Influence of component positioning on impingement in conventional total shoulder arthroplasty.
Clinical experience suggests that component impingement can lead to eccentric implant loading and thereby cause glenoid loosening in conventional total shoulder arthroplasty. This study tests the hypothesis that certain implant component positioning configurations may lead to impingement within the physiological range of motion. A rigid-body model of the shoulder comprising the scapula and humerus was constructed. Within this 3D model, a commercially available total shoulder arthroplasty implant was positioned according to manufacturer guidelines. The configuration was modified around this default position to investigate the associated angle of inferior and superior impingement during glenohumeral elevation, as well as in lateral impingement during axial rotation at both 0 degrees and 60 degrees of glenohumeral elevation. Glenoid component size, version, inclination and inferior-superior offset as well as humeral component size, torsion, inclination, offset and height were examined. The influence of the humeral calcar anatomy was also investigated. Certain implant configurations caused component impingement in the physiological range of motion. The most sensitive parameters affecting impingement were: (1) the inclination of the glenoid component, (2) the inferior-superior position of the humeral component along the resection line and (3) the prominence of the humeral calcar. Glenoid offset and inclination and humeral head offset and height directly affected subacromial impingement. This study suggests that several intraoperatively adjustable implant positioning parameters can influence the likelihood of implant impingement in conventional total shoulder arthroplasty, and that the geometry of the humeral calcar should be taken into consideration when designing an operative strategy for shoulder joint replacement.


Interleukin-2 lymphokine-activated killer cell therapy of non-Hodgkin's lymphoma and Hodgkin's disease.
We conducted a phase II study utilizing interleukin-2 (IL-2) with lymphokine-activated killer (LAK) cells as therapy for non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD). IL-2 was given at a fixed dose of 3 x 10(6) U/m2/day administered as a 24-h continuous intravenous infusion with LAK cells. Nineteen extensively treated patients were entered and 15 were evaluable. In general, this regimen was reasonably well tolerated with mild toxicities that were rapidly reversible. Patients who completed therapy did so without dose attenuations. However, discontinuation of therapy was necessary in four patients due to atypical toxicities that were not clearly dose related. Two patients (one NHL and one HD) had partial remissions of brief duration, four had disease stabilization, and seven had progressive disease. While there were not sufficient numbers to evaluate critically any NHL or HD subtype, this regimen does not appear to have significant activity for either disease.


Alcohol consumption and the risk of incident atrial fibrillation among people with cardiovascular disease.
Moderate alcohol consumption may reduce cardiovascular events, but little is known about its effect on atrial fibrillation in people at high risk of such events. We examined the association between moderate alcohol consumption and the risk of incident atrial fibrillation among older adults with existing cardiovascular disease or diabetes. We analyzed data for 30 433 adults who participated in 2 large antihypertensive drug treatment trials and who had no atrial fibrillation at baseline. The patients were 55 years or older and had a history of cardiovascular disease or diabetes with end-organ damage. We classified levels of alcohol consumption according to median cut-off values for low, moderate and high intake based on guidelines used in various countries, and we defined binge drinking as more than 5 drinks a day. The primary outcome measure was incident atrial fibrillation. A total of 2093 patients had incident atrial fibrillation. The age- and sex-standardized incidence rate per 1000 person-years was 14.5 among those with a low level of alcohol consumption, 17.3 among those with a moderate level and 20.8 among those with a high level. Compared with participants who had a low level of consumption, those with higher levels had an increased risk of incident atrial fibrillation (adjusted hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.04-1.26, for moderate consumption; 1.32, 95% CI 0.97-1.80, for high consumption). Results were similar after we excluded binge drinkers. Among those with moderate alcohol consumption, binge drinkers had an increased risk of atrial fibrillation compared with non-binge drinkers (adjusted HR 1.29, 95% CI 1.02-1.62). Moderate to high alcohol intake was associated with an increased incidence of atrial fibrillation among people aged 55 or older with cardiovascular disease or diabetes. Among moderate drinkers, the effect of binge drinking on the risk of atrial fibrillation was similar to that of habitual heavy drinking.


Functional assessment of encapsulated citral for controlling necrotic enteritis in broiler chickens.
Development of viable alternatives to antibiotics to control necrotic enteritis (NE) caused by Clostridium perfringensis becoming urgent for chicken production due to pessures on poultry producers to limit or stop the use of antibiotics in feed. We have previously identified citral as a potential alternative to antibiotics. Citral has strong antimicrobial activity and can be encasupsulated in a powder form for protection from loss during feed processing, storage, and intestinal delivery. In the present study, encapsulated citral was evaluated both in vitro and in vivo for its antimicrobial activity against C. perfringens Encapsulation did not adversely affect the antimicrobial activity of citral. In addition, encapsulated citral was superior to the unencapsulated form in retaining its antimicrobial activity after treatment with simulated gastrointestinal fluids and in the presence of chicken intestinal digesta. In addition, the higher antimicrobial activity of encapsulated citral was confirmed in digesta samples from broilers that had been gavaged with encapsulated or unencapsulated citral. In broilers infected with C. perfringens, the diets supplemented with encapsualted citral at both 250 and 650 μg/g significantly reduced intestinal NE lesions, which was comparable to the effect of bacitracin- and salinomycin-containing diets. However, supplementation with the encapsulated citral appeared to have no significant impact on the intestinal burden of Lactobacillus These data indicate that citral can be used to control NE in chickens after proper protection by encapsulation.


The Lindley Weibull Distribution: properties and applications.
We introduce a new three-parameter lifetime model called the Lindley Weibull distribution, which accommodates unimodal and bathtub, and a broad variety of monotone failure rates. We provide a comprehensive account of some of its mathematical properties including ordinary and incomplete moments, quantile and generating functions and order statistics. The new density function can be expressed as a linear combination of exponentiated Weibull densities. The maximum likelihood method is used to estimate the model parameters. We present simulation results to assess the performance of the maximum likelihood estimation. We prove empirically the importance and flexibility of the new distribution in modeling two data sets.


Single-shot electron-beam bunch length measurements.
We report subpicosecond electro-optic measurements of the length of individual relativistic electron bunches. The longitudinal electron-bunch shape is encoded electro-optically on to the spectrum of a chirped laser pulse. The electron-bunch length is determined by analyzing individual laser-pulse spectra obtained with and without the presence of an electron bunch. Since the length of the chirped laser pulse can be easily changed, the electron bunch can be visualized on different time scales. This single-shot imaging technique is a promising method for real-time electron-bunch diagnostics.


The impact of Staphylococcus aureus concentration on the development of pulmonary lesions and cytokine expression after intravenous inoculation of pigs.
Acute respiratory distress syndrome is a common complication in severe sepsis. In pigs, the lungs play an important role in clearing systemic bacterial infections due to pulmonary intravascular macrophages found specifically in pigs. However, this increases the exposure of the porcine lungs to pathogens and potential injury. The authors propose that increasing the concentration of the inoculum without changing the bacterial dose will lead to severe sepsis with pronounced pulmonary lesions. This could potentially create a risk of cytokine spillover to the circulation, leading to an increased systemic response. Eight Danish Landrace pigs, approximately 10 weeks old, were inoculated twice with a low or once with a high concentration of Staphylococcus aureus. Three pigs were sham-inoculated. The animals were grouped based on macro- and microscopic lung lesions. The mRNA expression of local pulmonary inflammatory markers was compared to protein levels of systemic inflammatory markers. The most severe pulmonary lesions were observed in animals receiving the high S. aureus concentration, indicating that severity of lesions is dependent on inoculum concentration rather than total numbers of bacteria. Furthermore, local mRNA expression of inflammatory cytokines appeared to be dependent on the magnitude and severity of tissue destruction, including the ability to confine the lesions. Increasing mRNA levels of serum amyloid A could be a confident marker of severity of pulmonary lesions. Since no correlation was observed between local and systemic levels of inflammatory cytokines, this finding could indicate an ability of the porcine lung to compartmentalize the local inflammatory response and thus restrict systemic contribution.


Synthesis of highly uniform Cu2O spheres by a two-step approach and their assembly to form photonic crystals with a brilliant color.
Monodisperse semiconductor colloidal spheres with a high refractive index hold great potential for building photonic crystals with a strong band gap, but the difficulty in separating the nucleation and growth processes makes it challenging to prepare highly uniform semiconductor colloidal spheres. Herein, real monodisperse Cu2O spheres were prepared via a hot-injection & heating-up two-step method using diethylene glycol as a milder reducing agent. The diameter of the as prepared Cu2O spheres can be tuned from 90 nm to 190 nm precisely. The SEM images reveal that the obtained Cu2O spheres have a narrow size distribution, which permits their self-assembly to form photonic crystals. The effects of precursor concentration and heating rates on the size and morphology of the Cu2O spheres were investigated in detail. The results indicate that the key points of the method include the burst nucleation to form seeds at a high temperature followed by rapid cooling to prevent agglomeration, and appropriate precursor concentration as well as a moderate growth rate during the further growth process. Importantly, photonic crystal films exhibiting a brilliant structural color were fabricated with the obtained monodisperse Cu2O spheres as building blocks, proving the possibility of making photonic crystals with a strong band gap. The developed method was also successfully applied to prepare monodisperse CdS spheres with diameters in the range from 110 nm to 210 nm.


Evaluation of internal medicine residents as exercise role models and associations with self-reported counseling behavior, confidence, and perceived success.
Patients perceive physicians who practice healthy personal behaviors as more credible and better able to motivate patients to make healthy lifestyle choices. To evaluate internal medicine resident physicians as role models for promoting exercise by an assessment of physician physical activity behavior, cardiovascular fitness, physical activity knowledge, personal use of behavior modification techniques, attitudes toward personal physical activity practice, and confidence (i.e., self-efficacy) in the knowledge and personal utilization of behavior modification techniques and to explore the associations with self-reported patient counseling behavior, confidence, and perceived success. Cross-sectional study of internal medicine resident physicians with a self-administered survey, treadmill fitness testing, and a 7-day physical activity recall. Fifty-one resident physicians agreed to participate (response rate = 81%). Fitness levels were below average for 60%, average for 25%, and above average or excellent for 15%. The mean energy expenditure was 234 kcal/kg/week, with 41% of physicians meeting recommended physical activity guidelines. Few reported high self-efficacy (33%) or perceived success (25%) in the ability to be regularly active. Few demonstrated adequate knowledge useful for patient counseling (e.g., listing 3 ways to integrate physical activity into daily life [27%], calculating target heart rate [29%], and identifying personal exercise stages of change [25%]). Personal use of behavior modification techniques was reported infrequently. Although 88% reported confidence in the knowledge of exercise benefits, less than half reported confidence in the knowledge of local facilities, American College of Sports Medicine (ACSM) guidelines, and behavior modification techniques. Multiple linear regression demonstrated that a higher level of training (p = .02) and a greater confidence in the knowledge of ACSM guidelines (p = .048, total R2 = .21) independently predicted more frequent self-reported counseling. Sex (i.e., male; p = .01) and greater physical activity self-efficacy (p = .017, total R2 = .23) independently predicted greater perceived counseling success. Greater physical activity enjoyment (p = .03) and greater perceived success at engaging in regular physical activity (p = .028, total R2 = .28) independently predicted greater counseling self-efficacy. Most internal medicine resident physicians may not be adequate role models for promoting exercise adherence. Confidence in the knowledge of current guidelines, personal physical activity enjoyment, and perceived success and self-efficacy in engaging in regular physical activity may be useful targets for enhancing resident physician physical activity counseling for their patients.


Genetic diversity and connectivity of deep-sea hydrothermal vent metapopulations.
Deep-sea hydrothermal vents provide ephemeral habitats for animal communities that depend on chemosynthetic primary production. Sporadic volcanic and tectonic events destroy local vent fields and create new ones. Ongoing dispersal and cycles of extirpation and colonization affect the levels and distribution of genetic diversity in vent metapopulations. Several species exhibit evidence for stepping-stone dispersal along relatively linear, oceanic, ridge axes. Other species exhibit very high rates of gene flow, although natural barriers associated with variation in depth, deep-ocean currents, and lateral offsets of ridge axes often subdivide populations. Various degrees of impedance to dispersal across such boundaries are products of species-specific life histories and behaviours. Though unrelated to the size of a species range, levels of genetic diversity appear to correspond with the number of active vent localities that a species occupies within its range. Pioneer species that rapidly colonize nascent vents tend to be less subdivided and more diverse genetically than species that are slow to establish colonies at vents. Understanding the diversity and connectivity of vent metapopulations provides essential information for designing deep-sea preserves in regions that are under consideration for submarine mining of precious metals.


C-C chemokine receptor type 6 modulates the biological function of osteoblastogenesis by altering the expression levels of Osterix and OPG/RANKL.
Circulating inflammatory factors affect osteoblast and osteoclast formation and activity in osteoporosis. Estrogen affects the migration of Th17 cells via the C-C chemokine receptor type 6 (CCR6) and C-C chemokine ligand 20 (CCL20) signaling pathways to modulate bone metabolism; however, it is unclear whether and how CCR6 modulates bone homeostasis. In the present study, CCR6 knockout (CCR6-/-) mice were selected to investigate the effects of CCR6 in the regulation of homeostasis of osteoblasts and osteoclasts. Primary osteoblasts were isolated from the calvarium of newborn CCR6-/- or wild-type mice, followed by osteoblastic differentiation culture in vitro. CCR6 deletion reduced osteoblast activity in terms of alkaline phosphatase (ALP) activity and inhibited osteoblast mineralization according to the results of Alizarin Red S staining, whereas it did not affect the proliferation of osteoblasts. CCR6 deletion inhibited Osterix mRNA expression in osteoblasts during the late stage of mineralization in vitro, while it did not affect mRNA expression levels of runt-related transcription factor 2 (Runx2) and Collagen-1. The ratio of osteoprotegerin (OPG) /receptor activator of nuclear factor κ-Β ligand (RANKL) mRNA level in osteoblasts was decreased by CCR6 deficiency in the culture treated with 1,25(OH)2D3/PGE2, while there was no effect observed in the normal culture environment. The results provide novel insights, such as that CCR6 deletion suppresses osteoblast differentiation by downregulating the expression levels of the transcription factor Osterix, and indirectly promotes osteoclast production by increasing transcription of RANKL. This may be one of the mechanisms via which CCR6 deletion regulates bone metabolism.


Bringing light into the dark: effects of compression clothing on performance and recovery.
To assess original research addressing the effect of the application of compression clothing on sport performance and recovery after exercise, a computer-based literature research was performed in July 2011 using the electronic databases PubMed, MEDLINE, SPORTDiscus, and Web of Science. Studies examining the effect of compression clothing on endurance, strength and power, motor control, and physiological, psychological, and biomechanical parameters during or after exercise were included, and means and measures of variability of the outcome measures were recorded to estimate the effect size (Hedges g) and associated 95% confidence intervals for comparisons of experimental (compression) and control trials (noncompression). The characteristics of the compression clothing, participants, and study design were also extracted. The original research from peer-reviewed journals was examined using the Physiotherapy Evidence Database (PEDro) Scale. Results indicated small effect sizes for the application of compression clothing during exercise for short-duration sprints (10-60 m), vertical-jump height, extending time to exhaustion (such as running at VO2max or during incremental tests), and time-trial performance (3-60 min). When compression clothing was applied for recovery purposes after exercise, small to moderate effect sizes were observed in recovery of maximal strength and power, especially vertical-jump exercise; reductions in muscle swelling and perceived muscle pain; blood lactate removal; and increases in body temperature. These results suggest that the application of compression clothing may assist athletic performance and recovery in given situations with consideration of the effects magnitude and practical relevance.


Speed of change in pancreatic mass and in intestinal bacteriology of parenterally fed rats.
1. Indices of pancreatic mass and bacterial counts for jejunal and ileal mucosa were studied in rats after 3, 6, 10 and 15 days of total parenteral nutrition and compared with the results from orally fed and sham intravenously fed control rats. 2. Pancreatic wet weight corrected for body weight decreased significantly by 31--42% after 3, 6, 10 and 15 days of total parenteral nutrition. The most striking decrease occurred within 3 days. Other indices of pancreatic mass (protein and DNA) showed a similar pattern suggesting pancreatic hypoplasia. There was more DNA per g of pancreas, indicating that unless there were changes in tissue water cellular hypotrophy must have accompanied the hypoplasia. 3. Pancreatic RNA also decreased significantly after 3--10 days of total parenteral nutrition, suggesting reduced protein synthesis. 4. Bacterial counts (log number) whether expressed as number/unit length of intestine or number/g wet weight of mucosa were decreased for anaerobic bacteria in the jejunum after 3--15 days of total parenteral nutrition. In the ileum both aerobic and anaerobic bacteria increased after 6 days of parenteral nutrition and then decreased significantly. 5. The changes in bacterial flora are unlikely to account for the adaptive hypoplasia seen in the intestine of intravenously fed rats.


Cancer-malaria: hidden connections.
Cancer and malaria exemplify two maladies historically assigned to separated research spaces. Cancer, on the one hand, ranks among the top priorities in the research agenda of developed countries. Its rise is mostly explained by the ageing of these populations and linked to environment and lifestyle. Malaria, on the other hand, represents a major health burden for developing countries in the Southern Hemisphere. These two diseases also belong to separate fields of medicine: non-communicable diseases for cancer and communicable diseases for malaria.


Retinoids induced astrocytic differentiation with down regulation of telomerase activity and enhanced sensitivity to taxol for apoptosis in human glioblastoma T98G and U87MG cells.
We hypothesized that induction of differentiation with retinoid could increase sensitivity to microtubule-binding drug taxol (TXL) for apoptosis in human glioblastoma T98G and U87MG cells. Treatment of cells with 1 microM all-trans retinoic acid (ATRA) or 1 microM 13-cis retinoic acid (13-CRA) for 7 days induced astrocytic differentiation, overexpression of glial fibrillary acidic protein (GFAP), and also down regulated telomerase expression and activity, thereby increased sensitivity to TXL for apoptosis. Treatment of glioblastoma cells with TXL triggered production of reactive oxygen species (ROS), induced phosphorylation of p38 mitogen-activated protein kinase (MAPK), and activated the redox-sensitive c-Jun NH(2)-terminal kinase 1 (JNK1) pathway. Moreover, TXL activated Raf-1 kinase for phosphorylation and inactivation of anti-apoptotic Bcl-2 protein. The events of apoptosis included increase in expression of Bax, down regulation of Bcl-2 and baculoviral inhibitor-of-apoptosis protein (IAP) repeat containing (BIRC) proteins, mitochondrial release of cytochrome c and Smac into the cytosol, increase in intracellular free [Ca(2+)], and activation of calpain, caspase-9, and caspase-3. Increased activity of caspase-3 cleaved inhibitor of caspase-activated DNase (ICAD) to release and translocate CAD to the nucleus for DNA fragmentation. Involvement of stress signaling kinases and proteolytic activities of calpain and caspase-3 in apoptosis was confirmed by pretreating cells with specific inhibitors. Taken together, our results suggested that retinoid (ATRA or 13-CRA) induced astrocytic differentiation with down regulation of telomerase activity to increase sensitivity to TXL to enhance apoptosis in glioblastoma cells. Thus, combination of retinoid and TXL could be an effective therapeutic strategy for controlling the growth of glioblastoma.


An attempt to hybridize Drosophila species using pole cell transplantation.
We have made hybrid embryos in Drosophila by pole cell transplants, by transferring pole cells from two species, D. rajasekari and D. eugracilis, into sterile D. melanogaster hosts. These females were then mated to melanogaster males and the older these females were, the further their hybrid offspring developed. In the case of the rajasekari/melanogaster hybrids, the embryos form cuticle but had defective heads, while the eugracilis/melanogaster hatched as larvae that grew but did not moult to the second instar. Hybrid pole cells could be transferred to melanogaster hosts but they failed to make eggs.


Redesigning chemicals policy: a very different approach.
The chemical policies of the 1970s were limited by the assumptions that lie at their foundation and focused narrowly on only the most hazardous chemicals. The effective management of chemicals requires policies that focus on the entire body of chemicals and the production systems that make them. The future will require comprehensive chemicals policies that work within a systems framework to phase out the most hazardous chemicals, progressively transition away from the remaining chemicals of concern by substituting safer chemicals and technologies, and invest heavily in a new generation of safer and more sustainable chemicals.


The pathogenesis of gait hypokinesia in Parkinson's disease.
To identify the fundamental deficit in gait hypokinesia in Parkinson's disease (PD) we conducted a series of experiments that compared PD subjects with age- and height-matched controls in their capacity to regulate either stride length, cadence (steps per minute) or both parameters to three conditions. In the first condition the spatial and temporal parameters of gait were documented for slow, normal and fast walking. The second condition compared parkinsonian gait with the walking pattern of elderly controls whilst controlling for two movement speeds: fast (control preferred) speed and slow (PD preferred) speed. In the third condition we examined the ability of PD subjects to regulate one parameter (e.g. stride length) when the other two parameters (e.g. velocity and cadence) were held at control values. A total of 34 PD subjects and 34 matched controls were tested using a footswitch stride analysis system that measured the spatial and temporal parameters of gait for a series of 10 m walking trials. Parkinsonian subjects exhibited marked gait hypokinesia in each of the experiments. Although they retained the capacity to vary their gait velocity in a similar manner to controls, their range of response was reduced. Within the lower velocity range, PD subjects could vary their speed of walking by adjusting cadence and, to a lesser extent, stride length. However, when the speed of walking was controlled, the stride length was found to be shorter and the cadence higher in PD subjects than in controls. Stride length could not be upgraded by internal control mechanisms in response to a fixed cadence set for age and height-matched velocity. In contrast, cadence was readily modulated by external cues and by internal control mechanisms when stride length was fixed to the values obtained for age- and height-matched controls. It was concluded that regulation of stride length is the fundamental problem in gait hypokinesia and the relative increase in cadence exhibited by PD subjects is a compensatory mechanism for the difficulty in regulating stride length. These findings are discussed in the context of the hypothesized role of the basal ganglia in generating internal cues for the maintenance of the gait sequence and in relation to the structuring of movement rehabilitation strategies.


Effect of a Lower vs Higher Positive End-Expiratory Pressure Strategy on Ventilator-Free Days in ICU Patients Without ARDS: A Randomized Clinical Trial.
It is uncertain whether invasive ventilation can use lower positive end-expiratory pressure (PEEP) in critically ill patients without acute respiratory distress syndrome (ARDS). To determine whether a lower PEEP strategy is noninferior to a higher PEEP strategy regarding duration of mechanical ventilation at 28 days. Noninferiority randomized clinical trial conducted from October 26, 2017, through December 17, 2019, in 8 intensive care units (ICUs) in the Netherlands among 980 patients without ARDS expected not to be extubated within 24 hours after start of ventilation. Final follow-up was conducted in March 2020. Participants were randomized to receive invasive ventilation using either lower PEEP, consisting of the lowest PEEP level between 0 and 5 cm H2O (n = 476), or higher PEEP, consisting of a PEEP level of 8 cm H2O (n = 493). The primary outcome was the number of ventilator-free days at day 28, with a noninferiority margin for the difference in ventilator-free days at day 28 of -10%. Secondary outcomes included ICU and hospital lengths of stay; ICU, hospital, and 28- and 90-day mortality; development of ARDS, pneumonia, pneumothorax, severe atelectasis, severe hypoxemia, or need for rescue therapies for hypoxemia; and days with use of vasopressors or sedation. Among 980 patients who were randomized, 969 (99%) completed the trial (median age, 66 [interquartile range {IQR}, 56-74] years; 246 [36%] women). At day 28, 476 patients in the lower PEEP group had a median of 18 ventilator-free days (IQR, 0-27 days) and 493 patients in the higher PEEP group had a median of 17 ventilator-free days (IQR, 0-27 days) (mean ratio, 1.04; 95% CI, 0.95-∞; P = .007 for noninferiority), and the lower boundary of the 95% CI was within the noninferiority margin. Occurrence of severe hypoxemia was 20.6% vs 17.6% (risk ratio, 1.17; 95% CI, 0.90-1.51; P = .99) and need for rescue strategy was 19.7% vs 14.6% (risk ratio, 1.35; 95% CI, 1.02-1.79; adjusted P = .54) in patients in the lower and higher PEEP groups, respectively. Mortality at 28 days was 38.4% vs 42.0% (hazard ratio, 0.89; 95% CI, 0.73-1.09; P = .99) in patients in the lower and higher PEEP groups, respectively. There were no statistically significant differences in other secondary outcomes. Among patients in the ICU without ARDS who were expected not to be extubated within 24 hours, a lower PEEP strategy was noninferior to a higher PEEP strategy with regard to the number of ventilator-free days at day 28. These findings support the use of lower PEEP in patients without ARDS. ClinicalTrials.gov Identifier: NCT03167580.


Pyruvate kinase M2 is a poor prognostic marker of and a therapeutic target in ovarian cancer.
Pyruvate kinase M2 (PKM2) regulates glycolysis and oxidative phosphorylation; however, the role of PKM2 in ovarian cancer remains largely unknown. We investigated whether ovarian cancer metabolism could provide insight into the development of therapeutic strategies. We performed immunohistochemical staining for PKM2 on a tissue microarray for multivariate analysis. It revealed that patients exhibiting higher PKM2 expression were significantly associated with malignancy groups (p < 0.001) and pathogenesis models (p < 0.001), had poor progression-free survival rates (p = 0.01) as compared with patients exhibiting lower PKM2 levels, and yielded a hazard ratio of death of 2.02 (95% confidence interval: 0.70-5.85). In cell lines, PKM2 inhibitor significantly inhibited the glycolytic rate according to cellular glucose consumption (p < 0.001). We also utilized Seahorse assays to assess metabolism-related cell-specific factors and the impact of PKM2 inhibitors. Energy shifts as per Seahorse analysis showed attenuation of the extracellular acidification rate (p < 0.05) and no significant difference in oxygen-consumption rate in SKOV3 cells. Treatment with PKM2 inhibitor suppressed ovarian cancer growth and cell migration in vitro and inhibited tumor growth without significant toxicity in a xenograft study. PKM2 inhibition disturbed Warburg effects and inhibited ovarian cancer cell growth. Targeting PKM2 may constitute a promising therapy for patients with ovarian cancer, and clinical trials involving shikonin are warranted.


Barriers and enablers of physical activity engagement for patients with COPD in primary care.
Given that physical activity (PA) has a positive impact on COPD symptoms and prognosis, this study examined the factors that both encourage and limit participation in PA for individuals with COPD in a primary care setting from the perspective of social cognitive theory. A purposive sample of 26 individuals with a range of COPD severity (age range: 50-89 years; males =15) were recruited from primary care to participate in one of four focus groups. Thematic analysis was undertaken to identify key concepts related to their self-efficacy beliefs. Several barriers and enablers closely related to self-efficacy beliefs and symptom severity were identified. The main barriers were health related (fatigue, mobility problems, breathing issues caused by the weather), psychological (embarrassment, fear, frustration/disappointment), attitudinal (feeling in control of their condition, PA perception, older age perception), and motivational. The main enabling factors were related to motivation (autonomous or controlled), attitudes, self-regulation, and performance accomplishments. When designing interventions for individuals with COPD, it is important to understand the patient-specific social cognitive influences on PA participation. This information can then inform individually tailored management planning.


Oscillatory brain activity during acute exercise: Tonic and transient neural response to an oddball task.
Intense physical exercise exerts measurable changes at various physiological levels that are well documented in the literature. However, despite the key role of the brain in processing inputs from internal organ systems and the external environment to coordinate and optimize behavior, little is known about brain dynamics during exercise. The present study investigates tonic and transient oscillatory brain activity in a group of participants performing an oddball task during a single bout of aerobic exercise. Twenty young males (19-32 years) were recruited for two experimental sessions on separate days. EEG activity was recorded during a session of cycling at 80% (moderate-to-high intensity) of VO2max (maximum rate of oxygen consumption) while participants responded to infrequent targets (red square and big blue circle) presented among frequent nontargets (small blue circle). This was compared to a (baseline) light intensity session (30% VO2max ) to control any potential effect of dual tasking (i.e., pedaling and performing the oddball task). A cluster-based nonparametric permutations test revealed an increase in power across the entire frequency spectrum during the moderate-to-high intensity exercise compared to light intensity. Furthermore, the more salient target (red square) elicited a lower increase in (stimulus-evoked) theta power in the 80% VO2max than in the light intensity condition. Alpha and lower beta power decreased less in the standard trials (small blue circle) during the moderate-to-high exercise condition than in the light exercise condition. The present study unveils, for the first time, a complex brain activity pattern during vigorous exercise while attending to task-relevant stimuli.


Diffusion tensor imaging of the median nerve: intra-, inter-reader agreement, and agreement between two software packages.
To assess intra-, inter-reader agreement, and the agreement between two software packages for magnetic resonance diffusion tensor imaging (DTI) measurements of the median nerve. Fifteen healthy volunteers (seven men, eight women; mean age, 31.2 years) underwent DTI of both wrists at 1.5 T. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of the median nerve were measured by three readers using two commonly used software packages. Measurements were repeated by two readers after 6 weeks. Intraclass correlation coefficients (ICC) and Bland-Altman analysis were used for statistical analysis. ICCs for intra-reader agreement ranged from 0.87 to 0.99, for inter-reader agreement from 0.62 to 0.83, and between the two software packages from 0.63 to 0.82. Bland-Altman analysis showed no differences for intra- and inter-reader agreement and agreement between software packages. The intra-, inter-reader, and agreement between software packages for DTI measurements of the median nerve were moderate to substantial suggesting that user- and software-dependent factors contribute little to variance in DTI measurements.


The proportion cured of patients diagnosed with Stage III-IV cutaneous malignant melanoma in Sweden 1990-2007: A population-based study.
The survival in cutaneous malignant melanoma (CMM) is highly dependent on the stage of the disease. Stage III-IV CMM patients are at high risk of relapse with a heterogeneous outcome, but not all experience excess mortality due to their disease. This group is referred to as the cure proportion representing the proportion of patients who experience the same mortality rate as the general population. The aim of this study was to estimate the cure proportion of patients diagnosed with Stage III-IV CMM in Sweden. From the population-based Swedish Melanoma Register, we included 856 patients diagnosed with primary Stage III-IV CMM, 1990-2007, followed-up through 2013. We used flexible parametric cure models to estimate cure proportions and median survival times (MSTs) of uncured by sex, age, tumor site, ulceration status (in Stage III patients) and disease stage. The standardized (over sex, age and site) cure proportion was lower in Stage IV CMMs (0.15, 95% CI 0.09-0.22) than non-ulcerated Stage III CMMs (0.48, 95% CI 0.41-0.55) with a statistically significant difference of 0.33 (95% CI = 0.24-0.41). Ulcerated Stage III CMMs had a cure proportion of 0.27 (95% CI 0.21-0.32) with a statistically significant difference compared to non-ulcerated Stage III CMMs (difference 0.21; 95% CI = 0.13-0.30). The standardized MST of uncured was approximately 9-10 months longer for non-ulcerated versus ulcerated Stage III CMMs. We could demonstrate a significantly better outcome in patients diagnosed with non-ulcerated Stage III CMMs compared to ulcerated Stage III CMMs and Stage IV disease after adjusting for age, sex and tumor site.


The synthesis of inhibitors for processing proteinases and their action on the Kex2 proteinase of yeast.
Peptidyl chloromethane and sulphonium salts containing multiple Arg and Lys residues were synthesized as potential inhibitors of prohormone and pro-protein processing proteinases. The potencies of these compounds were assayed by measuring the kinetics of inactivation of the yeast Kex2 proteinase, the prototype of a growing family of eukaryotic precursor processing proteinases. The most potent inhibitor, Pro-Nvl-Tyr-Lys-Arg-chloromethane, was based on cleavage sites in the natural Kex2 substrate pro-alpha-factor. This inhibitor exhibited a Ki of 3.7 nM and a second-order inactivation rate constant (k2/Ki) of 1.3 x 10(7) M-1.s-1 comparable with the value of kcat./Km obtained with Kex2 for the corresponding peptidyl methylcoumarinylamide substrate. The enzyme exhibited sensitivity to the other peptidyl chloromethanes over a range of concentrations, depending on peptide sequence and alpha-amino decanoylation, but was completely resistant to peptidyl sulphonium salts. Kinetics of inactivation by these new inhibitors of a set of 'control' proteinases, including members of both the trypsin and subtilisin families, underscored the apparent specificity of the compounds most active against Kex2 proteinase.


Advances in bone surgery: the Er:YAG laser in oral surgery and implant dentistry.
The erbium-doped yttrium aluminium garnet (Er:YAG) laser has emerged as a possible alternative to conventional methods of bone ablation because of its wavelength of 2.94 μm, which coincides with the absorption peak of water. Over the last decades in several experimental and clinical studies, the widespread initial assumption that light amplification for stimulated emission of radiation (laser) osteotomy inevitably provokes profound tissue damage and delayed wound healing has been refuted. In addition, the supposed disadvantage of prolonged osteotomy times could be overcome by modern short-pulsed Er:YAG laser systems. Currently, the limiting factors for a routine application of lasers for bone ablation are mainly technical drawbacks such as missing depth control and a difficult and safe guidance of the laser beam. This article gives a short overview of the development process and current possibilities of noncontact Er:YAG laser osteotomy in oral and implant surgery.


Correlating data from different sensors to increase the positive predictive value of alarms: an empiric assessment.
Alarm fatigue from high false alarm rate is a well described phenomenon in the intensive care unit (ICU). Progress to further reduce false alarms must employ a new strategy. Highly sensitive alarms invariably have a very high false alarm rate. Clinically useful alarms have a high Positive-Predictive Value. Our goal is to demonstrate one approach to suppressing false alarms using an algorithm that correlates information across sensors and replicates the ways that human evaluators discriminate artifact from real signal. After obtaining IRB approval and waiver of informed consent, a set of definitions, (hypovolemia, left ventricular shock, tamponade, hemodynamically significant ventricular tachycardia, and hemodynamically significant supraventricular tachycardia), were installed in the monitors in a 10 bed cardiothoracic ICU and evaluated over an 85 day study period. The logic of the algorithms was intended to replicate the logic of practitioners, and correlated information across sensors in a way similar to that used by practitioners. The performance of the alarms was evaluated via a daily interview with the ICU attending and review of the tracings recorded over the previous 24 hours in the monitor. True alarms and false alarms were identified by an expert clinician, and the performance of the algorithms evaluated using the standard definitions of sensitivity, specificity, positive predictive value, and negative predictive value. Between 1 and 221 instances of defined events occurred over the duration of the study, and the positive predictive value of the definitions varied between 4.1% and 84%. Correlation of information across alarms can suppress artifact, increase the positive predictive value of alarms, and can employ more sophisticated definitions of alarm events than present single-sensor based systems.


The effect of load length, width and mass on transport rate in the grass-cutting ant Atta vollenweideri.
In the present study we investigated the economics of load transport in the grass-cutting ant Atta vollenweideri by focusing on the effects of load mass, width and length on individual transport rates. Both running speed of foragers and the amount of material transported a given distance per unit time, i.e. gross material transport rate, were evaluated in both field and laboratory colonies. In order to separate the effects of load mass, load length and width on transport rate, workers were presented with paper fragments which differed twofold either in length, width or mass, but not in the other parameters. When controlling for fragment mass, both running speed of foragers and gross material transport rate were observed to be higher when they carried short fragments: A twofold increase in fragment length had a marked negative effect on manoeuvrability during transport and, as a consequence, on material transport rate. In contrast, if fragment mass was doubled and length maintained, running speed differed according to the mass of the loads, with heavier fragments being transported at the slower pace. For the sizes tested, heavy fragments yielded a higher transport rate in spite of the slower speed of transport, as they did not slow down foragers so much that it counterbalanced the positive effects of fragment mass on material transport rate. Doubling the width of the fragments without changing their mass had no influence on running speed and transport rate. When presented with a choice of dropped fragments differing in the size variables mentioned above, workers discriminated among fragments of different size and preferred shorter fragments, thus rejecting loads that are associated with higher travel times and lower material transport rates. It is argued that, based on the energetics of cutting, workers might maximize their individual harvesting rate by cutting long grass fragments, since the longer a grass fragment, the larger the amount of material harvested per unit cutting effort. Our results indicate, however, that larger loads negatively affect transport rates. The sizes of the fragments cut by grass-cutting ants under natural conditions may represent the outcome of an evolutionary trade-off between maximizing harvesting rate at the cutting site and minimizing the effects of fragment size on material transport rates.


When learning order affects sensitivity to base rates: challenges for theories of causal learning.
In three experiments we investigated whether two procedures of acquiring knowledge about the same causal structure, predictive learning (from causes to effects) versus diagnostic learning (from effects to causes), would lead to different base-rate use in diagnostic judgments. Results showed that learners are capable of incorporating base-rate information in their judgments regardless of the direction in which the causal structure is learned. However, this only holds true for relatively simple scenarios. When complexity was increased, base rates were only used after diagnostic learning, but were largely neglected after predictive learning. It could be shown that this asymmetry is not due to a failure of encoding base rates in predictive learning because participants in all conditions were fairly good at reporting them. The findings present challenges for all theories of causal learning.


Perception of causes of omissions in the assessment of patients with chest pain.
There is growing evidence that errors and omissions often occur in the nursing assessment and care of patients. As yet, the impact of audit has been insufficient to correct these deficiencies, possibly because audit does not primarily focus on the causes of deficiencies. The purpose of this study was to examine the perceived causes of omissions in the assessment of patients with chest pain and to compare these with omissions detected in an audit of the assessment records. The type of attributions nurses used to explain the causes of the omissions was also investigated. Following an audit of the assessment records of patients with chest pain, 88 nurses were invited to answer a 51-item questionnaire relating to the types of omissions which occurred in the assessment of patients with chest pain. The results showed a marked discrepancy between the frequency of reported omissions and those found in the assessment records. The most common causes of omissions reported by the nurses were patients' condition, work overload, lack of time, poor assessment documentation, not realizing that the assessment had not been fully carried out and different nurses being involved in the assessment of patients. Nurses overwhelmingly attributed the causes of omissions to external or environmental factors rather than internal ones such as lack of knowledge or fatigue, which have implications for the types of strategies that might be used to improve care.


Positional pathway screen of wnt signaling genes in schizophrenia: association with DKK4.
Wnt signaling has been implicated in schizophrenia from studies of gene expression in patients, from an understanding of the function of reported susceptibility genes and from experimental studies of psychoactive drugs. This diverse evidence suggests that wnt signaling genes, defined as pathway participants, modifiers or targets, are good candidates as susceptibility factors. We performed a combined positional and candidate association screen by identifying known wnt signaling genes in regions linked to schizophrenia. In a staged study we examined over 50 single nucleotide polymorphisms (SNPs) in 28 wnt signaling genes, first in trios of Chinese origin and then in a case-control series from Hong Kong. In both sets, Dickkopf 4 (DKK4) was associated with schizophrenia - with an odds ratio of 3.9 (p < .01, CI = 1.3-11.1) in the combined sample. As DKK family members have previously been found to show altered expression in schizophrenia brain and to bind to neuregulin, this finding suggests that DKK4 may play a role in schizophrenia pathogenesis.


Conjugation of complex polyubiquitin chains to WRNIP1.
Werner helicase interacting protein 1 (WRNIP1) is a ubiquitin-binding protein that undergoes extensive post-translational modification including ubiquitination, sumoylation, and phosphorylation. These post-translational modifications are expected to regulate the function of WRNIP1 in the DNA damage response. In this study, we use a denaturing tandem affinity purification technique along with mass spectrometry to show that, unlike most ubiquitin-binding proteins, WRNIP1 is polyubiquitinated. WRNIP1 polyubiquitination is reminiscent of the well-characterized phenomenon of the coupled monoubiquitination of ubiquitin-binding proteins in that this polyubiquitination is dependent on the presence of an intact ubiquitin-binding domain. The polyubiquitin chains conjugated to WRNIP1 are linked through lysines 11, 48, and 63. This study presents the first evidence for the conjugation of K11-K48-K63 polyubiquitin chains to a specific substrate in vivo. Polyubiquitination is likely to regulate WRNIP1's function in the DNA damage response, as UV radiation induces the hyperubiquitination of WRNIP1. Polyubiquitination with noncanonical intraubiquitin linkages may represent a unique mode of regulation of UBZ domain-containing proteins.


Three-year follow-up and event rates in the international REduction of Atherothrombosis for Continued Health Registry.
To determine 3-year event rates in outpatients with vascular disease enrolled in the REduction of Atherothrombosis for Continued Health (REACH) Registry. REACH enrolled 67 888 outpatients with atherothrombosis [established coronary artery disease (CAD), cerebrovascular disease, or peripheral arterial disease (PAD)], or with at least three atherothrombotic risk factors, from 44 countries. Among the 55 499 patients at baseline with symptomatic disease, 39 675 were eligible for 3-year follow-up, and 32 247 had data available (81% retention rate). Among the symptomatic patients at 3 years, 92% were taking an antithrombotic agent, 91% an antihypertensive, and 76% were on lipid-lowering therapy. For myocardial infarction (MI)/stroke/vascular death, 1- and 3-year event rates for all patients were 4.2 and 11.0%, respectively. Event rates (MI/stroke/vascular death) were significantly higher for patients with symptomatic disease vs. those with risk factors only at 1 year (4.7 vs. 2.3%, P < 0.001) and at 3 years (12.0 vs. 6.0%, P < 0.001). One and 3-year rates of MI/stroke/vascular death/rehospitalization were 14.4 and 28.4%, respectively, for patients with symptomatic disease. Rehospitalization for a vascular event other than MI/stroke/vascular death was common at 3 years (19.0% overall; 33.6% for PAD; 23.0% for CAD). For patients with symptomatic vascular disease in one vascular bed vs. multiple vascular beds, 3-year event rates for MI/stroke/vascular death/rehospitalization were 25.5 vs. 40.5% (P < 0.001). Despite contemporary therapy, outpatients with symptomatic atherothrombotic vascular disease experience high rates of recurrent vascular events and rehospitalizations.


Barriers along the care cascade of HIV-infected men in a large urban center of Brazil.
Global and national HIV/AIDS policies utilize the care cascade to emphasize the importance of continued engagement in HIV services from diagnosis to viral suppression. Several studies have documented barriers that men experience in accessing services at specific stages of care, but few have analyzed how these barriers operate along the care cascade. Brazil offers a unique setting for analyzing barriers to HIV care because it is a middle-income country with a large HIV epidemic and free, universal access to HIV/AIDS services. Semi-structured interviews were conducted in 2011 with HIV-infected men (n = 25) receiving care at the only HIV/AIDS state reference center in Salvador, Brazil, the third largest city in the country. Interviews were transcribed and coded for analysis. Researchers identified barriers to services along the care cascade: health service-related obstacles (poor-quality care, lengthy wait times, and drug supply problems); psychosocial and emotional challenges (fear of disclosure and difficulty accepting HIV diagnosis); indirect costs (transportation and absenteeism at work or school); low perceived risk of HIV; and toxicity and complexity of antiretroviral drug (ARV) regimens. The stages of the care cascade interrupted by each barrier were also identified. Most barriers affected multiple, and often all, stages of care, while toxicity and complexity of ARV regimens was only present at a single care stage. Efforts to eliminate more prevalent barriers have the potential to improve care continuity at multiple stages. Going forward, assessing the relative impact of barriers along one's entire care trajectory can help tailor improvements in service provision, facilitate achievement of viral suppression, and improve access to life-saving testing, treatment, and care.


gamma(c) cytokines provide multiple homeostatic signals to naive CD4(+) T cells.
Cytokines signaling through receptors sharing the common gamma chain (gamma(c)), including IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, are critical for the generation and peripheral homeostasis of B, T and NK cells. To identify unique or redundant roles for gamma(c) cytokines in naive CD4(+) T cells, we compared monoclonal populations of CD4(+) T cells from TCR-Tg mice that were gamma(c) (+), gamma(c) (-), CD127(-/-) or CD122(-/-). We found that gamma(c) (-) naive CD4(+) T cells failed to accumulate in the peripheral lymphoid organs and the few remaining cells were characterized by small size, decreased expression of MHC class I and enhanced apoptosis. By over-expressing human Bcl-2, peripheral naive CD4(+) T cells that lack gamma(c) could be rescued. Bcl-2(+) gamma(c) (-) CD4(+) T cells demonstrated enhanced survival characteristics in vivo and in vitro, and could proliferate normally in vitro in response to antigen. Nevertheless, Bcl-2(+) gamma(c) (-) CD4(+) T cells remained small in size, and this phenotype was not corrected by enforced expression of an activated protein kinase B. We conclude that gamma(c) cytokines (primarily but not exclusively IL-7) provide Bcl-2-dependent as well as Bcl-2-independent signals to maintain the phenotype and homeostasis of the peripheral naive CD4(+) T cell pool.


Social-psychological factors affecting help-seeking for emotional problems.
Predictors of the attitudinal measure of orientation toward help-seeking for emotional problems have been shown to include demographic, network, and personality variables. This research determined whether these same variables predict the behavioral outcome measure of help-seeking, both in general and from professional services in particular. Help-seeking in response to emotional problems was studied in a sample of Australian adolescents. General help-seeking was predicted by more symptoms of psychological distress, being female, availability of social support, knowing someone who had sought professional help, and the personality characteristics of high private self-consciousness and willingness to disclose mental health. When only those with evident emotional distress were considered, only gender and willingness to disclose remained significant predictors. These same variables did not account for those who sought professional help rather than relying upon their informal network. Level of psychological distress was the only significant predictor of professional consultation. Psychological symptoms and gender were shown to be more relevant predictors of the behavioral measure of help-seeking than network or personality characteristics.


Drosophila host defense after oral infection by an entomopathogenic Pseudomonas species.
Drosophila has been shown to be a valuable model for the investigation of host-pathogen interactions. Study of the Drosophila immune response has been hampered, however, by the lack of true Drosophila pathogens. In nearly all studies reported, the bacteria used were directly injected within the body cavity of the insect, bypassing the initial steps of a natural interaction. Here, we report the identification of a previously uncharacterized bacterial species, Pseudomonas entomophila (Pe), which has the capacity to induce the systemic expression of antimicrobial peptide genes in Drosophila after ingestion. In contrast to previously identified bacteria, Pe is highly pathogenic to both Drosophila larvae and adults, and its persistence in larvae leads to a massive destruction of gut cells. Using this strain, we have analyzed the modulation of the larval transcriptome upon bacterial infection. We found that natural infection by Pe induces a dramatic change in larval gene expression. In addition to immunity genes, our study identifies many genes associated with Pe pathogenesis that have been previously unreported.


Human Plasmacytoid Dendritic Cells Display and Shed B Cell Maturation Antigen upon TLR Engagement.
The BAFF-APRIL system is best known for its control of B cell homeostasis, and it is a target of therapeutic intervention in autoimmune diseases and lymphoma. By analyzing the expression of the three receptors of this system, B cell maturation Ag (BCMA), transmembrane activator and CAML interactor, and BAFF receptor, in sorted human immune cell subsets, we found that BCMA was transcribed in plasmacytoid dendritic cells (pDCs) in both blood and lymphoid tissue. Circulating human pDCs contained BCMA protein without displaying it on the cell surface. After engagement of TLR7/8 or TLR9, BCMA was detected also on the cell surface of pDCs. The display of BCMA on the surface of human pDCs was accompanied by release of soluble BCMA (sBCMA); inhibition of γ-secretase enhanced surface expression of BCMA and reduced the release of sBCMA by pDCs. In contrast with human pDCs, murine pDCs did not express BCMA, not even after TLR9 activation. In this study, we extend the spectrum of BCMA expression to human pDCs. sBCMA derived from pDCs might determine local availability of its high-affinity ligand APRIL, because sBCMA has been shown to function as an APRIL-specific decoy. Further, therapeutic trials targeting BCMA in patients with multiple myeloma should consider possible effects on pDCs.


Effects of Acute Ketamine Infusion on Visual Working Memory: Event-Related Potentials.
Working memory (WM) deficits are a core feature of schizophrenia. Electrophysiological studies suggest that impaired early visual processing may contribute to impaired WM in the visual domain. Abnormal N-methyl-D-aspartate (NMDA) receptor function has been implicated both in WM and in early visual processing deficits in schizophrenia. We investigated whether ketamine, a noncompetitive NMDA antagonist, would replicate in healthy volunteers the WM performance and early visual processing abnormalities we and others have reported in patients with schizophrenia. Forty-four healthy volunteers were randomly assigned to receive intravenous ketamine or placebo. During infusion, the effects of ketamine were recorded using standardized psychiatric scales. Visual evoked potentials (P100 and P300 components) were recorded during performance of a delayed matching to sample task. Ketamine induced mild psychosis-like symptoms and impaired WM performance. It also significantly increased the P100 amplitude, while P300 amplitude decreased in a load-dependent manner. Amplitudes of P100 during retrieval correlated with cognitive performance only in the placebo group. We confirmed previous studies showing that ketamine reproduces the impairment of WM performance and smaller P300 amplitudes observed in schizophrenia. However, ketamine increased visual P100 amplitude in contrast to our observation of reduced P100 amplitudes in established schizophrenia. The effects of ketamine on WM and P300 are likely to involve impaired NMDA function, as these receptors are implicated in changes of synaptic strength underlying associative learning and memory. Increased P100 amplitude may reflect the secondary disinhibition of cortical glutamate release that occurs after NMDA blockade.


Association of epicardial and visceral adipose tissue in relation to subclinical cardiac dysfunction in Chinese: Danyang study.
Our study aims to examine the associations of visceral adipose tissue (VAT) and epicardial adipose tissue (EAT) with subclinical cardiac dysfunction in a Chinese population. Cross-sectional. EAT and VAT are the most important ectopic fat pools which were previously shown to be associated with subclinical cardiac dysfunction. However, few studies simultaneously measured both EAT thickness and VAT area, and explored their associations with cardiac dysfunction. Our study aims to examine the associations of VAT and EAT with subclinical cardiac dysfunction in a Chinese population. The study subjects were recruited from Danyang County from 2018 to 2019. Using Philips CX50, we recorded EAT thickness at the end-systole in a long-axis view. The subclinical systolic and diastolic function were assessed by two-dimensional speckle tracking, and transmitral and tissue Doppler imaging, respectively. Using Omron HDS-2000, we measured VAT area by dual bioelectrical impedance analysis. The 1558 participants (age, 52.3±12.8 years) included 930 (59.7%) women. Compared with women, men had higher VAT area (99.4 vs 70.1 cm2; p<0.0001) but lower EAT thickness (4.02 vs 4.46 mm; p<0.0001). In simple correlation analyses, EAT thickness and VAT area were positively associated with E/e' ratio (r=0.16 to 0.20; all p<0.0001) and negatively with global longitudinal strain (GLS) and e' (r=-0.12 to -0.37; all p<0.0001). Furthermore, VAT area was associated with left ventricular ejection fraction (LVEF) (r=-0.14; p<0.0001). After adjustment for confounding factors, the association of EAT with GLS and that of VAT with e' and E/e' ratio remained significant (all p≤0.001), whereas the associations of EAT with subclinical diastolic dysfunction and that of VAT with systolic function became non-significant (all p≥0.11). Analyses on further adjustment for LVEF showed similar results. Increased EAT thickness was associated with worse subclinical systolic dysfunction, while greater VAT area was associated with early diastolic dysfunction.


Treatment efficacy and methotrexate-related toxicity in patients with rheumatoid arthritis receiving methotrexate in combination with adalimumab.
Treatment of rheumatoid arthritis (RA) with a combination of methotrexate (MTX)+adalimumab (ADA) is more effective than ADA monotherapy. We assessed the toxicity of different doses of MTX and treatment efficacy of ADA+MTX in two trials. Data originated from CONCERTO, in patients with early RA initiating ADA+ 2.5, 5, 10 or 20 mg/week MTX for 26 weeks; and MUSICA, in patients with an inadequate response to MTX initiating ADA+ 7.5 or 20 mg/week MTX for 24 weeks. Efficacy was assessed by the American College of Rheumatology 50 (ACR50). Patient-reported MTX-related toxicity information was collected at each visit on 18 prespecified MTX-related adverse events (AE) in the MTX label. In CONCERTO, ACR50 rates increased over time, ranging from 54% to 68% at week 26, while AE rates remained steady, ranging from 2.4% to 17.8% at week 26. Of 395 patients, 113 (28.6%) reported 345 MTX-related AEs, including one serious AE (SAE, excessive fatigue and/or malaise); 10 AEs (in two patients) led to study discontinuation. In MUSICA, ACR50 rates increased over time, and were 32.3% and 37.5% at week 24, while MTX-related AE rates remained steady and were 6.5% at week 24. Of 309 patients, 71 (23%) reported 185 MTX-related AEs, including 5 SAEs (four infections and one fever/chills); six AEs (in four patients) led to study discontinuation. In patients with RA initiating ADA+MTX combination, treatment efficacy was achieved and increased throughout both trials, while rates of MTX-related AEs remained steady. MTX-related AEs were observed in up to 30% of patients and most were mild. MTX was discontinued by 0.5%-1.3% of patients. MUSICA (NCT01185288), CONCERTO (NCT01185301), Post results.


Extracellular vesicle sizing and enumeration by nanoparticle tracking analysis.
Nanoparticle tracking analysis (NTA) is a light-scattering technique that is useful for the rapid sizing and enumeration of extracellular vesicles (EVs). As a relatively new method, NTA has been criticised for a lack of standardisation. We propose the use of silica microspheres for the calibration of NTA measurements and describe in detail a protocol for the analysis of EVs by NTA which should minimise many of the sources of variability and imprecision associated with this technique.


Evidence on physical activity and falls prevention for people aged 65+ years: systematic review to inform the WHO guidelines on physical activity and sedentary behaviour.
Exercise prevents falls in older adults. Regular updates of estimated effects of exercise on falls are warranted given the number of new trials, the increasing number of older people globally and the major consequences of falls and fall-related injuries. This update of a 2019 Cochrane Review was undertaken to inform the World Health Organization guidelines on physical activity and sedentary behaviour. Searches were conducted in six databases. We included randomised controlled trials evaluating effects of any form of physical activity as a single intervention on falls in people aged 60+ years living in the community. Analyses explored dose-response relationships. The certainty of the evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). This review included 116 studies, involving 25,160 participants; nine new studies since the 2019 Cochrane Review. Exercise reduces the rate of falls by 23% (pooled rate ratio (RaR) 0.77, 95% confidence interval (CI) 0.71 to 0.83, 64 studies, high certainty evidence). Subgroup analysis showed variation in effects of different types of exercise (p < 0.01). Rate of falls compared with control is reduced by 24% from balance and functional exercises (RaR 0.76, 95% CI 0.70 to 0.82, 39 studies, high certainty evidence), 28% from programs involving multiple types of exercise (commonly balance and functional exercises plus resistance exercises, RaR 0.72, 95% CI 0.56 to 0.93, 15 studies, moderate certainty evidence) and 23% from Tai Chi (RaR 0.77, 95% CI 0.61 to 0.97, 9 studies, moderate certainty evidence). The effects of programs that primarily involve resistance training, dance or walking remain uncertain. Interventions with a total weekly dose of 3+ h that included balance and functional exercises were particularly effective with a 42% reduction in rate of falls compared to control (Incidence Rate Ratio (IRR) 0.58, 95% CI 0.45 to 0.76). Subgroup analyses showed no evidence of a difference in the effect on falls on the basis of participant age over 75 years, risk of falls as a trial inclusion criterion, individual versus group exercise, or whether a health professional delivered the intervention. Given the strength of this evidence, effective exercise programs should now be implemented at scale.


Hydrodynamics of frontal striking in aquatic snakes: drag, added mass, and the possible consequences for prey capture success.
Transient locomotion under water is highly constrained by drag and added mass, yet some aquatic snakes catch their prey using a fast forward acceleration, with the mouth opened. These aquatic snakes show a convergence of their head shape in comparison with closely related species that do not forage under water. As both drag and added mass are related to some extent to the shape of the moving object, we explored how shape impacts the hydrodynamic forces applied to the head of a snake during a prey capture event. We compared two 3D-printed heads representing typical shapes of aquatically-foraging and non-aquatically-foraging snakes, and frontal strike kinematics based on in vivo observations. By using direct force measurements, we calculated the drag and added mass coefficient of the two models. Our results show that both drag and added mass are reduced in aquatic snakes. The drag coefficient of the aquatic model is 0.24, which is almost two times smaller than the non-aquatic model. The added mass coefficient of the aquatic model is 0.15 versus 0.24 for the non-aquatic model, showing that the convergence of head shape in aquatically foraging snakes is associated with a hydrodynamic advantage during frontal striking. The vorticity field measurements with particle image velocimetry show that a less intense recirculation bubble behind the jaw of the aquatic model, compared to the non-aquatic model, might be the basis of this advantage.


On the prospects of whole-genome association mapping in Saccharomyces cerevisiae.
Advances in sequencing technology have enabled whole-genome sequences to be obtained from multiple individuals within species, particularly in model organisms with compact genomes. For example, 36 genome sequences of Saccharomyces cerevisiae are now publicly available, and SNP data are available for even larger collections of strains. One potential use of these resources is mapping the genetic basis of phenotypic variation through genome-wide association (GWA) studies, with the benefit that associated variants can be studied experimentally with greater ease than in outbred populations such as humans. Here, we evaluate the prospects of GWA studies in S. cerevisiae strains through extensive simulations and a GWA study of mitochondrial copy number. We demonstrate that the complex and heterogeneous patterns of population structure present in yeast populations can lead to a high type I error rate in GWA studies of quantitative traits, and that methods typically used to control for population stratification do not provide adequate control of the type I error rate. Moreover, we show that while GWA studies of quantitative traits in S. cerevisiae may be difficult depending on the particular set of strains studied, association studies to map cis-acting quantitative trait loci (QTL) and Mendelian phenotypes are more feasible. We also discuss sampling strategies that could enable GWA studies in yeast and illustrate the utility of this approach in Saccharomyces paradoxus. Thus, our results provide important practical insights into the design and interpretation of GWA studies in yeast, and other model organisms that possess complex patterns of population structure.


Interactions between co-expressed Arabidopsis sucrose transporters in the split-ubiquitin system.
The Arabidopsis genome contains nine sucrose transporter paralogs falling into three clades: SUT1-like, SUT2 and SUT4. The carriers differ in their kinetic properties. Many transport proteins are known to exist as oligomers. The yeast-based split ubiquitin system can be used to analyze the ability of membrane proteins to interact. Promoter-GUS fusions were used to analyze the cellular expression of the three transporter genes in transgenic Arabidopsis plants. All three fusion genes are co-expressed in companion cells. Protein-protein interactions between Arabidopsis sucrose transporters were tested using the split ubiquitin system. Three paralogous sucrose transporters are capable of interacting as either homo- or heteromers. The interactions are specific, since a potassium channel and a glucose transporter did not show interaction with sucrose transporters. Also the biosynthetic and metabolizing enzymes, sucrose phosphate phosphatase and sucrose synthase, which were found to be at least in part bound to the plasma membrane, did not specifically interact with sucrose transporters. The split-ubiquitin system provides a powerful tool to detect potential interactions between plant membrane proteins by heterologous expression in yeast, and can be used to screen for interactions with membrane proteins as baits. Like other membrane proteins, the Arabidopsis sucrose transporters are able to form oligomers. The biochemical approaches are required to confirm the in planta interaction.


A comparison of radioactive calcium absorption tests with net calcium absorption.
1. Four different methods of calculating calcium absorption by radioactive calcium procedures have been compared with each other and with net calcium absorption in calcium-balance studies in 100 consecutive studies on 71 patients. 2. All four isotope procedures yielded highly significant correlations with net calcium absorption derived from the balance studies, but there was little to choose between the validity of the double-isotope and single-isotope procedure judged by these criteria. 3. The rate of calcium absorption calculated from one or other isotope procedure correlated better with net calcium absorption than did the fraction of the radioactive calcium absorbed. 4. The measurement of plasma radioactivity 1 h after single-isotope administration, corrected for body weight, proved almost as useful as the more complex procedures but would be expected to underestimate calcium absorption in states of very high bone turnover.


Intraocular pressure, ocular toxicity and neurotoxicity after administration of cannabinol or cannabigerol.
Cannabinol or cannabigerol was administered to cats topically in doses of 250, 500 and 1000 micrograms as a single drop or chronically via osmotic minipumps (20 micrograms hr-1) over a period of 9 days. While cannabinol had a modest effect on intraocular pressure after a single dose, it caused a more significant reduction in ocular tension during chronic administration. Cannabigerol had similar effects, but the magnitude of response to its chronic administration was greater. Cannabinol but not cannabigerol caused conjunctival erythema and hyperemia. After systemic administration of cannabinol (20, 40 or 80 mg kg-1) to rats, 8-13 Hz polyspike discharges appeared in the electrocorticogram during wakefulness and during rapid eye movement sleep episodes. Cannabigerol (10, 30 and 100 mg kg-1) lacked this effect. These results indicate that chronic administration of these cannabinoids lowers ocular tension considerably. Like marihuana and delta-9-tetrahydrocannabinol, cannabinol produced both ocular toxicity and neurotoxicity. As cannabigerol lacked these toxicities, it appears that the ocular hypotensive effect of this cannabinoid is somewhat dissociable from both the adverse central and ocular effects accompanying marihuana intake.


Mesocarnivore community structure under predator control: Unintended patterns in a conservation context.
Across the Mediterranean, conservation programmes often operate concomitantly with hunting interests within game-lands. Carnivore guilds lie at the interface between contrasting management goals, being simultaneously fundamental components of ecosystems and targets of predator control to reduce predation on game species. Here, we evaluate the composition and spatial structure of a mesocarnivore community in a protected area of Southeast Portugal, with high economic investment in conservation and significant hunting activity. Between June and August 2015, we deployed 77 camera-traps across a ~80 km2 area. We report on interspecific disparities in mesocarnivore occupancy and associated environmental determinants. Contrasting occupancy states suggest an unbalanced community, biased towards the widespread occurrence of the red fox Vulpes vulpes ([Formula: see text]) compared to other species (stone marten Martes foina, European badger Meles meles, Egyptian mongoose Herpestes ichneumon, common genet Genetta genetta, and Eurasian otter Lutra lutra) exhibiting spatially-restricted occupancy patterns ([Formula: see text]). The feral cat Felis silvestris catus was the exception ([Formula: see text]) and, together with the stone marten, exhibited a positive association with human settlements. These findings are consistent with theoretical predictions on how mesocarnivore communities are shaped by the effects of non-selective predator control, paradoxically favouring species with higher population growth rates and dispersal abilities, such as the red fox. Our results reinforce the need to understand the role of predator control as a community structuring agent with potential unintended effects, while exposing issues hindering such attempts, namely non-selective illegal killing or biased/concealed information on legal control measures.


Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock.
Extracellular purines, including adenosine and ATP, are potent endogenous immunomodulatory molecules. Inosine, a degradation product of these purines, can reach high concentrations in the extracellular space under conditions associated with cellular metabolic stress such as inflammation or ischemia. In the present study, we investigated whether extracellular inosine can affect inflammatory/immune processes. In immunostimulated macrophages and spleen cells, inosine potently inhibited the production of the proinflammatory cytokines TNF-alpha, IL-1, IL-12, macrophage-inflammatory protein-1alpha, and IFN-gamma, but failed to alter the production of the anti-inflammatory cytokine IL-10. The effect of inosine did not require cellular uptake by nucleoside transporters and was partially reversed by blockade of adenosine A1 and A2 receptors. Inosine inhibited cytokine production by a posttranscriptional mechanism. The activity of inosine was independent of activation of the p38 and p42/p44 mitogen-activated protein kinases, the phosphorylation of the c-Jun terminal kinase, the degradation of inhibitory factor kappaB, and elevation of intracellular cAMP. Inosine suppressed proinflammatory cytokine production and mortality in a mouse endotoxemic model. Taken together, inosine has multiple anti-inflammatory effects. These findings, coupled with the fact that inosine has very low toxicity, suggest that this agent may be useful in the treatment of inflammatory/ischemic diseases.


The role of benzodiazepines in breathlessness: a single site, open label pilot of sustained release morphine together with clonazepam.
Breathlessness at rest or on minimal exertion despite optimal treatment of underlying cause(s) is distressing and prevalent. Opioids can reduce the intensity of chronic refractory breathlessness and an anxiolytic may be of benefit. This pilot aimed to determine the safety and feasibility of conducting a phase III study on the intensity of breathlessness by adding regular benzodiazepine to low-dose opioid. This is a single site, open label phase II study of the addition of regular clonazepam 0.5 mg nocte orally to Kapanol(R) 10 mg (sustained release morphine sulphate) orally mane together with docusate/sennosides in people with modified Medical Research Council Scale ≥2. Breathlessness intensity on day four was the efficacy outcome. Participants could extend for another 10 days if they achieved >15% reduction over their own baseline breathlessness intensity. Eleven people had trial medication (eight males, median age 78 years (68 to 89); all had COPD; median Karnofsky 70 (50 to 80); six were on long-term home oxygen. Ten people completed day four. One person withdrew because of unsteadiness on day four. Five participants reached the 15% reduction, but only three went on to the extension study, all completing without toxicity. This study was safe, feasible and there appears to be a group who derive benefits comparable to titrated opioids. Given the widespread use of benzodiazepines for the symptomatic treatment of chronic refractory breathlessness and its poor evidence base, there is justification for a definitive phase III study.


Randomized trial of percutaneous tibial nerve stimulation versus Sham efficacy in the treatment of overactive bladder syndrome: results from the SUmiT trial.
The Study of Urgent PC vs Sham Effectiveness in Treatment of Overactive Bladder Symptoms (SUmiT) was a multicenter, double-blind, randomized, controlled trial comparing the efficacy of percutaneous tibial nerve stimulation to sham through 12 weeks of therapy. The improvement in global response assessment, voiding diary parameters, and overactive bladder and quality of life questionnaires was evaluated. A total of 220 adults with overactive bladder symptoms were randomized 1:1 to 12 weeks of treatment with weekly percutaneous tibial nerve stimulation or sham therapy. Overactive bladder and quality of life questionnaires as well as 3-day voiding diaries were completed at baseline and at 13 weeks. Subject global response assessments were completed at week 13. The 13-week subject global response assessment for overall bladder symptoms demonstrated that percutaneous tibial nerve stimulation subjects achieved statistically significant improvement in bladder symptoms with 54.5% reporting moderately or markedly improved responses compared to 20.9% of sham subjects from baseline (p <0.001). All individual global response assessment subset symptom components demonstrated statistically significant improvement from baseline to 13 weeks for percutaneous tibial nerve stimulation compared to sham. Voiding diary parameters after 12 weeks of therapy showed percutaneous tibial nerve stimulation subjects had statistically significant improvements in frequency, nighttime voids, voids with moderate to severe urgency and urinary urge incontinence episodes compared to sham. No serious device related adverse events or malfunctions were reported. This pivotal multicenter, double-blind, randomized, sham controlled trial provides level I evidence that percutaneous tibial nerve stimulation therapy is safe and effective in treating overactive bladder symptoms. The compelling efficacy of percutaneous tibial nerve stimulation demonstrated in this trial is consistent with other recently published reports and supports the use of peripheral neuromodulation therapy for overactive bladder.


How does cognitive behavior therapy for irritable bowel syndrome work? A mediational analysis of a randomized clinical trial.
Although multiple clinical trials support the efficacy of psychological treatments for reducing irritable bowel syndrome (IBS) symptoms, the mechanisms responsible for symptomatic improvement are unknown. One hypothesis is that psychological treatments work by alleviating comorbid psychological distress implicated in the worsening of bowel symptoms and quality of life. An alternative hypothesis assumes that changes in distress are not strictly a cause but a consequence of IBS that will decrease with symptomatic improvement. We evaluated these 2 hypotheses by applying structural equation modeling (SEM) to the data set of a large number (n = 147) of Rome II diagnosed participants randomized to CBT, psychoeducation, or wait list. Per Rome guidelines, the primary end point was global improvement of gastrointestinal (GI) symptoms measured 2 weeks after a 10-week regimen. Secondary end points were distress and quality of life (QOL). SEM analyses lend support to a model in which CBT is associated with improvements in IBS symptoms, but that therapeutic gains do not depend on changes in patients' overall level of psychological distress. Symptom severity, but not clinical status (pain catastrophizing, predominant bowel habits, symptom duration, abuse, diagnosable psychiatric disorder) or relevant sociodemographic variables (eg, gender, age), moderated treatment outcome. CBT has a direct effect on global IBS symptom improvement independent of its effects on distress. Improvement in IBS symptoms is associated with improvements in the QOL, which may lower distress. Symptom improvements are not moderated by variables reflecting the mental well-being of IBS patients.


A Survey of Coping Strategies With Stress in Patients With Acute Myocardial Infarction and Individuals Without a History of Fixed Myocardial Infarction.
This study aimed at investigating the coping strategies with stress in patients with acute myocardial infarction (MI) and individuals without a history of fixed MI and cardiovascular disorders. This case-control crossover study was conducted from March 2015 to February 2016 on 220 patients with acute MI (MI patients) as case group and 220 patients without any history of MI and cardiovascular diseases as the control group using availability sampling method. To collect the required data, demographic information questionnaire, Holms-Raheh life stress inventory, perceived stress questionnaire, and coping inventory for stressful situations (CISS) were applied. On the basis of our findings, 118 patients (53.6%) with MI used emotion-focused coping strategy. Ninety-seven patients (82.2%) with MI who used emotion-focused coping strategy had negative perceived stress. Additionally, 71 patients (60.2%) with MI who had used emotion-focused coping strategy suffered from very high level of stress. The most MI patients had very high level of stress while most people in control group had high level of stress. Most MI patients that had very high level of stress cope with it in emotion-focused coping strategy and it proves that people with higher levels of stress are more likely to use inefficient coping strategies.


Perceptions and experiences of violence among secondary school students in urban Jamaica.
To obtain information on the perceptions and experiences of violence among secondary school students in Kingston, Jamaica, and its environs. Data collection was carried out from September through December 1998. Two researchers administered questionnaires in 11 randomly selected secondary schools, to a total of 1 710 students who were in either grade 7 or grade 9 and who were aged 9-17 years old (mean of 13.2 years). Frequency distributions of the responses were compared by gender, age, grade level, socioeconomic status, and school type. Seventy-five percent of the students thought that someone who was reluctant to fight would be "picked on" more, 89% thought it generally wrong to hit other people, and 91% thought it wrong to insult other people. Eighty-four percent knew of students who carried knives or blades from such items as a scalpel or a utility knife to school, and 89% were worried about violence at school. Thirty-three percent had been victims of violence, and 60% had a family member who had been a victim of violence. Eighty-two percent thought that violent television shows could increase aggressive behavior. Factor analysis of selected responses was carried out, yielding five factors: neighborhood violence, school violence, perceptions of acceptable behaviors, level of concern about violence, and general experiences and perceptions of violence. The factors varied with gender, age, grade level, socioeconomic status, and school type. These results will help focus interventions aimed at reducing violence, provide a baseline for later comparisons of perceptions and experiences of violence, and offer a basis for comparing the experiences of young people in urban Jamaica with those of young persons elsewhere.


T-system optical signals associated with inward rectification in skeletal muscle.
The resting potential of many excitable cells, including skeletal muscle, cardiac muscle, nerve cell bodies and egg cells, is determined by a resting potassium conductance which shows inward rectification, allowing potassium ions to move more readily inward across the cell membrane than outward. In skeletal muscle, where inward rectification has been extensively studied, a large part of this conductance is located in the T-system membranes. However, to date, only the kinetic and voltage-dependent properties of this conductance have been studied from analyses of the membrane potential or current recorded at the fibre surface. We report here measurements, obtained using a voltage-sensing dye, of potential changes in the T-system membranes associated with the inwardly rectifying K+ current. Our results show that this conductance alters the time course and significantly attenuates the amplitude of the potential change across the tubular membranes. These optical data provide new evidence for the presence of this conductance in the T-system and, when analysed using a radial cable model for the T-system, provide an estimate of the distribution of the inward rectifier conductance over the surface and T-system which is in agreement with estimates obtained by other techniques.


Synthesis and application of ion-imprinted polymer nanoparticles for the determination of nickel ions.
Novel Ni(II) ion-imprinted polymers (Ni-IIP) nanoparticles were prepared by using Ni(II) ion-1,5-diphenyl carbazide (DPC) complex as the template molecule and methacrylic acid, ethylene glycol dimethacrylate (EGDMA) and 2,2'-azobisisobutyronitrile (AIBN) as the functional monomer, cross-linker and the radical initiator, respectively. The synthesized polymer particles were characterized physically and morphologically by using infrared spectroscopy (IR), thermo gravimetric analysis (TGA), X-ray diffraction (XRD) and scanning electron microscopic (SEM) techniques. Some parameters such as pH, weight of the polymer, adsorption time, elution time, eluent type and eluent volume which affects the efficiency of the polymer were studied. The preconcentration factor, relative standard deviation, and limit of detection of the method were found to be 100, 1.9%, and 0.002 μg mL(-1), respectively. The prepared ion-imprinted polymer particles have an increased selectivity toward Ni(II) ions over a range of competing metal ions with the same charge and similar ionic radius. The method was applied to the determination of nickel in tomato and some water samples.


A longitudinal study of the relationship between work engagement and symptoms of anxiety and depression.
This longitudinal study examined the dynamic relationship between work engagement (vigour and dedication) and symptoms of anxiety and depression. A sample of 3475 respondents from eight different occupational groups (lawyers, physicians, nurses, teachers, church ministers, bus drivers, people working in advertising and people working in information technology) in Norway supplied data at two points in time with a 2-year time interval. The advantages of longitudinal design were utilized, including testing of reversed causation and controlling for unmeasured third variables. In general, the results showed that the hypothesized normal causal relationship was superior to a reversed causation model. In other words, this study supported the assumption that work engagement is more likely to be the antecedent for symptoms of depression and anxiety than the outcome. In particular, the vigour facet of work engagement provides lower levels of depression and anxiety 2 years later. However, additional analyses modelling unmeasured third variables indicate that unknown third variables may have created some spurious effects on the pattern of the observed relationship. Implications of the findings are discussed in the paper.


Dose-Response Between Cardiovascular Risk Factors and Cardiovascular Mortality Among Incident Peritoneal Dialysis Patients.
Traditional cardiovascular (CV) risk factors (RFs) and their management targets may not be applicable to specific medical subpopulations, particularly dialysis patients. This study aimed to evaluate the dose-response association between measurements of RFs, cardiovascular mortality, and potential metabolic targets among Chinese patients initializing peritoneal dialysis (PD). Risk-set sampling was applied to two population based 1: 10 case-control studies of incident PD patients, matched by age, sex and the year of initialisation of PD: a main sample (204 cases and 2,040 controls) and a replication sample (81 cases and 810 controls). The dose-response association between continuous measurements of CV RFs (blood pressure, fasting glucose, body mass index, total cholesterol, phosphate and ejection fraction) at baseline and the 2-year CV mortality were analyzed using conditional Logistic regression. The final threshold was chosen based upon a significant break in the regression coefficients and achievement of the minimum Bayesian information criterion (BIC). A linear relationship was identified between fasting glucose and CV mortality. Non-linear associations between other measurements and CV mortality suggested potential metabolic treatment intensification thresholds as < 145/92mmHg for blood pressure, < 1.70mmol/L for phosphate, 24 kg/m2 for body mass index, 4.6mmol/L for total cholesterol, and > 60% for ejection fraction respectively. Our findings highlight the potential importance of more intensive glucose management, anti-hypertensive treatment and dietary management among PD patients. We recommend that the clinical relevance of these epidemiological associations be tested using randomized controlled trials of multifaceted interventions.


The efficiency and fidelity of 8-oxo-guanine bypass by DNA polymerases delta and eta.
A DNA lesion created by oxidative stress is 7,8-dihydro-8-oxo-guanine (8-oxoG). Because 8-oxoG can mispair with adenine during DNA synthesis, it is of interest to understand the efficiency and fidelity of 8-oxoG bypass by DNA polymerases. We quantify bypass parameters for two DNA polymerases implicated in 8-oxoG bypass, Pols delta and eta. Yeast Pol delta and yeast Pol eta both bypass 8-oxoG and misincorporate adenine during bypass. However, yeast Pol eta is 10-fold more efficient than Pol delta, and following bypass Pol eta switches to less processive synthesis, similar to that observed during bypass of a cis-syn thymine-thymine dimer. Moreover, yeast Pol eta is at least 10-fold more accurate than yeast Pol delta during 8-oxoG bypass. These differences are maintained in the presence of the accessory proteins RFC, PCNA and RPA and are consistent with the established role of Pol eta in suppressing ogg1-dependent mutagenesis in yeast. Surprisingly different results are obtained with human and mouse Pol eta. Both mammalian enzymes bypass 8-oxoG efficiently, but they do so less processively, without a switch point and with much lower fidelity than yeast Pol eta. The fact that yeast and mammalian Pol eta have intrinsically different catalytic properties has potential biological implications.


Evidence of persisting cognitive impairment in a case series of patients with locked-in syndrome.
Previous research on cognition and locked-in syndrome (LIS) is limited to single case reports, and usually reported normality of performance. Here, cognitive disorders in a group of LIS patients are investigated, using a specific test relying only on a yes/no response indicated by eye movements or verbally. Nine patients with LIS resulting from brainstem stroke were compared with seven patients with frontal or frontotemporal lesions and 16 matching normal control subjects. The test comprised 19 subtests of perception (visual and auditory recognition), oral comprehension (identity, words and sentences), written comprehension (words and sentences), orientation (in time and place), immediate and delayed memories (verbal and visuo-spatial information), calculation and problem solving, and analysis of verbal logic. LIS patients showed significant difficulties in auditory recognition (associative level), oral comprehension of complex sentences, delayed visuospatial memory, mental calculation and problem solving. Patients with hemispheric lesions were more severely impaired. Single case analysis revealed that four LIS patients showed cognitive disorders in at least three subtests. These disorders were not related to a specific localisation of lesions. Moderate and selective cognitive disorders can be observed in LIS patients. Systematic assessment is needed, because of their possible consequences for communication and rehabilitation protocols.


Metabolic potential of endophytic bacteria.
The bacterial endophytic microbiome promotes plant growth and health and beneficial effects are in many cases mediated and characterized by metabolic interactions. Recent advances have been made in regard to metabolite production by plant microsymbionts showing that they may produce a range of different types of metabolites. These substances play a role in defense and competition, but may also be needed for specific interaction and communication with the plant host. Furthermore, few examples of bilateral metabolite production are known and endophytes may modulate plant metabolite synthesis as well. We have just started to understand such metabolic interactions between plants and endophytes, however, further research is needed to more efficiently make use of beneficial plant-microbe interactions and to reduce pathogen infestation as well as to reveal novel bioactive substances of commercial interest.


Identification of Differentially Expressed Genes during Bacillus subtilis Spore Outgrowth in High-Salinity Environments Using RNA Sequencing.
In its natural habitat, the soil bacterium Bacillus subtilis often has to cope with fluctuating osmolality and nutrient availability. Upon nutrient depletion it can form dormant spores, which can revive to form vegetative cells when nutrients become available again. While the effects of salt stress on spore germination have been analyzed previously, detailed knowledge on the salt stress response during the subsequent outgrowth phase is lacking. In this study, we investigated the changes in gene expression during B. subtilis outgrowth in the presence of 1.2 M NaCl using RNA sequencing. In total, 402 different genes were upregulated and 632 genes were downregulated during 90 min of outgrowth in the presence of salt. The salt stress response of outgrowing spores largely resembled the osmospecific response of vegetative cells exposed to sustained high salinity and included strong upregulation of genes involved in osmoprotectant uptake and compatible solute synthesis. The σB-dependent general stress response typically triggered by salt shocks was not induced, whereas the σW regulon appears to play an important role for osmoadaptation of outgrowing spores. Furthermore, high salinity induced many changes in the membrane protein and transporter transcriptome. Overall, salt stress seemed to slow down the complex molecular reorganization processes ("ripening") of outgrowing spores by exerting detrimental effects on vegetative functions such as amino acid metabolism.