Getting doctors into the bush: general practitioners' preferences for rural location.
A key policy issue in many countries is the maldistribution of doctors across geographic areas, which has important effects on equity of access and health care costs. Many government programs and incentive schemes have been established to encourage doctors to practise in rural areas. However, there is little robust evidence of the effectiveness of such incentive schemes. The aim of this study is to examine the preferences of general practitioners (GPs) for rural location using a discrete choice experiment. This is used to estimate the probabilities of moving to a rural area, and the size of financial incentives GPs would require to move there. GPs were asked to choose between two job options or to stay at their current job as part of the Medicine in Australia: Balancing Employment and Life (MABEL) longitudinal survey of doctors. 3727 GPs completed the experiment. Sixty five per cent of GPs chose to stay where they were in all choices presented to them. Moving to an inland town with less than 5000 population and reasonable levels of other job characteristics would require incentives equivalent to 64% of current average annual personal earnings ($116,000). Moving to a town with a population between 5000 and 20,000 people would require incentives of at least 37% of current annual earnings, around $68,000. The size of incentives depends not only on the area but also on the characteristics of the job. The least attractive rural job package would require incentives of at least 130% of annual earnings, around $237,000. It is important to begin to tailor incentive packages to the characteristics of jobs and of rural areas.


ACA Litigation: Politics Pursued through Other Means.
Despite its passage a decade ago, the Affordable Care Act (ACA) remains a politically divisive law. These political divisions have long been on display in Congress, in the White House, and in states. A long-standing stalemate in Congress-where Republicans cannot repeal the law and Democrats cannot improve it-has emboldened efforts by the executive branch to act unilaterally to implement, or undermine, the ACA. In turn, the law's opponents and supporters have turned to the courts to promote their favored policy agendas through both broadside attacks on the law and targeted challenges to its implementation. Litigation has become politics pursued through other means. These challenges have often been brought, or opposed, by state attorneys general and governors, with red-state coalitions facing off against blue-state coalitions. ACA litigation has also been characterized by forum shopping, nationwide injunctions, and questions about the court as a truly adversarial forum. This article briefly reviews the history of ACA litigation, discusses these legal norms in the context of the historic health reform law, and considers the implications of this history and the changing judiciary for future health reform efforts.


Personality scale validities increase throughout medical school.
Admissions and personnel decisions rely on stable predictor-criterion relationships. The authors studied the validity of Big Five personality factors and their facets for predicting academic performance in medical school across multiple years, investigating whether criterion-related validities change over time. In this longitudinal investigation, an entire European country's 1997 cohort of medical students was studied throughout their medical school career (Year 1, N = 627; Year 7, N = 306). Over time, extraversion, openness, and conscientiousness factor and facet scale scores showed increases in operational validity for predicting grade point averages. Although there may not be any advantages to being open and extraverted for early academic performance, these traits gain importance for later academic performance when applied practice increasingly plays a part in the curriculum. Conscientiousness, perhaps more than any other personality trait, appears to be an increasing asset for medical students: Operational validities of conscientiousness increased from .18 to .45. In assessing the utility of personality measures, relying on early criteria might underestimate the predictive value of personality variables. Implications for personality measures to predict work performance are discussed.


Application of Struvite Alters the Antibiotic Resistome in Soil, Rhizosphere, and Phyllosphere.
Struvite recovered from wastewater is a renewable source of phosphorus and nitrogen and can be used as fertilizer for plant growth. However, antibiotics and resistome can be enriched in the struvite derived from wastewater. Robust understanding of the potential risks after struvite application to soils has remained elusive. Here, we profiled antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs) in struvite, soil, rhizosphere and phyllosphere of Brassica using high-throughput quantitative PCR. A total of 165 ARGs and 10 MGEs were detected. Application of struvite was found to increase both the abundance and diversity of ARGs in soil, rhizosphere and phyllosphere. In addition, ARGs shared exclusively between Brassica phyllosphere and struvite were identified, indicating that struvite was an important source of ARGs found in phyllosphere. Furthermore, OTUs shared between rhizosphere and phyllosphere were found to significantly correlate with ARGs, suggesting that microbiota in leaf and root could interconnect and ARGs might transfer from struvite to the surface of plants via rhizosphere using bacteria as spreading medium. These findings demonstrated that struvite as an organic fertilizer can facilitate the spread of antibiotic resistance into human food chain and this environment-acquired antibiotic resistance should be put into human health risk assessment system.


Change in health behaviours following acute coronary syndrome: Arab-Jewish differences.
Health-promoting behaviours after acute coronary syndrome (ACS) are effective in preventing recurrence. Ethnicity impacts on such behaviours. We assessed the independent association of Arab vs. Jewish ethnicity with persistence of smoking and physical inactivity 6 months after ACS in central Israel. Prospective cohort study. During their admission for ACS and subsequently 6 months later, 420 patients were interviewed about their smoking and exercise habits. The association of ethnicity with health-promoting behaviours was assessed by logistic regression adjusting for socio-demographic and clinical covariates. Smoking prevalence and physical inactivity were substantially higher among Arab patients than Jewish patients at admission (gender-adjusted prevalence rate ratio (RR) 2.25, 95% CI 1.80-2.81, p < 0.01 and RR 1.46, 95% CI 1.28-1.67, p < 0.001, respectively). The relative differences increased at 6 months (RR 2.94, 95% CI 2.13-4.07, p < 0.001 and RR 3.00, 95% CI 2.24-4.04, p < 0.001, respectively). Excess persistent smoking at 6 months among Arab vs. Jewish patients who were smokers at admission (adjusted OR 2.05, 95% CI 1.00-4.20, p = 0.049) was largely mediated through the 3.5-fold higher participation of Jewish patients in cardiac prevention and rehabilitation program (CPRP) (OR adjusted also for CPRP 1.31, 95% CI 0.59-2.93, p = 0.51). Greater persistent sedentary behaviour at 6 months among nonexercisers at admission among Arab patients (adjusted OR 3.68, 95% CI 1.93-7.02, p < 0.001) was partly mediated through attendance of CPRP (OR adjusted also for CPRP 2.38, 95% CI 1.19-4.76, p = 0.014). Culturally sensitive programmes need to be developed to enhance CPRP participation and favourable health-promoting changes among Arab patients. A comprehensive understanding of the determinants of the Arab-Jewish differences in efficacious health-promoting behaviours is crucial to inform appropriate ethnic-specific health-promoting strategies.


Refugees and displaced persons. War, hunger, and public health.
The number of refugees and internally displaced persons in need of protection and assistance has increased from 30 million in 1990 to more than 43 million today. War and civil strife have been largely responsible for this epidemic of mass migration that has affected almost every region of the world, including Europe. Since 1990, crude death rates (CDRs) during the early influx of refugees who crossed international borders have been somewhat lower than CDRs reported earlier among Cambodian and Ethiopian refugees. Nevertheless, CDRs among refugees arriving in Ethiopia, Kenya, Nepal, Malawi, and Zimbabwe since 1990 ranged from five to 12 times the baseline CDRs in the countries of origin. Among internally displaced populations in northern Iraq, Somalia, and Sudan, CDRs were extremely high, ranging from 12 to 25 times the baseline CDRs for the nondisplaced. Among both refugees and internally displaced persons, death rates among children less than 5 years of age were far higher than among older children and adults. In Bangladesh, the death rate in female Rohingya refugees was several times higher than in males. Preventable conditions such as diarrheal disease, measles, and acute respiratory infections, exacerbated often by malnutrition, caused most deaths. Although relief programs for refugees have improved since 1990, the situation among the internally displaced may have worsened. The international community should intervene earlier in the evolution of complex disasters involving civil war, human rights abuses, food shortages, and mass displacement. Relief programs need to be based on sound health and nutrition information and should focus on the provision of adequate shelter, food, water, sanitation, and public health programs that prevent mortality from diarrhea, measles, and other communicable diseases, especially among young children and women.


Uncertainty in Illness: Theory Review, Application, and Extension.
Mishel's uncertainty in illness theory provides a conceptual framework to explain how uncertainty is generated and how it affects psychological adjustment to the cancer experience. Since 1981, when it was created, researchers have used the theory to develop and test uncertainty management interventions in multiple populations of patients with cancer. This article reviews the theory's concepts and propositions, summarizes supporting evidence, and discusses extension of the theory, clinical implications, and future directions for research.


Comparative metagenomics of hydrocarbon and methane seeps of the Gulf of Mexico.
Oil and gas percolate profusely through the sediments of the Gulf of Mexico, leading to numerous seeps at the seafloor, where complex microbial, and sometimes animal communities flourish. Sediments from three areas (two cold seeps with contrasting hydrocarbon composition and a site outside any area of active seepage) of the Gulf of Mexico were investigated and compared. Consistent with the existence of a seep microbiome, a distinct microbial community was observed in seep areas compared to sediment from outside areas of active seepage. The microbial community from sediments without any influence from hydrocarbon seepage was characterized by Planctomycetes and the metabolic potential was consistent with detrital marine snow degradation. By contrast, in seep samples with methane as the principal hydrocarbon, methane oxidation by abundant members of ANME-1 was likely the predominant process. Seep samples characterized by fluids containing both methane and complex hydrocarbons, were characterized by abundant Chloroflexi (Anaerolinaceae) and deltaproteobacterial lineages and exhibited potential for complex hydrocarbon degradation. These different metabolic capacities suggested that microorganisms in cold seeps can potentially rely on other processes beyond methane oxidation and that the hydrocarbon composition of the seep fluids may be a critical factor structuring the seafloor microbial community composition and function.


Estimating individual cone fundamentals from their color-matching functions.
Estimation of individual spectral cone fundamentals from color-matching functions is a classical and longstanding problem in color science. In this paper we propose a novel method to carry out this estimation based on a linear optimization technique, employing an assumption of a priori knowledge of the retinal absorptance functions. The result is an estimation of the combined lenticular and macular filtration for an individual, along with the nine coefficients in the linear combination that relates their color-matching functions to their estimated spectral-cone fundamentals. We test the method on the individual Stiles and Burch color-matching functions and derive cone-fundamental estimations for different viewing fields and matching experiment repetition. We obtain cone-fundamental estimations that are remarkably similar to those available in the literature. This suggests that the method yields results that are close to the true fundamentals.


Experienced Demand Does Not Affect Subsequent Sleep and the Cortisol Awakening Response.
Stress is associated with subjective and objective sleep disturbances; however, it is not known whether stress disrupts sleep and relevant physiological markers of stress immediately after it is experienced. The present study examined whether demand, in the form of cognitive tasks, disrupted sleep and the cortisol awakening response (CAR), depending on whether it was experienced or just anticipated. Subjective and objective sleep was measured in 22 healthy adults on three nights (Nights 0-2) in a sleep laboratory using sleep diaries and polysomnography. Saliva samples were obtained at awakening, +15, +30, +45 and +60 minutes on each subsequent day (Day 1-3) and CAR measurement indices were derived: awakening cortisol levels, the mean increase in cortisol levels (MnInc) and total cortisol secretion (AUCG). On Night 1, participants were informed that they were required to complete a series of demanding cognitive tasks within the sleep laboratory during the following day. Participants completed the tasks as expected or unexpectedly performed sedentary activities. Compared to the no-demand group, the demand group displayed significantly higher levels of state anxiety immediately completing the first task. There were no subsequent differences between the demand and no-demand groups in Night 2 subjective sleep continuity, objective sleep continuity or architecture, or on any Day 3 CAR measure. These results indicate that sleep and the CAR are not differentially affected depending on whether or not an anticipated stressor is then experienced. This provides further evidence to indicate that the CAR is a marker of anticipation and not recovery. In order to disrupt sleep, a stressor may need to be personally relevant or of a prolonged duration or intensity.


Effect of Adjunctive Raloxifene Therapy on Severity of Refractory Schizophrenia in Women: A Randomized Clinical Trial.
A substantial proportion of women with schizophrenia experience debilitating treatment-refractory symptoms. The efficacy of estrogen in modulating brain function in schizophrenia has to be balanced against excess exposure of peripheral tissue. Raloxifene hydrochloride is a selective estrogen receptor modulator (mixed estrogen agonist/antagonist) with potential psychoprotective effects and fewer estrogenic adverse effects. To determine whether adjunctive raloxifene therapy reduces illness severity in women with refractory schizophrenia. This 12-week, double-blind, placebo-controlled, randomized clinical trial with fortnightly assessments was performed at an urban tertiary referral center and a regional center from January 1, 2006, to December 31, 2014. Participants included 56 women with schizophrenia or schizoaffective disorder and marked symptom severity despite substantial and stable antipsychotic doses. Data were analyzed using intention to treat as the basis. Adjunctive raloxifene hydrochloride, 120 mg/d, or placebo for 12 weeks. The primary outcome was the change in the Positive and Negative Syndrome Scale (PANSS) total score. Clinical response (defined as a ≥20% decrease in PANSS total score from baseline) and change in PANSS subscale scores, mood, cognition, reproductive hormone levels, and adverse events were also assessed. Of the 56 participants (mean [SD] age, 53 [7.7] years; age range, 40-70 years; mean [SD] duration of psychotic illness, 24 [11] years), 26 were randomized to raloxifene and 30 were randomized to placebo. Raloxifene produced a greater reduction in the PANSS total score relative to placebo (β = -6.37; 95% CI, -11.64 to -1.10; P = .02) and resulted in an increased probability of a clinical response (hazard ratio, 5.79; 95% CI, 1.46 to 22.97; P = .01). A significant reduction was found in the PANSS general symptom scores for the raloxifene compared with the placebo (β = -3.72; 95% CI, -6.83 to -0.61; P = .02) groups. For patients who completed the full 12-week trial, there was not a statistically significant treatment effect on PANSS positive symptom scores (β for change in raloxifene vs placebo, -1.92; 95% CI, -3.83 to 0.00; P = .05). Change in mood, cognition, and reproductive hormone levels and the rate of adverse events did not differ between groups. Raloxifene hydrochloride, 120 mg/d, reduces illness severity and increases the probability of a clinical response in women with refractory schizophrenia. This large trial of raloxifene in this patient population offers a promising, well-tolerated agent that has potential application in clinical practice. clinicaltrials.gov Identifier: NCT00361543.


Discovery and characterization of small molecule Rac1 inhibitors.
Aberrant activation of Rho GTPase Rac1 has been observed in various tumor types, including pancreatic cancer. Rac1 activates multiple signaling pathways that lead to uncontrolled proliferation, invasion and metastasis. Thus, inhibition of Rac1 activity is a viable therapeutic strategy for proliferative disorders such as cancer. Here we identified small molecule inhibitors that target the nucleotide-binding site of Rac1 through in silico screening. Follow up in vitro studies demonstrated that two compounds blocked active Rac1 from binding to its effector PAK1. Fluorescence polarization studies indicate that these compounds target the nucleotide-binding site of Rac1. In cells, both compounds blocked Rac1 binding to its effector PAK1 following EGF-induced Rac1 activation in a dose-dependent manner, while showing no inhibition of the closely related Cdc42 and RhoA activity. Furthermore, functional studies indicate that both compounds reduced cell proliferation and migration in a dose-dependent manner in multiple pancreatic cancer cell lines. Additionally, the two compounds suppressed the clonogenic survival of pancreatic cancer cells, while they had no effect on the survival of normal pancreatic ductal cells. These compounds do not share the core structure of the known Rac1 inhibitors and could serve as additional lead compounds to target pancreatic cancers with high Rac1 activity.


Photomorphogenesis for robot self-assembly: adaptivity, collective decision-making, and self-repair.
Self-assembly in biology is an inspiration for engineered large-scale multi-modular systems with desirable characteristics, such as robustness, scalability, and adaptivity. Previous works have shown that simple mobile robots can be used to emulate and study self-assembly behaviors. However, many of these studies were restricted to rather static and inflexible aggregations in predefined shapes, and were limited in adaptivity compared to that observed in nature. We propose a photomorphogenesis approach for robots using our vascular morphogenesis model-a light-stimuli directed method for multi-robot self-assembly inspired by the tissue growth of trees. Robots in the role of 'leaves' collect a virtual resource that is proportional to a real, sensed environmental feature. This is then used to build a virtual underlying network that shares a common resource throughout the whole robot aggregate and determines where it grows or shrinks as a reaction to the dynamic environment. In our approach the robots use supplemental bioinspired models to collectively select a leading robot to decide who starts to self-assemble (and where), or to assemble static aggregations. The robots then use our vascular morphogenesis model to aggregate in a directed way preferring bright areas, hence resembling natural phototropism (growth towards light). Our main result is that the assembled robots are adaptive and able to react to dynamic environments by collectively and autonomously rearranging the aggregate, discarding outdated parts, and growing new ones. In representative experiments, the self-assembling robots collectively make rational decisions on where to grow. Cutting off parts of the aggregate triggers a self-organizing repair process in the robots, and the parts regrow. All these capabilities of adaptivity, collective decision-making, and self-repair in our robot self-assembly originate directly from self-organized behavior of the vascular morphogenesis model. Our approach opens up opportunities for self-assembly with reconfiguration on short time-scales with high adaptivity of dynamic forms and structures.


Low Prognostic Nutritional Index (PNI) Predicts Unfavorable Distant Metastasis-Free Survival in Nasopharyngeal Carcinoma: A Propensity Score-Matched Analysis.
Poor nutritional status is associated with progression and advanced disease in patients with cancer. The prognostic nutritional index (PNI) may represent a simple method of assessing host immunonutritional status. This study was designed to investigate the prognostic value of the PNI for distant metastasis-free survival (DMFS) in patients with nasopharyngeal carcinoma (NPC). A training cohort of 1,168 patients with non-metastatic NPC from two institutions was retrospectively analyzed. The optimal PNI cutoff value for DMFS was identified using the online tool "Cutoff Finder". DMFS was analyzed using stratified and adjusted analysis. Propensity score-matched analysis was performed to balance baseline characteristics between the high and low PNI groups. Subsequently, the prognostic value of the PNI for DMFS was validated in an external validation cohort of 756 patients with NPC. The area under the receiver operating characteristics curve (AUC) was calculated to compare the discriminatory ability of different prognostic scores. The optimal PNI cutoff value was determined to be 51. Low PNI was significantly associated with poorer DMFS than high PNI in univariate analysis (P<0.001) as well as multivariate analysis (P<0.001) before propensity score matching. In subgroup analyses, PNI could also stratify different risks of distant metastases. Propensity score-matched analyses confirmed the prognostic value of PNI, excluding other interpretations and selection bias. In the external validation cohort, patients with high PNI also had significantly lower risk of distant metastases than those with low PNI (Hazards Ratios, 0.487; P<0.001). The PNI consistently showed a higher AUC value at 1-year (0.780), 3-year (0.793) and 5-year (0.812) in comparison with other prognostic scores. PNI, an inexpensive and easily assessable inflammatory index, could aid clinicians in developing individualized treatment and follow-up strategies for patients with non-metastatic NPC.


Aging-related neurostructural, neuropathological, and behavioral changes associated with herpes simplex virus type 1 brain infection in mice.
To date, the main advances in understanding Alzheimer's disease (AD) have revolved around the genetic variants associated with the familial form of the disease, yet the majority of cases are sporadic. The main risk factor for AD is aging, followed by production of the E4 isoform of apolipoprotein E (APOE). Female gender also increases the risk of developing AD. Herpes simplex virus type 1 (HSV-1) has been epidemiologically and experimentally associated with AD, although no studies on its effects over aging have been undertaken. To assess the potential aging-related consequences of HSV-1 brain infection, 2 month-old wild-type and apoE-deficient mice were infected with the virus, and over the next 16 months analyses made of cerebral viral load, neuropathological, morphological, and metabolic changes in the brain, and cognitive performance. Viral load in the central nervous system (CNS) increased with age. The viral load in the brains of aged apoE+/+ female mice was 43 times that seen in apoE-/- male mice. No MRI-detectable morphological differences nor any clear neuropathological differences were seen between 18 month-old infected and mock-infected mice, although differences were seen in younger animals. Neuroinfection was associated with memory deficit and a reduction in metabolic indicators of CNS health.


Copper ion as a new leakage tracer.
Most failures of root canal treatments are caused by bacteria. Studies showed that the most common cause of endodontic failures were the incomplete obturation of the root canal and the lack of adequate apical seal. Some in-vitro methods are used to estimate sealing quality, generally by measuring microleakage that allows the tracer agent to penetrate the filled canal. Conventional methods of evaluating the seal of endodontically treated teeth are complicated and have some drawbacks. We used copper ion diffusion method to assess the leakage and the results were compared to dye penetration method. The crowns of 21 extracted teeth were cut off at the CEJ level. After preparing the canals, the teeth were placed in tubes containing saline. They were divided randomly into 15 experimental cases; 3 positive and 3 negative controls. Positive controls were filled by single cone without sealer while the experimental and the negative control groups were filled by lateral technique. The coronal portion of gutta was removed and 9mm was left. The external surface of each tooth was coated with nail polish. Two millimeters of apical portion was immersed into 9ml of distilled water and 0.3ml of CuSO4 solution was injected into the coronal portion. After 2 days, copper sulfate was measured by an atomic absorption spectrophotometer. The teeth were then immersed in 2% methylene blue for 24 hours, sectioned and the extent of dye penetration was measured by a stereomicroscope. The maximum and minimum recorded copper ion concentrations for the experimental group were 18.37 and 2.87ppm respectively. The maximum and minimum recorded dye penetrations for the experimental group were 8.5 and 3.5mm respectively. The statistical analysis, adopting paired samples test, showed poor correlation between average recorded results of two methods. Based on our results, there was no significant correlation between the dye penetration and the copper ion diffusion methods.


Immunotypes of a quaternary site of HIV-1 vulnerability and their recognition by antibodies.
HIV-1 is neutralized by a class of antibodies that preferentially recognize a site formed on the assembled viral spike. Such quaternary structure-specific antibodies have diverse neutralization breadths, with antibodies PG16 and PG9 able to neutralize 70 to 80% of circulating HIV-1 isolates while antibody 2909 is specific for strain SF162. We show that alteration between a rare lysine and a common N-linked glycan at position 160 of HIV-1 gp120 is primarily responsible for toggling between 2909 and PG16/PG9 neutralization sensitivity. Quaternary structure-specific antibodies appear to target antigenic variants of the same epitope, with neutralization breadth determined by the prevalence of recognized variants among circulating isolates.


Use of a clay modeling task to reduce chocolate craving.
Elaborated Intrusion theory (EI theory; Kavanagh, Andrade, & May, 2005) posits two main cognitive components in craving: associative processes that lead to intrusive thoughts about the craved substance or activity, and elaborative processes supporting mental imagery of the substance or activity. We used a novel visuospatial task to test the hypothesis that visual imagery plays a key role in craving. Experiment 1 showed that spending 10 min constructing shapes from modeling clay (plasticine) reduced participants' craving for chocolate compared with spending 10 min 'letting your mind wander'. Increasing the load on verbal working memory using a mental arithmetic task (counting backwards by threes) did not reduce craving further. Experiment 2 compared effects on craving of a simpler verbal task (counting by ones) and clay modeling. Clay modeling reduced overall craving strength and strength of craving imagery, and reduced the frequency of thoughts about chocolate. The results are consistent with EI theory, showing that craving is reduced by loading the visuospatial sketchpad of working memory but not by loading the phonological loop. Clay modeling might be a useful self-help tool to help manage craving for chocolate, snacks and other foods.


Mechanical testing of implant-supported anterior crowns with different implant/abutment connections.
This study evaluated the reliability and failure modes of anterior implants with internal-hexagon (IH), external-hexagon (EH), or Morse taper (MT) implant-abutment interface designs. The postulated hypothesis was that the different implant-abutment connections would result in different reliability and failure modes when subjected to step-stress accelerated life testing (SSALT) in water. Sixty-three dental implants (4 × 10 mm) were divided into three groups (n = 21 each) according to connection type: EH, IH, or MT. Commercially pure titanium abutments were screwed to the implants, and standardized maxillary central incisor metallic crowns were cemented and subjected to SSALT in water. The probability of failure versus number of cycles (95% two-sided confidence intervals) was calculated and plotted using a power-law relationship for damage accumulation. Reliability for a mission of 50,000 cycles at 150 N (90% two-sided confidence intervals) was calculated. Polarized-light and scanning electron microscopes were used for failure analyses. The beta values (confidence intervals) derived from use-level probability Weibull calculation were 3.34 (2.22 to 5.00), 1.72 (1.14 to 2.58), and 1.05 (0.60 to 1.83) for groups EH, IH, and MT, respectively, indicating that fatigue was an accelerating factor for all groups. Reliability was significantly different between groups: 99% for MT, 96% for IH, and 31% for EH. Failure modes differed; EH presented abutment screw fracture, IH showed abutment screw and implant fractures, and MT displayed abutment and abutment screw bending or fracture. The postulated hypothesis that different implant-abutment connections to support anterior single-unit replacements would result in different reliability and failure modes when subjected to SSALT was accepted.


The relationship between aerobic fitness and neural oscillations during visuo-spatial attention in young adults.
While the cognitive benefits of aerobic fitness have been widely investigated, current findings in young adults remain unclear. Specifically, little is known about how these effects are reflected in the time-frequency domain. This study thus assessed the relationship between aerobic fitness and neural oscillations during visuo-spatial attention. A between-subjects design that included 20 participants with higher aerobic fitness (age = 21.95 ± 2.24 years; VO2max = 58.98 ± 6.94 ml/kg/min) and 20 age- and gender-matched lower aerobic fitness participants (age = 23.25 ± 2.07 years; VO2max = 35.87 ± 3.41 ml/kg/min) was used to examine the fitness-related differences in performance and neuroelectric indexes during a Posner visuo-spatial attention paradigm. The results demonstrated that high-fitness participants, in comparison with their low-fitness counterparts, showed faster reaction times as well as greater modulation of oscillatory theta and beta power during target processing, regardless of cue types. Moreover, the neurocognitive correlation showed that higher theta power was related to better task performance. Collectively, these findings suggest that aerobic fitness is associated with general enhanced attentional control in relation to visuo-spatial processing, as evidenced through greater motor preparation and in particular the up-regulation of attentional processing in healthy young adults. The present study may contribute to current knowledge by revealing the relationship between aerobic fitness and modulation of brain oscillations.


Routine diagnostic X-ray examinations and increased frequency of chromosome translocations among U.S. radiologic technologists.
The U.S. population has nearly one radiographic examination per person per year, and concern about cancer risks associated with medical radiation has increased. Radiologic technologists were surveyed to determine whether their personal cumulative exposure to diagnostic X-rays was associated with increased frequencies of chromosome translocations, an established radiation biomarker and possible intermediary suggesting increased cancer risk. Within a large cohort of U.S. radiologic technologists, 150 provided a blood sample for whole chromosome painting and were interviewed about past X-ray examinations. The number and types of examinations reported were converted to a red bone marrow (RBM) dose score with units that approximated 1 mGy. The relationship between dose score and chromosome translocation frequency was assessed using Poisson regression. The estimated mean cumulative RBM radiation dose score was 49 (range, 0-303). After adjustment for age, translocation frequencies significantly increased with increasing RBM dose score with an estimate of 0.004 translocations per 100 cell equivalents per score unit (95% confidence interval, 0.002-0.007; P < 0.001). Removing extreme values or adjustment for gender, cigarette smoking, occupational radiation dose, allowing practice X-rays while training, work with radioisotopes, and radiotherapy for benign conditions did not affect the estimate. Cumulative radiation exposure from routine X-ray examinations was associated independently with increased chromosome damage, suggesting the possibility of elevated long-term health risks, including cancer. The slope estimate was consistent with expectation based on cytogenetic experience and atomic bomb survivor data.


One-dimensional vertical dust strings in a glass box.
The oscillation spectrum of a one-dimensional vertical dust string formed inside a glass box on top of the lower electrode in a gaseous electronics conference (GEC) reference cell was studied. A mechanism for creating a single vertical dust string is described. It is shown that the oscillation amplitudes, resonance frequencies, damping coefficients, and oscillation phases of the dust particles separate into two distinct groups. One group exhibits low damping coefficients, increasing amplitudes, and decreasing resonance frequencies for dust particles closer to the lower electrode. The other group shows high damping coefficients but anomalous resonance frequencies and amplitudes. At low oscillation frequencies, the two groups are also separated by a π phase difference. One possible cause for the difference in behavior between the two groups is discussed.


Protein synthesis in isolated enterocytes from septic or endotoxaemic rats: regulation by glutamine.
1. We studied the effect of sepsis and the regulation by glutamine of protein synthesis in enterocytes isolated from the small intestine of rats. 2. Sepsis was induced by caecal ligation and puncture; control rats were sham operated. Enterocytes were isolated from the jejunum and incubated in a medium containing [3H]phenylalanine. 3. Sixteen hours after caecal ligation and puncture, protein synthesis, measured as incorporation of radioactivity into protein, was increased by 65%, 89% and 137% respectively in enterocytes from the tips and mid-portions of the villi and from the crypts. 4. Addition of glutamine to incubated enterocytes stimulated protein synthesis in a dose-dependent manner, and this effect was most pronounced in crypt cells from septic rats. The effect of glutamine on protein synthesis was duplicated by equimolar concentrations of acetoacetate or 3-hydroxybutyrate, both of which may serve as fuel for enterocytes, and was blocked by the glutaminase inhibitor 6-diazo-5-oxo-L-norleucine. 5. The results suggest that sepsis stimulates protein synthesis in enterocytes and that glutamine regulates protein synthesis in the same cells, probably by energy provision.


Comparison of intraosseous pentobarbital administration and thoracic compression for euthanasia of anesthetized sparrows (Passer domesticus) and starlings (Sturnus vulgaris).
OBJECTIVE To compare intraosseous pentobarbital treatment (IPT) and thoracic compression (TC) on time to circulatory arrest and an isoelectric electroencephalogram (EEG) in anesthetized passerine birds. ANIMALS 30 wild-caught adult birds (17 house sparrows [Passer domesticus] and 13 European starlings [Sturnus vulgaris]). PROCEDURES Birds were assigned to receive IPT or TC (n = 6/species/group). Birds were anesthetized, and carotid arterial pulses were monitored by Doppler methodology. Five subdermal braided-wire electrodes were used for EEG. Anesthetic depth was adjusted until a continuous EEG pattern was maintained, then euthanasia was performed. Times from initiation of euthanasia to cessation of carotid pulse and irreversible isoelectric EEG (indicators of death) were measured. Data (medians and first to third quartiles) were summarized and compared between groups within species. Necropsies were performed for all birds included in experiments and for another 6 birds euthanized under anesthesia by TC (4 sparrows and 1 starling) or IPT (1 sparrow). RESULTS Median time to isoelectric EEG did not differ significantly between treatment groups for sparrows (19.0 and 6.0 seconds for TC and IPT, respectively) or starlings (88.5 and 77.5 seconds for TC and IPT, respectively). Median times to cessation of pulse were significantly shorter for TC than for IPT in sparrows (0.0 vs 18.5 seconds) and starlings (9.5 vs 151.0 seconds). On necropsy, most (14/17) birds that underwent TC had grossly visible coelomic, pericardial, or perihepatic hemorrhage. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that TC might be an efficient euthanasia method for small birds. Digital pressure directly over the heart during TC obstructed venous return, causing rapid circulatory arrest, with rupture of the atria or vena cava in several birds. The authors propose that cardiac compression is a more accurate description than TC for this procedure.


Translating/Creating a Culturally Responsive Spanish-Language Mobile App for Visit Preparation: Case Study of "Trans-Creation".
Health information technology (IT) tools are increasingly used to improve patient care. However, implementation of English-only health IT tools could potentially worsen health disparities for non-English speakers. We aim to describe the "trans-creation" process of developing linguistically and culturally appropriate health IT tools through a detailed case analysis of a waiting room health mobile app designed to help Spanish-speaking Latino people prepare for primary care visits. We adapted the English-language Visit Planner mobile app for Spanish-speaking Latino patients. We applied culturally defined themes derived from prior published research and input by both skilled linguists and potential end users. Initial changes were iteratively reviewed and edited by a team of writers, health care educators, subject matter experts, patients, and providers. The trans-creation process resulted in the following key culturally mediated changes to the tool: replacing the "provider" actors with "patient" actors; changing the choice of "Stress at Home or Work" (represented by an icon of a house) to "Mi Familia" (translation: my family; icon is an outline of family members holding hands); replacing the English terms "anxiety" and "depression" with "Me siento desanimado"(translation: I am feeling down) to avoid mental health stigma; and using more concise text translation to ensure the wording fit the available on-screen space. The trans-creation process of cultural and linguistic adaptation led to several design changes that would not have been implemented if we had simply translated the words from English to Spanish.


Use of an accelerometer and a microphone as gas detectors in the online quantitative detection of hydrogen released from ammonia borane by gas chromatography.
The use of an accelerometer as a gas detector in gas chromatography (GC) is described for the first time. A milli-whistle was connected to the outlet of the GC capillary. When the eluted and GC carrier gases pass through the capillary and milli-whistle, a sound is produced. After a fast Fourier transform (FFT), the sound wave generated from the milli-whistle is picked up by a microphone and the resulting vibration of the milli-whistle body can be recorded by an accelerometer. The release of hydrogen gas, as the result of thermal energy, from ammonia borane (NH3BH3), which has been suggested as a storage medium for hydrogen, was selected as the model sample. The findings show that the frequencies generated, either by sound or by the vibration from the whistle body, were identical. The concentration levels of the released hydrogen gas can be determined online, based on the frequency changes. Ammonia borane was placed in a brass reservoir, heated continually, and the released hydrogen gas was directly injected into the GC inlet at 0.5 min intervals, using a home-built electromagnetic pulse injector. The concentration of hydrogen for each injection can be calculated immediately. When the ammonia borane was encapsulated within a polycarbonate (PC) microtube array membrane, the temperature required for the release of hydrogen can be decreased, which would make such a material more convenient for use. The findings indicate that 1.0 mg of ammonia borane can produce hydrogen in the range of 1.0-1.25 mL, in the temperature range of 85-115 °C.


Rethinking race/ethnicity, income, and childhood asthma: racial/ethnic disparities concentrated among the very poor.
Past studies of the prevalence of childhood asthma have yielded conflicting findings as to whether racial/ethnic disparities remain after other factors, such as income, are taken into account. The objective of this study was to examine the association of race/ethnicity and family income with the prevalence of childhood asthma and to assess whether racial/ethnic disparities vary by income strata. Cross-sectional data on 14,244 children aged <18 years old in the 1997 National Health Interview Survey were examined. The authors used logistic regression to analyze the independent and joint effects of race/ethnicity and income-to-federal poverty level (FPL) ratio, adjusting for demographic covariates. The main outcome measure was parental report of the child having ever been diagnosed with asthma. Bivariate analyses, based on weighted percentages, revealed that asthma was more prevalent among non-Hispanic black children (13.6%) than among non-Hispanic white children (11.2%; p<0.01), but the prevalence of asthma did not differ significantly between Hispanic children (10.1%) and non-Hispanic white children (11.2%; p=0.13). Overall, non-Hispanic black children were at higher risk for asthma than non-Hispanic white children (adjusted odds ratio [OR]=1.20; 95% confidence interval [CI] 1.03, 1.40), after adjustment for sociodemographic variables, including the ratio of annual family income to the FPL. Asthma prevalence did not differ between Hispanic children and non-Hispanic white children in adjusted analyses (adjusted OR=0.85; 95% CI 0.71, 1.02). Analyses stratified by income revealed that only among children from families with incomes less than half the FPL did non-Hispanic black children have a higher risk of asthma than non-Hispanic white children (adjusted OR=1.99; 95% CI 1.09, 3.64). No black vs. white differences existed at other income levels. Subsequent analyses of these very poor children that took into account additional potentially explanatory variables did not attenuate the higher asthma risk for very poor non-Hispanic black children relative to very poor non-Hispanic white children. Non-Hispanic black children were at substantially higher risk of asthma than non-Hispanic white children only among the very poor. The concentration of racial/ethnic differences only among the very poor suggests that patterns of social and environmental exposures must overshadow any hypothetical genetic risk.


[Brain-gut axis dysfunction].
There is a bidirectional relation between the central nervous system and the digestive tract, i.e., the brain-gut axis. Numerous data argue for a dysfunction of the brain-gut axis in the pathophysiology of irritable bowel syndrome (IBS). Visceral hypersensitivity is a marker of IBS as well as of an abnormality of the brain-gut axis. This visceral hypersensitivity is peripheral and/or central in origin and may be the consequence of digestive inflammation or an anomaly of the nociceptive message treatment at the spinal and/or supraspinal level. Stress is involved in the genesis and maintenance of IBS. Disturbances of the autonomic nervous system are observed in IBS as a consequence of brain-gut axis dysfunction. The contribution of the neurosciences, in particular brain imaging techniques, has contributed to the better understanding of IBS physiopathology. The better knowledge of brain-gut axis dysfunction has therapeutic implications, either through drugs and/or cognitive and behavioral therapies.


Effects of prenatal depressive symptoms on maternal and infant cortisol reactivity.
Prenatal depression is associated with adverse offspring outcomes, and the prevailing mechanistic theory to account for mood-associated effects implicates alterations of the maternal and foetal hypothalamic-pituitary adrenal (HPA) axes. Recent research suggests that depression may be associated with a failure to attenuate cortisol reactivity during early pregnancy. The aim of the current study is to investigate whether this effect continues into mid and late gestation. A further aim is to test whether maternal prenatal cortisol reactivity directly predicts infant cortisol reactivity. One hundred three pregnant women were recruited during either the second or third trimester. Depressive symptoms were assessed by self-report, and maternal salivary cortisol responses to a stressor (infant distress film) were measured. Approximately 2 months after birth, mothers (n = 88) reported postnatal depression and infant salivary cortisol responses to inoculation were measured. Prenatal depression was not associated with cortisol reactivity to acute stress in mid and late pregnancy. Similarly, neither prenatal depression nor maternal prenatal cortisol reactivity predicted infant cortisol reactivity to inoculation at 2 months. If the effects of prenatal depression on foetal and infant development are mediated by alterations of the maternal and foetal HPA axes, then early pregnancy may be a particularly vulnerable period. Alternatively, changes to HPA reactivity may not be as central to this association as previously thought.


Maternal inheritance of an inactive type III deiodinase gene allele affects mouse pancreatic β-cells and disrupts glucose homeostasis.
Dio3 is the most distal gene of the imprinted Dlk1-Dio3 gene locus and is expressed according to parental origin. Dio3 encodes the type 3 deiodinase (D3), a thioredoxin-fold like containing selenoenzyme that inactivates thyroid hormone and dampens thyroid hormone signaling. Here we used heterozygous animals with disruption of the Dio3 gene to study the allelic expression pattern of Dio3 in pancreatic β-cells and the metabolic phenotype resulting from its inactivation. Adult heterozygous mice with disruption of the Dio3 gene with maternal inheritance of the inactive Dio3 allele exhibited a total loss of D3 activity in isolated pancreatic islets, approximately 30% reduction in total pancreatic islet area, a marked decrease in insulin2 mRNA and in vivo glucose intolerance. In contrast, inheritance of the inactive Dio3 allele from the father did not affect D3 activity in isolated pancreatic islets and did not result in a pancreatic phenotype. Furthermore, exposure of pancreatic explants, D3-expressing MIN6-C3 cells or isolated pancreatic islets to 100 nM T3 for 24 hours reduced insulin2 mRNA by approximately 50% and the peak of glucose-induced insulin secretion. An unbiased analysis of T3-treated pancreatic islets revealed the down-regulation of 21 gene sets (false discovery rate q value < 25%) involved in nucleolar function and transcription of rRNA, ribonucleotide binding, mRNA translation, and membrane organization. We conclude that the Dio3 gene is preferentially expressed from the maternal allele in pancreatic islets and that the inactivation of this allele is sufficient to disrupt glucose homeostasis by reducing the pancreatic islet area, insulin2 gene expression, and glucose-stimulated insulin secretion.


What professional activities do general practitioners find most meaningful? Cross sectional survey of Norwegian general practitioners.
Health reforms in many countries affect the scope and nature of primary care. General Practitioners (GPs) are expected to spend more time developing public health, preventive health care, coordination of care and teamwork. We aimed to explore which professional activities GPs consider to be meaningful and how they would like to prioritise tasks. In a cross sectional online survey 3,270 GPs were invited to consider twenty different activities in general practice. They were asked to rate each of them on a Likert scale anchored from 1 (not meaningful) to 5 (very meaningful). They then selected three activities from the item list on which they would like to spend more time and three activities on which they would like to spend less time. We used multinomial logistic regression to explore associations between the GPs' preferences for time spent on preventive health care activities and age, gender and practice characteristics. Approximately 40% (n=1,308) responded. The most meaningful activities were handling common symptoms and complaints (94% scored 4 or 5), chronic somatic diseases (93%), terminal care (80%), chronic psychiatric diseases (77%), risk conditions (76%) and on call emergency services (70%). In terms of priority the same items prevailed except that GPs would like to spend less time on emergency services. Items with low priority were health certificates, practice administration, meetings with local health authorities, medically unexplained symptoms, addiction medicine, follow up of people certified unfit for work, psychosocial problems, preventive health clinics for children and school health services. In multivariate regression models physician and practice characteristics explained no more than 10% of the variability in the GPs' preferences for time spent on preventive health care services. The GPs found diagnosis and treatment of diseases most meaningful. Their priorities were partly at odds with those of the health authorities and policy makers.


Impact of Environmental Factors on Bacteriocin Promoter Activity in Gut-Derived Lactobacillus salivarius.
Bacteriocin production is regarded as a desirable probiotic trait that aids in colonization and persistence in the gastrointestinal tract (GIT). Strains of Lactobacillus salivarius, a species associated with the GIT, are regarded as promising probiotic candidates and have a number of associated bacteriocins documented to date. These include multiple class IIb bacteriocins (salivaricin T, salivaricin P, and ABP-118) and the class IId bacteriocin bactofencin A, which show activity against medically important pathogens. However, the production of a bacteriocin in laboratory media does not ensure production under stressful environmental conditions, such as those encountered within the GIT. To allow this issue to be addressed, the promoter regions located upstream of the structural genes encoding the L. salivarius bacteriocins mentioned above were fused to a number of reporter proteins (green fluorescent protein [GFP], red fluorescent protein [RFP], and luciferase [Lux]). Of these, only transcriptional fusions to GFP generated signals of sufficient strength to enable the study of promoter activity in L. salivarius. While analysis of the class IIb bacteriocin promoter regions indicated relatively weak GFP expression, assessment of the promoter of the antistaphylococcal bacteriocin bactofencin A revealed a strong promoter that is most active in the absence of the antimicrobial peptide and is positively induced in the presence of mild environmental stresses, including simulated gastric fluid. Taken together, these data provide information on factors that influence bacteriocin production, which will assist in the development of strategies to optimize in vivo and in vitro production of these antimicrobials.


Interaction of oxytocin with Ca2+: I. CD and fluorescence spectral characterization and comparison with vasopressin.
Extracellular Ca2+ is required for the action of oxytocin and both the hormone and its receptor have binding sites for divalent metal cations. To characterize the cation-bound form of oxytocin, we monitored the binding of Ca2+ and Mg2+ to oxytocin as well as peptides representing its ring and tail regions in trifluoroethanol, a lipid-mimetic solvent, using CD and fluorescence spectroscopy. Binding Ca2+ (Kd approximately 50 microM) caused drastic CD and fluorescence changes leading to a helical conformation. Mg2+ caused CD changes smaller than and opposite to Ca2+. However, the helical structure was enhanced when both Ca2+ and Mg2+ were present together. CD changes in the tail peptide of oxytocin showed its ability to bind Ca2+ and Mg2+ whereas the vasopressin tail peptide did not bind either cation. CD spectral changes on Ca2+ and Mg2+ binding to tocinoic acid (the ring moiety of oxytocin) were much smaller than those of oxytocin. These data suggest that the tail segment of oxytocin potentiates Ca2+ binding by the ring. While vasopressin displayed a CD spectrum similar to that of oxytocin, CD spectra of its cation-bound forms were markedly different from those of oxytocin; the Ca(2+)-induced CD changes in vasopressin were very much smaller and of opposite sign, and Mg(2+)-induced ones significantly larger than in oxytocin. Taken together, our observations bring out the structural differences between oxytocin and vasopressin in the context of their interaction with Ca2+ and Mg2+. This may be relevant to understanding the differences in the bioactive conformations and receptor interactions of the two hormones.


Hydricity, electrochemistry, and excited-state chemistry of Ir complexes for CO2 reduction.
We prepared electron-rich derivatives of [Ir(tpy)(ppy)Cl]+ with modification of the bidentate (ppy) or tridentate (tpy) ligands in an attempt to increase the reactivity for CO2 reduction and the ability to transfer hydrides (hydricity). Density functional theory (DFT) calculations reveal that complexes with dimethyl-substituted ppy have similar hydricities to the non-substituted parent complex, and photocatalytic CO2 reduction studies show selective CO formation. Substitution of tpy by bis(benzimidazole)-phenyl or -pyridine (L3 and L4, respectively) induces changes in the physical properties that are much more pronounced than from the addition of methyl groups to ppy. Theoretical data predict [Ir(L3)(ppy)(H)] as the strongest hydride donor among complexes studied in this work, but [Ir(L3)(ppy)(NCCH3)]+ cannot be reduced photochemically because the excited state reduction potential is only 0.52 V due to the negative ground state potential of -1.91 V. The excited state of [Ir(L4)(ppy)(NCCH3)]2+ is the strongest oxidant among complexes studied in this work and the singly-reduced species is formed readily upon photolysis in the presence of tertiary amines. Both [Ir(L3)(ppy)(NCCH3)]+ and [Ir(L4)(ppy)(NCCH3)]2+ exhibit electrocatalytic current for CO2 reduction. While a significantly greater overpotential is needed for the L3 complex, a small amount of formate (5-10%) generation in addition to CO was observed as predicted by the DFT calculations.


First Report of Natural Infection by 'Candidatus Liberibacter solanacearum' in Bittersweet Nightshade (Solanum dulcamara) in the Columbia Basin of Eastern Oregon.
Potatoes are a major crop in the Columbia Basin of Oregon and Washington, representing an annual farm gate value of almost $750 million. Zebra chip disease (ZC), a new and economically important disease of potato, was first reported in Oregon and Washington in 2011 (1). The disease is caused by the bacterium 'Candidatus Liberibacter solanacearum' (Lso, also referred to as 'Ca. L. psyllaurous'), which is vectored by the potato psyllid (Bactericera cockerelli Sulc) (1,2). Identifying alternative hosts for Lso may facilitate management of ZC disease, which has increased potato production costs in the region. The perennial weed, bittersweet nightshade (Solanum dulcamara L.), is a year-round host of the potato psyllid (3) and is also a suspected host of Lso. However, little is known about the role of this weed in ZC epidemiology. Naturally occurring bittersweet nightshade plants (n = 21) were sampled at six different locations near Hermiston, Oregon, between May and October in 2012. These plants exhibited several symptoms associated with Lso, ranging from asymptomatic to slight purpling, chlorosis, or scorching of the foliage. However, S. dulcamara exhibits similar symptoms under a variety of environmental conditions (drought stress, etc.); therefore, it was difficult to identify potentially infected plants based solely on symptomology. Leaf and stem tissue (n = 21) was analyzed with high-fidelity PCR using species-specific primers for the 16S rDNA gene, CLipoF, and OI2c (2,4). Approximately 27.3% of the plants tested positive for Lso using these primers, including plants from the following locations on 16 April, 16 May, and 24 May, respectively: Hat Rock, OR (45°55.033' N, 119°10.495' W), Irrigon, OR (45°54.560' N, 119°24.857' W), and Stanfield, OR (45°46.971' N, 119°13.203' W). Three plants were selected for further PCR analysis with primers for the outer membrane protein gene, 1482f and 2086r (1). Amplicons obtained with both sets of PCR primers were directly sequenced. A BLAST analysis showed that the 16S rDNA gene sequence (993 to 1,000 bp) shared 99 to 100% identity with several Lso accessions, including JN848751.1 (from Washington) and JN848753.1 (from Oregon). Likewise, the outer membrane protein gene sequence (600 to 601 bp) shared 99 to 100% identity with 'Ca. L. solanacearum' accession KC768330.1 (from Honduras). All six sequences were deposited in GenBank (Accession Nos. KJ854199 to KJ854204). According to these findings, bittersweet nightshade may be an important annual source of Lso in the region, particularly since it serves as a host for the potato psyllid. Potato psyllids were also detected at two of the locations with infected S. dulcamara: Irrigon, OR, and Stanfield, OR. A subsample of the psyllids collected in 2012 were analyzed with PCR and Lso was detected in a sample from Stanfield, OR (5). Identifying perennial hosts of Lso promotes a better understanding of both ZC disease epidemiology and management. To our knowledge, this is the first report of Lso causing natural infections in S. dulcamara in the United States. References: (1) J. M. Crosslin et al. Plant Dis. 96:452, 2012. (2) S. Jagoueix et al. Mol. Cell. Probes 10:43, 1996. (3) A. F. Murphy et al. Am. J. Pot. Res. 90:294, 2013. (4) G. A. Secor et al. Plant Dis. 93:574, 2009. (5) K. D. Swisher et al. Am. J. Pot. Res. 90:570, 2013.


Variation in referral and access to new psychological therapy services by age: an empirical quantitative study.
Older people with common mental health problems (CMHPs) are known to have reduced rates of referral to psychological therapy. To assess referral rates to the Improving Access to Psychological Therapies (IAPT) services, contact with a therapist, and clinical outcome by age. Empirical research study using patient episodes of care from South West of England IAPT services. By analysing 82 513 episodes of care (2010-2011), referral rates and clinical improvement were compared with both total population and estimated prevalence in each age group using IAPT data. Probable recovery of those completing treatment was calculated for each group. Estimated prevalence of CMHPs peaks in 45-49-year-olds (20.59% of population). The proportions of patients identified with CMHPs being referred peaks at 20-24 years (22.95%) and reduces with increase in age thereafter to 6.00% for 70-74-year-olds. Once referred, the proportion of those attending first treatment increases with age between 20 years (57.34%) and 64 years (76.97%). In addition, the percentage of those having a clinical improvement gradually increases from the age of 18 years (12.94%) to 69 years (20.74%). Younger adults are more readily referred to IAPT services. However, as a proportion of those referred, probabilities of attending once, attending more than once, and clinical improvement increase with age. It is uncertain whether optimum levels of referral have been reached for young adults. It is important to establish whether changes to service configuration, treatment options, and GP behaviour can increase referrals for middle-aged and older adults.


A systematic screen reveals new elements acting at the G2/M cell cycle control.
The major cell cycle control acting at the G2 to mitosis transition is triggered in all eukaryotes by cyclin-dependent kinases (CDKs). In the fission yeast Schizosaccharomyces pombe the activation of the G2/M CDK is regulated primarily by dephosphorylation of the conserved residue Tyr15 in response to the stress-nutritional response and cell geometry sensing pathways. To obtain a more complete view of the G2/M control we have screened systematically for gene deletions that advance cells prematurely into mitosis. A screen of 82% of fission yeast non-essential genes, comprising approximately 3,000 gene deletion mutants, identified 18 genes that act negatively at mitotic entry, 7 of which have not been previously described as cell cycle regulators. Eleven of the 18 genes function through the stress response and cell geometry sensing pathways, both of which act through CDK Tyr15 phosphorylation, and 4 of the remaining genes regulate the G2/M transition by inputs from hitherto unknown pathways. Three genes act independently of CDK Tyr15 phosphorylation and define additional uncharacterized molecular control mechanisms. Despite extensive investigation of the G2/M control, our work has revealed new components of characterized pathways that regulate CDK Tyr15 phosphorylation and new components of novel mechanisms controlling mitotic entry.


Work productivity of people with a psychiatric disability working in social firms.
Several factors impact work productivity in employees with a psychiatric condition. In the context of social firms (SFs) the goal of this study is to test a theoretical model to predict work productivity across time, while considering worker and workplace factors. 222 people with a psychiatric disability employed in SFs were enrolled in a longitudinal study (6 month follow up) and completed the baseline battery of questionnaires on health (severity of symptoms), individual (self-esteem as a worker) and organizational factors (organizational constraints and supervisory support), and their work productivity (also measured at follow-up). Path analysis was used to test the hypothetical model, assessing individual and organizational factors in the context of social firms that could facilitate or hamper work productivity in the immediate term (T1), as well as the stability of work productivity in the middle/long term (T2 or 6 month follow up). Work productivity of people with a psychiatric disability was affected negatively by severity of the symptoms, organizational constraints, and positively by self- esteem as a worker at T1. The stability of work productivity was significant across time (T2). Supervisor support was only related to work productivity at 6 month follow-up. The results highlight the importance of the supportive workplaces for people with mental disorders that SFs provide, and the stability of work productivity across time. Supervisor support seems to have a delayed impact on work productivity. In future studies, researchers could determine how individual and organizational variables influence job tenure of employees with a psychiatric disability.


Striatal phosphodiesterase 10A and medial prefrontal cortical thickness in patients with schizophrenia: a PET and MRI study.
The enzyme phosphodiesterase 10A (PDE10A) is abundant in striatal medium spiny neurons and has been implicated in the pathophysiology of schizophrenia in animal models and is investigated as a possible new pharmacological treatment target. A reduction of prefrontal cortical thickness is common in schizophrenia, but how this relates to PDE10A expression is unknown. Our study aim was to compare, we believe for the first time, the striatal non-displaceable binding potential (BPND) of the new validated PDE10A ligand [11C]Lu AE92686 between patients with schizophrenia and healthy controls. Furthermore, we aimed to assess the correlation of PDE10A BPND to cortical thickness. Sixteen healthy male controls and 10 male patients with schizophrenia treated with clozapine, olanzapine or quetiapine were investigated with positron emission tomography (PET) and magnetic resonance imaging (MRI). Striatal binding potential (BPND) of [11C]Lu AE92686 was acquired through dynamic PET scans and cortical thickness by structural MRI. Clinical assessments of symptoms and cognitive function were performed and the antipsychotic dosage was recorded. Patients with schizophrenia had a significantly lower BPND of [11C]Lu AE92686 in striatum (P=0.003) than healthy controls. The striatal BPND significantly correlated to cortical thickness in the medial prefrontal cortex and superior frontal gyrus across patients with schizophrenia and healthy controls. No significant correlation was observed between the BPND for [11C]Lu AE92686 in striatum and age, schizophrenia symptoms, antipsychotic dosage, coffee consumption, smoking, duration of illness or cognitive function in the patients. In conclusion, PDE10A may be important for functioning in the striato-cortical interaction and in the pathophysiology of schizophrenia.


Acoustofluidics 11: Affinity specific extraction and sample decomplexing using continuous flow acoustophoresis.
Acoustic standing wave technology combined with ligand complexed microbeads offers a means for affinity specific selection of target analytes from complex samples. When realized in a microfluidic format we can capitalize on laminar flow and acoustic forces that can drive cells or microbeads across fluid interfaces. Given this, we have the ability to perform carrier fluid (suspending medium) exchange operations in continuous flow in microfluidic chips based solely on acoustofluidic properties. A key issue here is to ensure that a minimum of the original carrier fluid follows the cells/particles across the fluid interface. Simple processing protocols can be achieved that may outperform macroscale magnetic bead-based sample extraction or centrifugation steps, which can also be straightforwardly integrated with downstream analytical instrumentation. This tutorial outlines some basic fluidic configurations for acoustophoresis based sample decomplexing and details the different system parameters that will impact the outcome of an acoustophoresis based affinity extraction experiment or a cell medium exchange step. Examples are given of both targeted extraction of microbes and selective elusion of molecular species.


Trifluoroethanol-induced activity and structural changes in bos taurus copper- and zinc-containing superoxide dismutase.
Superoxide dismutase (SOD, EC 184.108.40.206) plays an important antioxidant defense role in organisms exposed to oxygen. Copper- and zinc-containing SOD (Cu/Zn-SOD) catalysis and the change in folding behavior of this enzyme in response to inactivators are therefore of interest. We studied the inhibitory effects of trifluoroethanol (TFE) on the activity and conformation of a Cu/Zn-SOD from Bos taurus. We found that TFE inactivated the enzyme and disrupted the tertiary and secondary structures of Cu/Zn-SOD. Kinetic studies showed that TFE-induced inactivation of Cu/Zn-SOD follows first-order reaction kinetics and that TFE binding sites are distinct from the copper- and zinc-containing active site. These structural changes occurred prior to enzyme activity loss. A computational docking simulation of Cu/Zn-SOD and TFE (binding energy of Dock 6.3: -11.52 kcal/mol) suggested that THR37, ASP40, and GLU119, which are located near the active site, interact with TFE. Evaluation of the ligand binding kinetics of Cu/Zn-SOD during unfolding in the presence of TFE combined with computational prediction allowed us to gain insight into the inactivation of Cu/Zn-SOD.


Novel Victorivirus from a Pakistani Isolate of Alternaria alternata Lacking a Typical Translational Stop/Restart Sequence Signature.
The family Totiviridae currently contains five genera Totivirus, Victorivirus, Leishmavirus, Trichomonasvirus, and Giardiavirus. Members in this family generally have a set of two-open reading frame (ORF) elements in their genome with the 5'-proximal ORF (ORF1) encoding a capsid protein (CP) and the 3'-proximal one (ORF2) for RNA-dependent RNA polymerase (RdRp). How the downstream open reading frames (ORFs) are expressed is genus-specific. All victoriviruses characterized thus far appear to use the stop/restart translation mechanism, allowing for the expression of two separate protein products from bicitronic genome-sized viral mRNA, while the totiviruses use a -1 ribosomal frame-shifting that leads to a fusion product of CP and RdRp. We report the biological and molecular characterization of a novel victorivirus termed Alternaria alternata victorivirus 1 (AalVV1) isolated from Alternaria alternata in Pakistan. The phylogenetic and molecular analyses showed AalVV1 to be distinct from previously reported victoriviruses. AalVV1 appears to have a sequence signature required for the -1 frame-shifting at the ORF1/2 junction region, rather than a stop/restart key mediator. By contrast, SDS-polyacrylamide gel electrophoresis and peptide mass fingerprinting analyses of purified virion preparations suggested the expression of two protein products, not a CP-RdRp fusion product. How these proteins are expressed is discussed in this study. Possible effects of infection by this virus were tested in two fungal species: A. alternata and RNA silencing proficient and deficient strains of Cryphonectria parasitica, a model filamentous fungus. AalVV1 showed symptomless infection in all of these fungal strains, even in the RNA silencing deficient C. parasitica strain.


Investigation of light propagation models to determine the optical properties of tissue from interstitial frequency domain fluence measurements.
Four models, standard diffusion approximation (SDA), single Monte Carlo (SMC), delta-P1, and isotropic similarity (ISM), are developed and evaluated as forward calculation tools in the estimation of tissue optical properties. The inverse calculation uses the ratio of the fluences and phase difference at two locations close to an intensity modulated isotropic source to recover the reduced scattering coefficient mus' and the absorption coefficient mua. Diffusion theory allows recovery of optical properties (OPs) within 5% for media with mus'mua>10. The performance of the delta-P1 model is similar to SDA, with limited enhanced accuracy. The collimation approximation may limit the use of the delta-P1 model for spherical geometry, and/or the fluence may not be accurately calculated by this model. The SMC model is the best, recovering OPs within 10% regardless of the albedo. However, the necessary restriction of the searched OPs space is inconvenient. The performance of ISM is similar to that of diffusion theory for media with mus'mua>10, and better for 1<mus'mua<10, i.e., determines absorption within 5% and reduced scattering within 20%. In practice, satisfactory estimates (within 5 to 10%) can be achieved using SDA to recover mus' and ISM to recover mua for media with mus'mua>5.


Short-Term Responses in Maximum Quantum Yield of PSII (Fv/Fm) to ex situ Temperature Treatment of Populations of Bryophytes Originating from Different Sites in Hokkaido, Northern Japan.
There is limited knowledge available on the thermal acclimation processes for bryophytes, especially when considering variation between populations or sites. This study investigated whether short-term ex situ thermal acclimation of different populations showed patterns of site dependency and whether the maximum quantum yield of PSII (Fv/Fm) could be used as an indicator of adaptation or temperature stress in two bryophyte species: Pleurozium schreberi (Willd. ex Brid.) Mitt. and Racomitrium lanuginosum (Hedw.) Brid. We sought to test the hypothesis that differences in the ability to acclimate to short-term temperature treatment would be revealed as differences in photosystem II maximum yield (Fv/Fm). Thermal treatments were applied to samples from 12 and 11 populations during 12 or 13 days in growth chambers and comprised: (1) 10/5 °C; (2) 20/10 °C; (3) 25/15 °C; (4) 30/20 °C (12 hours day/night temperature). In Pleurozium schreberi, there were no significant site-dependent differences before or after the experiment, while site dependencies were clearly shown in Racomitrium lanuginosum throughout the study. Fv/Fm in Pleurozium schreberi decreased at the highest and lowest temperature treatments, which can be interpreted as a stress response, but no similar trends were shown by Racomitrium lanuginosum.


Formation of N-nitrosamines by micelle-catalysed nitrosation of aliphatic secondary amines.
N-Nitrosamines are an important class of potent human carcinogens and mutagens that can be present in water and wastewater. For instance, N-nitrosamines can be formed by reaction of nitrosating agents such as NO+ or N2O3 formed from nitrite under acidic conditions with secondary amine precursors by an acid-catalysed nitrosation pathway. This study investigates the catalytic effect of cationic and anionic micelles on the nitrosation of secondary aliphatic amines in the presence of nitrite at different pH values. The results of this study demonstrate that the nitrosation of hydrophobic secondary amines (e.g., dipropylamine and dibutylamine) by nitrite was significantly enhanced in the presence of micelles of the cationic surfactant cetyltrimethylammonium chloride whereas anionic micelles formed by sodium dodecylsulfate did not significantly enhance the formation of N-nitrosamines. Rate enhancements of up to 100-fold were observed for the formation of N-nitrosodibutylamine in the presence of cetyltrimethylammonium chloride. The magnitude of the catalytic effect of cationic micelles on the nitrosation reaction depended mainly of the hydrophobicity of the amine precursors (i.e., alkyl chain length), the stability and the charge of the micelles and pH. One important enhancement factor is the lowering of the pKa of the precursor alkylammonium ion due to the electrical potential at the micelle-water interface by up to ∼2.5 pH units. These results suggest that cationic micelle-forming surfactants might play a role in the formation of N-nitrosamines in wastewater, consumer products and in industrial processes using high concentrations of cationic surfactants.


Anti-TNF modulation reduces myocardial inflammation and improves cardiovascular function in systemic rheumatic diseases.
Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are common disorders associated with increased rates of cardiovascular disease (CVD), but the contribution of cytokine-induced inflammation to impaired cardiovascular function in these conditions remains poorly understood. We assessed the effect of anti-TNF therapy on myocardial and vascular function, myocardial tissue characteristics and perfusion in inflammatory arthropathy and systemic rheumatic disease (IASRD) patients, using cardiovascular magnetic resonance (CMR). 20 RA patients, 7 AS patients, 5 PsA patients without previously known CVD scheduled to commence anti-TNF therapy and 8 RA patients on standard disease modifying antirheumatic drugs underwent CMR at 1.5 T, including cine, tagging, pulse wave velocity (PWV), T2-weighted, native and postcontrast T1 mapping, ECV quantification, rest and stress perfusion and late gadolinium enhancement (LGE) imaging. Following anti-TNF therapy, there was significant reversal of baseline subclinical cardiovascular dysfunction, as evidenced by improvement in peak systolic circumferential strain (p < 0.001), peak diastolic circumferential strain rate (p < 0.001), and total aortic PWV, (p < 0.001). This was accompanied by a reduction in myocardial inflammation, as assessed by T2-weighted imaging (p = 0.005), native T1 mapping (p = 0.009) and ECV quantification (p = 0.001), as well as in serum inflammatory markers like CRP (p < 0.001) and ESR (p < 0.001), and clinical measures of disease activity (DAS28-CRP, p = 0.001; BASDAI, p < 0.001). A trend towards improvement in myocardial perfusion was observed (p = 0.07). Focal myocardial fibrosis, as detected by LGE CMR was not altered by anti-TNF therapy (p = 0.92). Anti-TNF therapy reduces subclinical myocardial inflammation and improves cardiovascular function in RA, AS and PsA. CMR may be used to track disease progression and response to therapy. Future CMR-based studies to demonstrate effect of anti-TNF therapy modulation of vascular structure and function on hard clinical events and outcomes would be useful.


Dengue subgenomic flaviviral RNA disrupts immunity in mosquito salivary glands to increase virus transmission.
Globally re-emerging dengue viruses are transmitted from human-to-human by Aedes mosquitoes. While viral determinants of human pathogenicity have been defined, there is a lack of knowledge of how dengue viruses influence mosquito transmission. Identification of viral determinants of transmission can help identify isolates with high epidemiological potential. Additionally, mechanistic understanding of transmission will lead to better understanding of how dengue viruses harness evolution to cycle between the two hosts. Here, we identified viral determinants of transmission and characterized mechanisms that enhance production of infectious saliva by inhibiting immunity specifically in salivary glands. Combining oral infection of Aedes aegypti mosquitoes and reverse genetics, we identified two 3' UTR substitutions in epidemic isolates that increased subgenomic flaviviral RNA (sfRNA) quantity, infectious particles in salivary glands and infection rate of saliva, which represents a measure of transmission. We also demonstrated that various 3'UTR modifications similarly affect sfRNA quantity in both whole mosquitoes and human cells, suggesting a shared determinism of sfRNA quantity. Furthermore, higher relative quantity of sfRNA in salivary glands compared to midgut and carcass pointed to sfRNA function in salivary glands. We showed that the Toll innate immune response was preferentially inhibited in salivary glands by viruses with the 3'UTR substitutions associated to high epidemiological fitness and high sfRNA quantity, pointing to a mechanism for higher saliva infection rate. By determining that sfRNA is an immune suppressor in a tissue relevant to mosquito transmission, we propose that 3'UTR/sfRNA sequence evolution shapes dengue epidemiology not only by influencing human pathogenicity but also by increasing mosquito transmission, thereby revealing a viral determinant of epidemiological fitness that is shared between the two hosts.


Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence.
In primary mammalian cells, oncogenic ras induces premature senescence, depending on an active MEK-extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. It has been unclear how activation of the mitogenic MEK-ERK pathway by ras can confer growth inhibition. In this study, we have found that the stress-activated MAPK, p38, is also activated during the onset of ras-induced senescence in primary human fibroblasts. Constitutive activation of p38 by active MKK3 or MKK6 induces senescence. Oncogenic ras fails to provoke senescence when p38 activity is inhibited, suggesting that p38 activation is essential for ras-induced senescence. Furthermore, we have demonstrated that p38 activity is stimulated by ras as a result of an activated MEK-ERK pathway. Following activation of MEK and ERK, expression of oncogenic ras leads to the accumulation of active MKK3/6 and p38 activation in a MEK-dependent fashion and subsequently induces senescence. Active MEK1 induces the same set of changes and provokes senescence relying on active p38. Therefore, oncogenic ras provokes premature senescence by sequentially activating the MEK-ERK and MKK3/6-p38 pathways in normal, primary cells. These studies have defined the molecular events within the ras signaling cascade that lead to premature senescence and, thus, have provided new insights into how ras confers oncogenic transformation in primary cells.


First Report of Anthracnose Caused by Colletotrichum sansevieriae on Sansevieria in Korea.
Sansevieria, Sansevieria trifasciata Prain, is cultivated in greenhouses and is used as a potted interior foliage plant in Korea. In April 2012, several plants (cv. Moonshine) exhibiting typical anthracnose symptoms from a local nursery were sent to the plant clinic of Gyeonggi-Do Agricultural Research and Extension Services for diagnosis. The leaf lesions began as round, partly water-soaked, pale greenish to grayish spots, which enlarged and ultimately coalesced, resulting in severe leaf blight. Concentric rings of blackish acervuli were formed in the expanding lesions of mostly 2 to 4 cm in diameter. Acervuli were mostly epiphyllous, circular to ellipsoid. Setae were aseptate to 3-septate, dark brown at the base, paler upwards, acicular, and up to 180 μm long. Conidia (n = 30) were oblong-elliptical to obovate, sometimes fusiform-elliptical, guttulate, hyaline, and 14 to 24 × 5 to 7.5 μm (mean 18.6 × 6.4 μm). Hyphopodial appressoria were dark brown to blackish, globose to clavate in outline, and 5 to 12 × 4 to 8 μm. Colonies on potato dextrose agar (PDA) were grayish-white, felted with cottony-white aerial mycelium on a gray to olivaceous gray background in culture. Gelatinous salmon- to orange-colored conidial masses were produced abundantly after one week's incubation. The morphological and cultural characteristics of the fungus were consistent with the description of Colletotrichum sansevieriae M. Nakamura & M. Ohzono (2,3). A voucher specimen was deposited in the Korea University herbarium (KUS-F26637). An isolate was deposited in the Korean Agricultural Culture Collection (Accession No. KACC46835). Fungal DNA was extracted with DNeasy Plant Mini DNA Extraction Kits (Qiagen Inc., Valencia, CA). The complete internal transcribed spacer (ITS) region of rDNA was amplified with the primers ITS1/ITS4 and sequenced. The resulting 569-bp sequences were deposited in GenBank (Accession No. KC847065). A BLAST search in GenBank exhibited 100% nucleotide identity with sequence of C. sansevieriae (JF911349) from the United States and >99% similarity with that of HQ433226 from Australia. To confirm pathogenicity, inoculum was prepared by harvesting conidia from 3-week-old cultures on PDA. A conidial suspension (2 × 106 conidia/ml) was sprayed over the five leaves of sansevieria 'Moonshine' wounded with a fine needle. Five leaves sprayed with sterile water served as controls. Plants were covered with plastic bags to maintain 100% relative humidity for 48 h and then kept in a greenhouse (22 to 28°C and 70 to 80% RH). Within 12 days, symptoms identical to those observed in originally infected leaf developed on all inoculated leaves. No symptoms were observed on control plants. C. sansevieriae was reisolated from the lesions of inoculated plants, fulfilling Koch's postulates. Sansevieria anthracnose associated with C. sansevieriae has been reported in Japan (2), Australia (1), and the United States (3). To our knowledge, this is the first report of sansevieria anthracnose in Korea. Our observations in sansevieria nurseries suggest that preventing wound infection as well as maintaining good plant hygiene in greenhouses might be main strategies for this disease. References: (1) R. Aldaoud et al. Australas. Plant Dis. Notes 6:60, 2011. (2) M. Nakamura et al. J. Gen. Plant Pathol. 72:253, 2006. (3) A. J. Palmateer et al. Plant Dis. 96:293, 2012.


Guidelines, policies, and barriers to kidney care: findings from a global survey.
An international survey led by the International Society of Nephrology in 2016 assessed the current capacity of kidney care worldwide. To better understand how governance and leadership guide kidney care, items pertinent to government priority, advocacy, and guidelines, among others, were examined. Of the 116 responding countries, 36% (n = 42) reported CKD as a government health care priority, which was associated with having an advocacy group (χ2 = 11.57; P = 0.001). Nearly one-half (42%; 49 of 116) of countries reported an advocacy group for CKD, compared with only 19% (21 of 112) for AKI. Over one-half (59%; 68 of 116) of countries had a noncommunicable disease strategy. Similarly, 44% (48 of 109), 55% (57 of 104), and 47% (47 of 101) of countries had a strategy for nondialysis CKD, chronic dialysis, and kidney transplantation, respectively. Nearly one-half (49%; 57 of 116) reported a strategy for AKI. Most countries (79%; 92 of 116) had access to CKD guidelines and just over one-half (53%; 61 of 116) reported guidelines for AKI. Awareness and adoption of guidelines were low among nonnephrologist physicians. Identified barriers to kidney care were factors related to patients, such as knowledge and attitude (91%; 100 of 110), physicians (84%; 92 of 110), and geography (74%; 81 of 110). Specific to renal replacement therapy, patients and geography were similarly identified as a barrier in 78% (90 of 116) and 71% (82 of 116) of countries, respectively, with the addition of nephrologists (72%; 83 of 116) and the health care system (73%; 85 of 116). These findings inform how kidney care is currently governed globally. Ensuring that guidelines are feasible and distributed appropriately is important to enhancing their adoption, particularly in primary care. Furthermore, increasing advocacy and government priority, especially for AKI, may increase awareness and strategies to better guide kidney care.


The immune system as a potential target for environmental estrogens (endocrine disrupters): a new emerging field.
It is now well known that natural (17beta-estradiol) and synthetic (e.g. diethylstilbestrol) estrogens not only affect the reproductive system, but also markedly influence the immune system. Recently, a new class of estrogens that is abundant in the environment (in industrial chemicals, pesticides, and surfactants) has been recognized. Some of these estrogenic chemicals (which are a large subgroup of endocrine disrupters) have also been shown to influence the immune system. This review assimilates growing evidence in wildlife, laboratory animals and to a limited extent in humans, which suggests that environmental chemicals may also affect the immune system. Further studies are needed to ascertain the immunological consequences of exposure to environmental estrogens, especially in humans. At the present time, it is not known whether the human immune system responds to a low dose of environmental estrogens or if environmental estrogens influence certain subsets of human populations, rather than the general population. Conceivably, an alteration of the immune system by environmental estrogens could affect the individuals' ability to mount well-regulated immune responses to microbial and vaccine antigens, allergens, self and tumor antigens. Possible changes in the immune system must be investigated routinely in toxicity studies. A comprehensive mechanistic understanding of potential immunomodulatory chemicals is needed. In this regard, relevant laboratory animals may be especially useful in identifying susceptible periods of life, whether both genders are equally affected, in analysis of changes in target lymphoid organs, and to determine the immunological effects of mixtures of chemicals.


Rumen protozoa are rich in polyunsaturated fatty acids due to the ingestion of chloroplasts.
Within this study, we investigated whether the polyunsaturated fatty acids (PUFA)-rich nature of rumen protozoa is a consequence of ingestion of PUFA-rich chloroplasts. Four Hereford x Friesian steers were offered hay [low 18:3 (n-3) and low chlorophyll concentration] followed by freshly cut perennial ryegrass [high 18:3 (n-3) and high chlorophyll concentration] for 16 days. On the 14th and 16th days, rumen protozoa as well as attached and planktonic bacteria were fractionated 1 h before (-1 h), 2 and 6 h postfeeding, and their fatty acid concentrations determined. Protozoa fractionated from fresh grass-fed steers were richer (P<0.05) in PUFA, except conjugated linoleic acid, for all time points compared with those from hay-fed steers. Protozoal density was higher (P<0.05) for grass compared with hay. Entodinomorphid abundance was 3.4 times higher on fresh grass (P<0.01) compared with hay. Confocal microscopy and transmission electron microscopy confirmed that Epidinium spp. were commonly saturated with intracellular cytoplasmic chloroplasts. These data suggest that engulfment of chloroplasts is a major contributor to the high 18:3 (n-3) concentration of protozoa.


Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence.
In an effort to identify new genes and analyse their expression patterns, 174,472 partial complementary DNA sequences (expressed sequence tags (ESTs)), totalling more than 52 million nucleotides of human DNA sequence, have been generated from 300 cDNA libraries constructed from 37 distinct organs and tissues. These ESTs have been combined with an additional 118,406 ESTs from the database dbEST, for a total of 83 million nucleotides, and treated as a shotgun sequence assembly project. The assembly process yielded 29,599 distinct tentative human consensus (THC) sequences and 58,384 non-overlapping ESTs. Of these 87,983 distinct sequences, 10,214 further characterize previously known genes based on statistically significant similarity to sequences in the available databases; the remainder identify previously unknown genes. Thirty tissues were sampled by over 1,000 ESTs each; only eight genes were matched by ESTs from all 30 tissues, and 227 genes were represented in 20 or more of the tissues sampled with more than 1,000 ESTs. Approximately 40% of identified human genes appear to be associated with basic energy metabolism, cell structure, homeostasis and cell division, 22% with RNA and protein synthesis and processing, and 12% with cell signalling and communication.


Solution structure of HndAc: a thioredoxin-like domain involved in the NADP-reducing hydrogenase complex.
The NADP-reducing hydrogenase complex from Desulfovibrio fructosovorans is a heterotetramer encoded by the hndABCD operon. Sequence analysis indicates that the HndC subunit (52 kDa) corresponds to the NADP-reducing unit, and the HndD subunit (63.5 kDa) is homologous to Clostridium pasteurianum hydrogenase. The role of HndA and HndB subunits (18.8 kDa and 13.8 kDa, respectively) in the complex remains unknown. The HndA subunit belongs to the [2Fe-2S] ferredoxin family typified by C. pasteurianum ferredoxin. HndA is organized into two independent structural domains, and we report in the present work the NMR structure of its C-terminal domain, HndAc. HndAc has a thioredoxin-like fold consisting in four beta-strands and two relatively long helices. The [2Fe-2S] cluster is located near the surface of the protein and bound to four cysteine residues particularly well conserved in this class of proteins. Electron exchange between the HndD N-terminal [2Fe-2S] domain (HndDN) and HndAc has been previously evidenced, and in the present studies we have mapped the binding site of the HndDN domain on HndAc. A structural analysis of HndB indicates that it is a FeS subunit with 41% similarity with HndAc and it contains a possible thioredoxin-like fold. Our data let us propose that HndAc and HndB can form a heterodimeric intermediate in the electron transfer between the hydrogenase (HndD) active site and the NADP reduction site in HndC.


Influence of highly distinctive structural properties on the excitability of pyramidal neurons in monkey visual and prefrontal cortices.
Whole-cell patch-clamp recordings and high-resolution 3D morphometric analyses of layer 3 pyramidal neurons in in vitro slices of monkey primary visual cortex (V1) and dorsolateral granular prefrontal cortex (dlPFC) revealed that neurons in these two brain areas possess highly distinctive structural and functional properties. Area V1 pyramidal neurons are much smaller than dlPFC neurons, with significantly less extensive dendritic arbors and far fewer dendritic spines. Relative to dlPFC neurons, V1 neurons have a significantly higher input resistance, depolarized resting membrane potential, and higher action potential (AP) firing rates. Most V1 neurons exhibit both phasic and regular-spiking tonic AP firing patterns, while dlPFC neurons exhibit only tonic firing. Spontaneous postsynaptic currents are lower in amplitude and have faster kinetics in V1 than in dlPFC neurons, but are no different in frequency. Three-dimensional reconstructions of V1 and dlPFC neurons were incorporated into computational models containing Hodgkin-Huxley and AMPA receptor and GABA(A) receptor gated channels. Morphology alone largely accounted for observed passive physiological properties, but led to AP firing rates that differed more than observed empirically, and to synaptic responses that opposed empirical results. Accordingly, modeling predicts that active channel conductances differ between V1 and dlPFC neurons. The unique features of V1 and dlPFC neurons are likely fundamental determinants of area-specific network behavior. The compact electrotonic arbor and increased excitability of V1 neurons support the rapid signal integration required for early processing of visual information. The greater connectivity and dendritic complexity of dlPFC neurons likely support higher level cognitive functions including working memory and planning.


Brain cell type specificity and gliosis-induced activation of the human cytomegalovirus immediate-early promoter in transgenic mice.
Human cytomegalovirus (HCMV) can cause debilitating, sometimes fatal, opportunistic infections in congenitally infected infants and in immunodeficient individuals such as patients with the acquired immunodeficiency syndrome (AIDS). Molecular mechanisms that determine cell type specificity of HCMV infection and latency are poorly understood. We recently described a transgenic mouse model for analysis of HCMV major immediate-early (IE) promoter regulation and showed that sites of IE promoter activity during murine embryogenesis correlate with known target tissues of congenital HCMV infection in human fetuses (Koedood et al., 1995). Among various permissive human tissues, the brain is a site where HCMV infections can be devastating. Here, we have used immunohistochemical double-labeling analysis to identify specific cell types with HCMV-IE promoter activity in brains of transgenic mice at several postnatal stages. IE promoter activity was restricted to some endothelial cells, ependymal cells, choroid plexus epithelia, and neurons at discrete locations in the forebrain, brainstem, and cerebellum. Endothelial cells and neurons with activity were proportionately more abundant in neonatal than in adult brains. Although the IE promoter was normally silent in most astrocytes, activity was strongly induced in reactive astrocytes in response to a neocortical stab lesion. The findings support a model, consistent with clinical literature on HCMV encephalitis, whereby tissue damage and gliosis caused by HCMV infection of endothelial and ependymal cells progressively renders adjacent permissive neurons and reactive astrocytes accessible to infection. This transgenic model system should facilitate identification of factors that regulate the HCMV IE promoter with regard to infection permissivity and reactivation from latency.


Expectations for Artificial Intelligence (AI) in Psychiatry.
Artificial intelligence (AI) is often presented as a transformative technology for clinical medicine even though the current technology maturity of AI is low. The purpose of this narrative review is to describe the complex reasons for the low technology maturity and set realistic expectations for the safe, routine use of AI in clinical medicine. For AI to be productive in clinical medicine, many diverse factors that contribute to the low maturity level need to be addressed. These include technical problems such as data quality, dataset shift, black-box opacity, validation and regulatory challenges, and human factors such as a lack of education in AI, workflow changes, automation bias, and deskilling. There will also be new and unanticipated safety risks with the introduction of AI. The solutions to these issues are complex and will take time to discover, develop, validate, and implement. However, addressing the many problems in a methodical manner will expedite the safe and beneficial use of AI to augment medical decision making in psychiatry.