion of both hydroxyl and methoxyl groups showed no effect (6.0 × 104 M-1 s-1). Infrared spectroscopy and theoretical calculations allowed a rationalization of these results and pointed out the crucial role of intramolecular H-bonds. We also show that a correct estimation of the rate constant of the reaction with ROO˙ radicals, by using BDE(OH) calculations, requires that the geometry of the radical is as close as possible to that of the parent phenol.


Does encapsulation protect embryos from the effects of ocean acidification? The example of Crepidula fornicata.
Early life history stages of marine organisms are generally thought to be more sensitive to environmental stress than adults. Although most marine invertebrates are broadcast spawners, some species are brooders and/or protect their embryos in egg or capsules. Brooding and encapsulation strategies are typically assumed to confer greater safety and protection to embryos, although little is known about the physico-chemical conditions within egg capsules. In the context of ocean acidification, the protective role of encapsulation remains to be investigated. To address this issue, we conducted experiments on the gastropod Crepidula fornicata. This species broods its embryos within capsules located under the female and veliger larvae are released directly into the water column. C. fornicata adults were reared at the current level of CO2 partial pressure (pCO2) (390 μatm) and at elevated levels (750 and 1400 μatm) before and after fertilization and until larval release, such that larval development occurred entirely at a given pCO2. The pCO2 effects on shell morphology, the frequency of abnormalities and mineralization level were investigated on released larvae. Shell length decreased by 6% and shell surface area by 11% at elevated pCO2 (1400 μatm). The percentage of abnormalities was 1.5- to 4-fold higher at 750 μatm and 1400 μatm pCO2, respectively, than at 390 μatm. The intensity of birefringence, used as a proxy for the mineralization level of the larval shell, also decreased with increasing pCO2. These negative results are likely explained by increased intracapsular acidosis due to elevated pCO2 in extracapsular seawater. The encapsulation of C. fornicata embryos did not protect them against the deleterious effects of a predicted pCO2 increase. Nevertheless, C. fornicata larvae seemed less affected than other mollusk species. Further studies are needed to identify the critical points of the life cycle in this species in light of future ocean acidification.


Inhibition of thoughts and actions in obsessive-compulsive disorder: extending the endophenotype?
Obsessive-compulsive disorder (OCD) has been associated with impairments in stop-signal inhibition, a measure of motor response suppression. The study used a novel paradigm to examine both thought suppression and response inhibition in OCD, where the modulatory effects of stimuli relevant to OCD could also be assessed. Additionally, the study compared inhibitory impairments in OCD patients with and without co-morbid depression, as depression is the major co-morbidity of OCD. Volitional response suppression and unintentional thought suppression to emotive and neutral stimuli were examined using a novel thought stop-signal task. The thought stop-signal task was administered to non-depressed OCD patients, depressed OCD patients and healthy controls (n=20 per group). Motor inhibition impairments were evident in OCD patients, while motor response performance did not differ between patients and controls. Switching to a new response but not motor inhibition was affected by stimulus relevance in OCD patients. Additionally, unintentional thought suppression as measured by repetition priming was intact. OCD patients with and without depression did not differ on any task performance measures, though there were significant differences in all self-reported measures. Results support motor inhibition deficits in OCD that remain stable regardless of stimulus meaning or co-morbid depression. Only switching to a new response was influenced by stimulus meaning. When response inhibition was successful in OCD patients, so was the unintentional suppression of the accompanying thought.


Community-acquired pneumonia: the annual cost to the National Health Service in the UK.
The aim of this study was to estimate the direct annual healthcare costs to the UK National Health Service (NHS) of managing community-acquired pneumonia. Using a prevalence-based burden of illness approach, health service resource use and corresponding costs attributable to the management of community-acquired pneumonia during 1992/1993 in the UK were obtained from published sources and commercial databases, and supplemented by a telephone survey of general practitioners, finance directors, community nurses, receptionists and nurses in out-patient respiratory clinics, ambulance services, and consultant respiratory physicians. The study was appraised by a Peer Review Panel, representing a cross-section of experts from different locations. This study was a predefined subgroup analysis of a previous, larger study that estimated the annual cost to the NHS of treating all community-acquired lower respiratory tract infections. The analysis shows that there are 261,000 episodes of community-acquired pneumonia annually in the UK, costing 440.7 million pounds at 1992/1993 prices (32% of the annual cost for all community-acquired lower respiratory tract infections). Approximately 83,153 annual cases of community-acquired pneumonia are treated in hospital (32% of all episodes) and account for 96% of the annual cost. The average cost for managing pneumonia in the community is 100 pounds per episode, compared to 1,700-5,100 pounds when the patient is hospitalized, depending on the length of hospitalization. Hospitalization accounts for 87% of the total annual cost. In conclusion, community-acquired pneumonia in the UK incurs a direct healthcare cost of 440.7 million pounds annually at 1992/1993 prices. Developing and implementing strategies to prevent and minimize hospitalization will significantly reduce this annual cost and should be assessed in future studies.


Rejuvenation of senescent cells-the road to postponing human aging and age-related disease?
Cellular senescence is the state of permanent inhibition of cell proliferation. Replicative senescence occurs due to the end replication problem and shortening telomeres with each cell division leading to DNA damage response (DDR). The number of short telomeres increases with age and age-related pathologies. Stress induced senescence, although not accompanied by attrition of telomeres, is also attributed to the DDR induced by irreparable DNA lesions in telomeric DNA. Senescent cells characterized by the presence of γH2AX, the common marker of double DNA strand breaks, and other senescence markers including activity of SA-β-gal, accumulate in tissues of aged animals and humans as well as at sites of pathology. It is believed that cellular senescence evolved as a cancer barrier since non-proliferating senescent cells cannot be transformed to neoplastic cells. On the other hand senescent cells favor cancer development, just like other age-related pathologies, by creating a low grade inflammatory state due to senescence associated secretory phenotype (SASP). Reversal/inhibition of cellular senescence could prolong healthy life span, thus many attempts have been undertaken to influence cellular senescence. The two main approaches are genetic and pharmacological/nutritional modifications of cell fate. The first one concerns cell reprogramming by induced pluripotent stem cells (iPSCs), which in vitro is effective even in cells undergoing senescence, or derived from very old or progeroid patients. The second approach concerns modification of senescence signaling pathways just like TOR-induced by pharmacological or with natural agents. However, knowing that aging is unavoidable we cannot expect its elimination, but prolonging healthy life span is a goal worth serious consideration.


New 3-Cyano-2-Substituted Pyridines Induce Apoptosis in MCF 7 Breast Cancer Cells.
The synthesis of new 3-cyano-2-substituted pyridines bearing various pharmacophores and functionalities at position 2 is described. The synthesized compounds were evaluated for their in vitro anti-cancer activities on five cancer cell lines using 5-FU as reference compound. The results revealed that the benzohydrazide derivative 9a induced growth inhibition in human breast cancer cell line MCF-7 with an IC50 value of 2 μM and it showed lower cytotoxicity on MCF-12a normal breast epithelial cells. Additionally, 9a induced apoptotic morphological changes and induced apoptosis in MCF-7 in a dose and time-dependent manner according to an enzyme linked immunosorbent apoptosis assay which is further confirmed by a TUNEL assay. Flow cytometric analysis indicated that 9a arrested MCF-7 cells in the G1 phase, which was further confirmed by increased expression of p21 and p27 and reduced expression of CDK2 and CDK4. Western blot data revealed significant upregulation of the expression of p53, Bax, caspase-3 and down-regulation of Bcl-2, Mdm-2 and Akt. Additionally, 9a increased the release of cytochrome c from mitochondria to cytoplasm which provokes the mitochondrial apoptotic pathway while it showed no significant change on the expression of the death receptor proteins procaspase-8, caspase-8 and FAS. Furthermore, 9a reduced the expression of phospho AKT and β-catenin in dose dependent manner while inhibiting the expression of migration-related genes such as matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGF). Our findings suggest that compound 9a could be considered as a lead structure for further development of more potent apoptosis inducing agents with anti-metastatic activities.


International drug price comparisons: quality assessment.
To quantitatively summarize results (i.e., prices and affordability) reported from international drug price comparison studies and assess their methodological quality. A systematic search of the most relevant databases-Medline, Embase, International Pharmaceutical Abstracts (IPA), and Scopus, from their inception to May 2009-was conducted to identify original research comparing international drug prices. International drug price information was extracted and recorded from accepted papers. Affordability was reported as drug prices adjusted for income. Study quality was assessed using six criteria: use of similar countries, use of a representative sample of drugs, selection of specific types of prices, identification of drug packaging, different weights on price indices, and the type of currency conversion used. Of the 1 828 studies identified, 21 were included. Only one study adequately addressed all quality issues. A large variation in study quality was observed due to the many methods used to conduct the drug price comparisons, such as different indices, economic parameters, price types, basket of drugs, and more. Thus, the quality of published studies was considered poor. Results varied across studies, but generally, higher income countries had higher drug prices. However, after adjusting drug prices for affordability, higher income countries had more affordable prices than lower income countries. Differences between drug prices and affordability in different countries were found. Low income countries reported less affordability of drugs, leaving room for potential problems with drug access, and consequently, a negative impact on health. The quality of the literature on this topic needs improvement.


Tilt-ellipsometry of object surface by specular reflection for three-dimensional shape measurement.
Ellipsometry by specular reflection has been reworked as a precise surface normal vector detection method for the geometrical shape study of a glossy object. When the object is illuminated by circularly polarized light, the surface normal vector defines the shape of the reflection polarization ellipse; the azimuth and ellipticity are determined by the angle of the incident plane and the angle of incidence, respectively. The tilt-ellipsometry principle of tilt detection is demonstrated experimentally with a metallic polygon and a cube sample.


Mobile element scanning (ME-Scan) by targeted high-throughput sequencing.
Mobile elements (MEs) are diverse, common and dynamic inhabitants of nearly all genomes. ME transposition generates a steady stream of polymorphic genetic markers, deleterious and adaptive mutations, and substrates for further genomic rearrangements. Research on the impacts, population dynamics, and evolution of MEs is constrained by the difficulty of ascertaining rare polymorphic ME insertions that occur against a large background of pre-existing fixed elements and then genotyping them in many individuals. Here we present a novel method for identifying nearly all insertions of a ME subfamily in the whole genomes of multiple individuals and simultaneously genotyping (for presence or absence) those insertions that are variable in the population. We use ME-specific primers to construct DNA libraries that contain the junctions of all ME insertions of the subfamily, with their flanking genomic sequences, from many individuals. Individual-specific "index" sequences are designed into the oligonucleotide adapters used to construct the individual libraries. These libraries are then pooled and sequenced using a ME-specific sequencing primer. Mobile element insertion loci of the target subfamily are uniquely identified by their junction sequence, and all insertion junctions are linked to their individual libraries by the corresponding index sequence. To test this method's feasibility, we apply it to the human AluYb8 and AluYb9 subfamilies. In four individuals, we identified a total of 2,758 AluYb8 and AluYb9 insertions, including nearly all those that are present in the reference genome, as well as 487 that are not. Index counts show the sequenced products from each sample reflect the intended proportions to within 1%. At a sequencing depth of 355,000 paired reads per sample, the sensitivity and specificity of ME-Scan are both approximately 95%. Mobile Element Scanning (ME-Scan) is an efficient method for quickly genotyping mobile element insertions with very high sensitivity and specificity. In light of recent improvements to high-throughput sequencing technology, it should be possible to employ ME-Scan to genotype insertions of almost any mobile element family in many individuals from any species.


Centrifugal assay for fluorescence-based cell adhesion adapted to the analysis of ex vivo cells and capable of determining relative binding strengths.
Cell adhesion assays are widely used to identify novel cellular ligands, novel cell surface receptors for these ligands and to elucidate the mechanisms responsible for the underlying cellular and molecular interactions. We report here the development of a novel centrifugal assay for fluorescence-based cell adhesion (CAFCA) that offers a number of advantages over the currently available assays. CAFCA is based on two centrifugation steps: one to allow for the synchronization of the initial cell-substratum contact and one to enable both a defined removal force to be exerted onto the cells for displacement of unbound cells and determination of the relative binding strengths of adhering cells. The fluorescently tagged cells are monitored in specifically devised, disposable microplate assemblies by a two-sided fluorescence detection through the computer-interfaced SPECTRAFLUOR microplate fluorometer. The assay is rapid, accurate, reproducible and adaptable to small numbers of delicate primary cells that can ideally be labeled with the fluorochrome calcein AM (or analogous vital fluorescent dyes). Most uniquely, CAFCA provides (i) means of assessing the precise number of cells bound to a given substratum out of the total amount of cells contained within the population to be analyzed and (ii) a means of establishing the attachment strengths (i.e., dynes/cell) in a high number of samples/conditions simultaneously. CAFCA is therefore expected to make a substantial methodological and conceptual contribution to the range of available assays aimed at examining cellular interactions in vitro and promises the potential of being able to transpose automated versions of these tests for routine use in laboratories.


A multi-SNP locus-association method reveals a substantial fraction of the missing heritability.
There are many known examples of multiple semi-independent associations at individual loci; such associations might arise either because of true allelic heterogeneity or because of imperfect tagging of an unobserved causal variant. This phenomenon is of great importance in monogenic traits but has not yet been systematically investigated and quantified in complex-trait genome-wide association studies (GWASs). Here, we describe a multi-SNP association method that estimates the effect of loci harboring multiple association signals by using GWAS summary statistics. Applying the method to a large anthropometric GWAS meta-analysis (from the Genetic Investigation of Anthropometric Traits consortium study), we show that for height, body mass index (BMI), and waist-to-hip ratio (WHR), 3%, 2%, and 1%, respectively, of additional phenotypic variance can be explained on top of the previously reported 10% (height), 1.5% (BMI), and 1% (WHR). The method also permitted a substantial increase (by up to 50%) in the number of loci that replicate in a discovery-validation design. Specifically, we identified 74 loci at which the multi-SNP, a linear combination of SNPs, explains significantly more variance than does the best individual SNP. A detailed analysis of multi-SNPs shows that most of the additional variability explained is derived from SNPs that are not in linkage disequilibrium with the lead SNP, suggesting a major contribution of allelic heterogeneity to the missing heritability.


Typhoid conjugate vaccines: a new tool in the fight against antimicrobial resistance.
Typhoid fever is an acute systemic infectious disease responsible for an estimated 12-20 million illnesses and over 150 000 deaths annually. In March, 2018, a new recommendation was issued by WHO for the programmatic use of typhoid conjugate vaccines in endemic countries. Health economic analyses of typhoid vaccines have informed funding decisions and national policies regarding vaccine rollout. However, by focusing only on averted typhoid cases and their associated costs, traditional cost-effectiveness analyses might underestimate crucial benefits of typhoid vaccination programmes, because the potential effect of typhoid vaccines on the treatment of patients with non-specific acute febrile illnesses is not considered. For every true case of typhoid fever, three to 25 patients without typhoid disease are treated with antimicrobials unnecessarily, conservatively amounting to more than 50 million prescriptions per year. Antimicrobials for suspected typhoid might therefore be an important selective pressure for the emergence and spread of antimicrobial resistance globally. We propose that large-scale, more aggressive typhoid vaccination programmes-including catch-up campaigns in children up to 15 years of age, and vaccination in lower incidence settings-have the potential to reduce the overuse of antimicrobials and thereby reduce antimicrobial resistance in many bacterial pathogens. Funding bodies and national governments must therefore consider the potential for broad reductions in antimicrobial use and resistance in decisions related to the rollout of typhoid conjugate vaccines.


The feasibility of community level interventions for pre-eclampsia in South Asia and Sub-Saharan Africa: a mixed-methods design.
Globally, pre-eclampsia and eclampsia are major contributors to maternal and perinatal mortality; of which the vast majority of deaths occur in less developed countries. In addition, a disproportionate number of morbidities and mortalities occur due to delayed access to health services. The Community Level Interventions for Pre-eclampsia (CLIP) Trial aims to task-shift to community health workers the identification and emergency management of pre-eclampsia and eclampsia to improve access and timely care. Literature revealed paucity of published feasibility assessments prior to initiating large-scale community-based interventions. Arguably, well-conducted feasibility studies can provide valuable information about the potential success of clinical trials prior to implementation. Failure to fully understand the study context risks the effective implementation of the intervention and limits the likelihood of post-trial scale-up. Therefore, it was imperative to conduct community-level feasibility assessments for a trial of this magnitude. A mixed methods design guided by normalization process theory was used for this study in Nigeria, Mozambique, Pakistan, and India to explore enabling and impeding factors for the CLIP Trial implementation. Qualitative data were collected through participant observation, document review, focus group discussion and in-depth interviews with diverse groups of community members, key informants at community level, healthcare providers, and policy makers. Quantitative data were collected through health facility assessments, self-administered community health worker surveys, and household demographic and health surveillance. Refer to CLIP Trial feasibility publications in the current and/or forthcoming supplement. Feasibility assessments for community level interventions, particularly those involving task-shifting across diverse regions, require an appropriate theoretical framework and careful selection of research methods. The use of qualitative and quantitative methods increased the data richness to better understand the community contexts. NCT01911494.


The analysis of the functions of human B and T cells in humanized NOD/shi-scid/gammac(null) (NOG) mice (hu-HSC NOG mice).
'Humanized mice' are anticipated to be a valuable tool for studying the human immune system, but the reconstituted human immune cells have not yet been well characterized. Here, we extensively investigated the differentiation and functions of human B and T cells in a supra-immunodeficient mouse strain, NOD/shi-scid/gammac(null) (NOG) reconstituted with CD34(+) hematopoietic stem cells obtained from umbilical cord blood. In these hu-HSC NOG mice, the development of human B cells was partially blocked, and a significant number of B-cell progenitors accumulated in the spleen. The mature CD19(+)IgM(+)IgD(+) human B cells of the hu-HSC NOG mice could produce IgG in vivo and in vitro by antigenic stimulation. In contrast, although human T cells with an apparently normal phenotype developed, most of them could neither proliferate nor produce IL-2 in response to antigenic stimulation by anti-CD3 and anti-CD28 antibodies in vitro. The positive selection of human T cells in the thymus was sufficiently functional, if not complete, and mainly mediated by mouse class II, suggesting that the human T cells lost their function in the periphery. We found that multiple mechanisms were involved in the T-cell abnormalities. Collectively, our results demonstrate that further improvements are necessary before humanized mice with a functional human immune system are achieved.


Spontaneous decrease in gastric secretory response to humoral stimuli.
The gastric response to pentagastrin was studied over a period of seven months in a healthy 25-year-old man without symptoms or history of gastrointestinal disease. An abrupt impairment of the gastric response to several stimulants was observed one month after starting the tests. Periodic testing since that time has shown no reversion to the type of response seen during the initial period of testing. A second subject with proved chronic duodenal ulceration presented an identical change in pattern of gastric response to stimulants.This study suggests that such a variation in the response to gastric stimulation in a subject with a normal stomach should be borne in mind when interpreting results of gastric secretory studies.


Study protocol for "MOVEdiabetes": a trial to promote physical activity for adults with type 2 diabetes in primary health care in Oman.
Benefits of physical activity in the management of diabetes are well documented. However, evidence on the effectiveness of interventions integrating physical activity in diabetes care is sparse especially in the countries of the Gulf Cooperation Council. The results from this study will increase our understanding of the use of multi-component interventions aimed at increasing physical activity levels in inactive adults with type 2 diabetes in primary health care in Oman. The study is a one year 1:1 cluster randomized controlled trial of the MOVEdiabetes programme (intervention) versus usual care in eight primary health care centres in Oman. The MOVEdiabetes programme utilizes face to face physical activity consultations promoting 150 min of moderate to vigorous physical activity per week (≥600MET-mins/week), pedometers to self-monitor step counts and monthly telephone WhatsApp messages for follow up support. Inactive adults with type 2 diabetes and no contraindication to physical activity will be recruited over a two months period, and followed up for 12 months. To demonstrate a 50% between group difference in physical activity levels (MET-mins/week) over 12 months, (at a power of 80%, and significance level of 5%), 128 participants would be required to complete the study (64 in each arm). Based on a drop-out rate of 20%, 154 participants would require to be recruited (77 in each arm). Assuming a recruitment rate of 70%, 220 potential eligible participants would need to be approached. The primary outcome is change in levels of physical activity measured by the Global Physical Activity Questionnaire. In addition, accelerometers will be used in a sub group to objectively assess physical activity. Secondary outcomes include changes in metabolic and cardiovascular biomarkers, change in self-reported health, social support, self-efficacy for physical activity, and perceived acceptability of the program. All intervention delivery and support costs will be monitored. This study will contribute to the evidence on the feasibility, cultural acceptability and efficacy of interventional approaches for increasing physical activity in primary care for persons with type 2 diabetes in Oman. International Standard Randomised Controlled Trials No: ISRCTN14425284 . Registered 12 April 2016.


Inhibition of amino acid transport system a by interleukin-1beta in trophoblasts.
The current study sought to investigate the influence of interleukin-1beta (IL-1beta) on the function of the amino acid transport system A in trophoblasts. BeWo choriocarcinoma cells were exposed to recombinant human IL-1beta in serum-free medium. Cells incubated with serum-free medium in the absence of IL-1beta were used as control. System A activity was determined in control and treated cells by measuring the uptake of alpha-(methylamino)isobutyric acid. The results obtained were confirmed by measuring system A activity in placental brush border membrane vesicles isolated from pregnant rats injected with IL-1beta. Treatment of BeWo cells with IL-1beta resulted in a time- and dose- dependent inhibition of system A. Treatment with IL-1beta also inhibited the uptake of arginine, and glutamate but had no significant effect on the uptake of leucine, tryptophan, and ascorbate. The inhibition of system A activity by IL-1beta was abolished in the presence of IL-1beta receptor antagonist. The inhibitory effect was associated with a decrease in the maximal velocity of the transport system with no effect on the substrate affinity. Steady-state levels of both SNAT1 and SNAT2 mRNA were reduced by IL-1beta treatment as evidenced by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. In rat placental brush border membrane vesicles isolated from IL-1beta-treated pregnant rats, system A activity was found to be decreased by approximately 40% compared to activity in control membrane vesicles. IL-1beta decreases SNAT1 and SNAT2 mRNA levels in trophoblasts, which is associated with a decrease in system A-mediated transport activity at the functional level. These findings may have important consequences under both physiologic conditions and pathologic conditions during pregnancy that are associated with elevated levels of IL-1beta.


Is technology still a major driver of health expenditure in the United States? Evidence from cointegration analysis with multiple structural breaks.
Using a longer span of available time series data and employing powerful unit root and cointegration tests that allow for multiple structural breaks, developed recently by Carrion-i-Silvestre et al. (Econ Theory 25:1754-1792, 2009), Perron and Yabu (J Bus Econ Stat 27:369-396, 2009), Kejriwal and Perron (J Econ 146(1):59-73, 2008; J Bus Econ Stat 28(4):503-522, 2010a; J Time Ser Anal 31:305-328, 2010b) and Maki (Econ Model 29:2011-2015, 2012), this paper empirically investigates, whether technology continues to be a major driver of real per capita health expenditure, along with some control variables such as per capita income and life expectancy, in the United States, during the period 1960-2012. Specifically, the paper applies the most recent cointegration tests under multiple structural breaks and extends the work of Okunade (J Health Econ 21(1):147-159, 2002) with the possibility whether a linear cointegration model with multiple structural breaks would provide a better economic model to quantify the impact of some major determinants of US real per capita health expenditure. This paper presents evidence to show that per capita real income, technology as indicated by four proxy measures and life expectancy at birth are some major drivers of real per capita health expenditure in the United States. Contrary to the available evidence in the literature, the finding of this paper is that the point aggregate income elasticity of health expenditure estimate is less than one, indicating that health care has evolved to become a necessity in the United States. Policy implications of the empirical findings are discussed in the paper.


Brief alcohol interventions for mandated college students: comparison of face-to-face counseling and computer-delivered interventions.
College students who violate alcohol policies are often mandated to participate in alcohol-related interventions. This study investigated (i) whether such interventions reduced drinking beyond the sanction alone, (ii) whether a brief motivational intervention (BMI) was more efficacious than two computer-delivered interventions (CDIs) and (iii) whether intervention response differed by gender. Randomized controlled trial with four conditions [brief motivation interventions (BMI), Alcohol 101 Plus™, Alcohol Edu for Sanctions(®), delayed control] and four assessments (baseline, 1, 6 and 12 months). Private residential university in the United States. Students (n = 677; 64% male) who had violated campus alcohol policies and were sanctioned to participate in a risk reduction program. Consumption (drinks per heaviest and typical week, heavy drinking frequency, peak and typical blood alcohol concentration), alcohol problems and recidivism. Piecewise latent growth models characterized short-term (1-month) and longer-term (1-12 months) change. Female but not male students reduced drinking and problems in the control condition. Males reduced drinking and problems after all interventions relative to control, but did not maintain these gains. Females reduced drinking to a greater extent after a BMI than after either CDI, and maintained reductions relative to baseline across the follow-up year. No differences in recidivism were found. Male and female students responded differently to sanctions for alcohol violations and to risk reduction interventions. BMIs optimized outcomes for both genders. Male students improved after all interventions, but female students improved less after CDIs than after BMI. Intervention effects decayed over time, especially for males.


Thymosin α 1: a novel therapeutic option for patients with refractory chronic purulent rhinosinusitis.
Chronic purulent rhinosinusitis (CPR) is an inflammatory condition of unknown origin. Although various medical and surgical treatment modalities are available, 5-10% of patients remain refractory. Immune deficiency is one of the underlying risk factors for this disease. Earlier studies demonstrated disturbances in cell-mediated immunity and defects in monocyte chemotaxis in CPR. Treatment with the thymic hormone preparation thymostimulin led to significant clinical improvement in patients and in vitro restoration of monocyte chemotaxis. Unfortunately, thymostimulin became unavailable, which has led to recent interest in the immunomodulatory effects of the thymic peptide thymosin α1, which has demonstrated some benefit for CPR. Our current in vitro work focuses on the potential effects of thymosin α1 on monocyte function and gene expression profiles in order to understand its effects and mechanisms of action. Future clinical studies will evaluate the potential significance of thymosin α1 in treatment of CPR patients.


Contractile responses to Bay K 8644 in rats with coarctation-induced hypertension.
This study examines potential-operated calcium channel function in rats made hypertensive by aortic coarctation. The hypothesis that channel function is influenced by elevated arterial pressure was tested by comparing contractile responses to elevated K+ and to the potential-operated calcium channel agonist, Bay K 8644, in aortic segments above (thoracic) and below (abdominal) the coarctation that are exposed to hypertensive and normotensive pressures, respectively. To control for vessel differences, the effects of Bay K 8644 were also examined in abdominal aortae from two-kidney, one-clip hypertensive rats. Sensitivity to K+ (EC15) was significantly greater in both thoracic and abdominal aortae from coarctation-hypertensive rats than in those from normotensive sham rats. In the thoracic aorta, maximal contractile response to Bay K 8644 (normalized to contraction produced by 100 mM K+) was significantly greater in coarctation-hypertensive rats (124 +/- 9%) than in sham rats (12 +/- 6%). However, Bay K 8644 did not elicit contraction in abdominal aortae from either group. When [K+]o was increased (19.2 mM), thoracic aortae from coarctation-hypertensive rats were more sensitive to Bay K 8644, but there were no differences in maximal responses among thoracic and abdominal aortae. Bay K 8644 evoked dose-dependent contraction in all abdominal aortic strips from two-kidney, one-clip hypertensive rats (maximum = 68 +/- 11%). In summary, vascular responsiveness to Bay K 8644 is increased in the thoracic but not abdominal aorta from coarctation-hypertensive rats, whereas sensitivity to elevated K+ is increased in both vessels. Enhanced K+ sensitivity in the abdominal aorta may be related to general effects of the cation on membrane potential. However, augmented responsiveness to Bay K 8644 suggests a specific alteration in the function of potential-operated calcium channels that is dependent upon elevated blood pressure and is not due to differences in responsiveness between the thoracic and abdominal aortae.


Robust Bayesian Fluorescence Lifetime Estimation, Decay Model Selection and Instrument Response Determination for Low-Intensity FLIM Imaging.
We present novel Bayesian methods for the analysis of exponential decay data that exploit the evidence carried by every detected decay event and enables robust extension to advanced processing. Our algorithms are presented in the context of fluorescence lifetime imaging microscopy (FLIM) and particular attention has been paid to model the time-domain system (based on time-correlated single photon counting) with unprecedented accuracy. We present estimates of decay parameters for mono- and bi-exponential systems, offering up to a factor of two improvement in accuracy compared to previous popular techniques. Results of the analysis of synthetic and experimental data are presented, and areas where the superior precision of our techniques can be exploited in Förster Resonance Energy Transfer (FRET) experiments are described. Furthermore, we demonstrate two advanced processing methods: decay model selection to choose between differing models such as mono- and bi-exponential, and the simultaneous estimation of instrument and decay parameters.


Traumatic brain injury in China.
China has more patients with traumatic brain injury (TBI) than most other countries in the world, making this condition a major public health concern. Population-based mortality of TBI in China is estimated to be approximately 13 cases per 100 000 people, which is similar to the rates reported in other countries. The implementation of various measures, such as safety legislation for road traffic, establishment of specialised neurosurgical intensive care units, and the development of evidence-based guidelines, have contributed to advancing prevention and care of patients with TBI in China. However, many challenges remain, which are augmented further by regional differences in TBI care. High-level care, such as intracranial pressure monitoring, is not universally available yet. In the past 30 years, the quality of TBI research in China has substantially improved, as evidenced by an increasing number of clinical trials done. The large number of patients with TBI and specialised trauma centres offer unique opportunities for TBI research in China. Furthermore, the formation and development of research collaborations between China and international groups are considered essential to advancing the quality of TBI care and research in China, and to improve quality of life in patients with this condition.


Electronic-cigarette use among young people in Wales: evidence from two cross-sectional surveys.
To examine the prevalence of electronic(e)-cigarette use, prevalence of e-cigarette and tobacco use by age, and associations of e-cigarette use with sociodemographic characteristics, tobacco and cannabis use among young people in Wales. Data from two nationally-representative cross-sectional surveys undertaken in 2013-2014. Logistic regression analyses, adjusting for school-level clustering, examined sociodemographic characteristics of e-cigarette use, and associations between e-cigarette use and smoking. Primary and secondary schools in Wales. Primary-school children aged 10-11 (n=1601) and secondary-school students aged 11-16 (n=9055). Primary-school children were more likely to have used e-cigarettes (5.8%) than tobacco (1.6%). Ever use of e-cigarettes remained more prevalent than ever use of tobacco until age 14-15. Overall, 12.3% of secondary-school students (aged 11-16) reported ever using e-cigarettes, with no differences according to gender, ethnicity or family affluence. The percentage of 'never smokers' reporting having used e-cigarettes was 5.3% at age 10-11 to 8.0% at age 15-16. The proportion of children who had ever used an e-cigarette and reported currently smoking increased from 6.9% among 10-11 year olds to 39.2% in 15-16 year olds. Only 1.5% (n=125) of 11-16 year-olds, including 0.3% of never smokers, reported regular e-cigarette use (use at least once a month). Current weekly smokers were 100 times more likely than non-smokers to report regular e-cigarette use (relative risk ratio (RRR=121.15; 95% CI 57.56 to 254.97). Regular e-cigarette use was also more likely among those who had smoked cannabis (RRR 53.03; 95% CI 38.87 to 80.65). Many young people (including never-smokers) have tried e-cigarettes. However, regular use is less common, and is associated with tobacco cigarette use. Longitudinal research is needed to understand age-related trajectories of e-cigarette use and to understand the temporal nature of relationships between e-cigarette and tobacco use.