Kinematic and neurophysiological consequences of an assisted-force-feedback brain-machine interface training: a case study.
In a proof-of-principle prototypical demonstration we describe a new type of brain-machine interface (BMI) paradigm for upper limb motor-training. The proposed technique allows a fast contingent and proportionally modulated stimulation of afferent proprioceptive and motor output neural pathways using operant learning. Continuous and immediate assisted-feedback of force proportional to rolandic rhythm oscillations during actual movements was employed and illustrated with a single case experiment. One hemiplegic patient was trained for 2 weeks coupling somatosensory brain oscillations with force-field control during a robot-mediated center-out motor-task whose execution approaches movements of everyday life. The robot facilitated actual movements adding a modulated force directed to the target, thus providing a non-delayed proprioceptive feedback. Neuro-electric, kinematic, and motor-behavioral measures were recorded in pre- and post-assessments without force assistance. Patient's healthy arm was used as control since neither a placebo control was possible nor other control conditions. We observed a generalized and significant kinematic improvement in the affected arm and a spatial accuracy improvement in both arms, together with an increase and focalization of the somatosensory rhythm changes used to provide assisted-force-feedback. The interpretation of the neurophysiological and kinematic evidences reported here is strictly related to the repetition of the motor-task and the presence of the assisted-force-feedback. Results are described as systematic observations only, without firm conclusions about the effectiveness of the methodology. In this prototypical view, the design of appropriate control conditions is discussed. This study presents a novel operant-learning-based BMI-application for motor-training coupling brain oscillations and force feedback during an actual movement.


Asthma Quality Measurement and Adverse Outcomes in Medicaid-Enrolled Children.
To determine the association between the asthma medication ratio (AMR) quality measure and adverse outcomes among Medicaid-enrolled children with asthma in Arkansas, given concerns regarding the utility of the AMR in evaluating pediatric risk of asthma-related adverse events (AAEs). We used the Arkansas All-Payer Claims Database to identify Medicaid-enrolled children with asthma using a nonrestrictive case definition and additionally using the standard Healthcare Effectiveness Data and Information Set (HEDIS) persistent asthma definition. We assessed the AMR using the traditional dichotomous HEDIS AMR categorization and across 4 expanded AMR categories. Regression models assessed associations between AMR and AAE including hospitalization and emergency department utilization, with models conducted overall and by race and ethnicity. Of the 22 788 children in the analysis, 9.0% had an AAE (6.7% asthma-related emergency department visits; 3.0% asthma-related hospitalizations). We found poor correlation between AMR and AAE, with higher rates of AAE (10.5%) among children with AMR ≥0.5 compared with AMR <0.5 (8.5%; P < .001), and similar patterns stratified by racial and ethnic subgroups. Expanded AMR categorization revealed notable differences in associations between AMR and AAEs, compared with traditional dichotomous categorization, with worse performance in Black children. The AMR performed poorly in identifying risk of adverse outcomes among Medicaid-enrolled children with asthma. These findings underscore concerns of the utility of the AMR in population health management and reliance on restrictive HEDIS definitions. New population health frameworks incorporating broader considerations that accurately identify at-risk children are needed to improve equity in asthma management and outcomes.


Redox interactions between Saccharomyces cerevisiae and Saccharomyces uvarum in mixed culture under enological conditions.
Wine yeast starters that contain a mixture of different industrial yeasts with various properties may soon be introduced to the market. The mechanisms underlying the interactions between the different strains in the starter during alcoholic fermentation have never been investigated. We identified and investigated some of these interactions in a mixed culture containing two yeast strains grown under enological conditions. The inoculum contained the same amount (each) of a strain of Saccharomyces cerevisiae and a natural hybrid strain of S. cerevisiae and Saccharomyces uvarum. We identified interactions that affected biomass, by-product formation, and fermentation kinetics, and compared the redox ratios of monocultures of each strain with that of the mixed culture. The redox status of the mixed culture differed from that of the two monocultures, showing that the interactions between the yeast strains involved the diffusion of metabolite(s) within the mixed culture. Since acetaldehyde is a potential effector of fermentation, we investigated the kinetics of acetaldehyde production by the different cultures. The S. cerevisiae-S. uvarum hybrid strain produced large amounts of acetaldehyde for which the S. cerevisiae strain acted as a receiving strain in the mixed culture. Since yeast response to acetaldehyde involves the same mechanisms that participate in the response to other forms of stress, the acetaldehyde exchange between the two strains could play an important role in inhibiting some yeast strains and allowing the growth of others. Such interactions could be of particular importance in understanding the ecology of the colonization of complex fermentation media by S. cerevisiae.


Cardiovascular effects of consumption of black versus English walnuts.
English walnuts have been shown to decrease cardiovascular disease risk; however, black walnuts do not appear to have not been studied for their cardioprotective effects. The purpose of this study was to determine the effects of English versus black walnut consumption on blood lipids, body weight, fatty-acid composition of red blood cell (RBC) membranes, and endothelial function. Consumption of 30 g of English walnuts per day for 30 days, by 36 human participants, improved blood lipids; the effects of black walnuts were dependent on the participant's sex. Addition of either nut to the diet did not result in weight gain. The fatty-acid composition of RBC membranes was favorably affected by walnut consumption. RBC polyunsaturated fatty acids increased after consumption of either type of nut; however, eicosapentaenoic acid increased significantly more after English walnut consumption. Endothelial function of 6 unmedicated humans with hypercholesterolemia was maintained after consumption of English walnuts with a meal high in high saturated fats; however, consumption of black walnuts with the same meal did not maintain endothelial function. Overall, these results support the recommendation that consumption of 1 oz of English walnuts per day may decrease cardiovascular risk, but more research on black walnut consumption is necessary before an appropriate recommendation can be made.


The tip of the iceberg for child abuse: the critical roles of the pediatric trauma service and its registry.
The incidence of child abuse is approximately 10% of all children presenting to an emergency department (ED), with a mortality rate less than 1%. By contrast, the characteristics of the subset of abused children presenting to a pediatric trauma service (PTS) is not well defined. This study was a retrospective evaluation of prospectively collected information from an urban Level I pediatric trauma registry from 1990 to 2002 (n = 11,919). Child abuse cases and their perpetrators were identified by E-codes. Patterns of injuries were examined by integer International Classification of Diseases, Ninth Revision codes, and diagnostic model was evaluated by discrimination and goodness-of-fit. A total of 171 cases of child abuse (1.4%) were identified, and the majority were boys (59%, p > 0.05 vs. nonabuse cases). The median age of the abused cohort was younger than 1 year old, and the number of abuse cases did not differ over time (mean, 11 per year.) Abused children present with a higher median Injury Severity Score (10 vs. 4, p < 0.01), more severe injuries of the head and integument, longer hospital lengths of stay (4 vs. 1 day, p < 0.01), and a higher mortality rate (12% vs. 2%, p < 0.01). The following variables emerged with significant association to abuse: fracture of base or vault of skull, contusion of eye, rib fracture, intracranial bleeding, multiple burns, and age. A new Diagnostic Index for Physical Child Abuse was created. Significant characteristics of the abused children in this pediatric trauma service include higher Injury Severity Score (especially in the head and integument), requirement for longer lengths of stay, and a nearly 10-times higher risk of death compared with the ED population. The Diagnostic Index for Physical Child Abuse is proposed as a new tool to assist in the identification of child abuse among pediatric trauma patients. An epidemiologic triangle for child abuse is described, with different prevalence and severity of child abuse seen at different levels of our health care system, starting with primary care providers, followed by the ED, the PTS, and ultimately the medical examiners. The number of cases decreases from the bottom to the top of the health care system, but the mortality rate increases as abuse escalates through the triangle. This establishes the PTS as possibly the final gatekeeper before an abused case becomes a fatality. These data emphasize the need for rigorous registry evaluation and subsequent evidence-based prevention initiatives.


Perceived Social Support in Persons With Heart Failure Living With an Implantable Cardioverter Defibrillator: A Cross-sectional Explorative Study.
The links between chronic illness, psychological well-being, and social support have previously been established. Social isolation and loneliness have shown an increased mortality risk for those with heart failure (HF). Increasingly more people with HF are living with an implantable cardioverter defibrillator (ICD), but only a few small-scale studies have focused on social support in this population. The aim of this study was to explore factors related to perceived social support in a large cohort of individuals with HF living with an ICD. All eligible adult ICD recipients in the Swedish ICD registry were invited to participate in this cross-sectional study. For this analysis, those with HF and complete data on perceived social support were included (N = 1550; age, 67.3 (SD, 9.8) years; 19.5% female). Most reported a high level of social support, but 18% did not. In logistic regression, living alone was the greatest predictor of low/medium support. Lower social support for those living alone was associated with poorer perceived health status, having symptoms of depression, and experiencing low perceived control. For those living with someone, lower support was associated with female gender, symptoms of depression and anxiety, and less control. Heart failure status and perceived symptom severity were not related to the outcome. One in five participants reported low/medium social support. Our study underlines the complex relationships between perceived social support, psychological well-being and perceived control over the heart condition. Multiple aspects need to be taken into account when developing interventions to provide psychosocial support and optimize outcomes in this patient group.


Serum B vitamin levels and risk of lung cancer.
B vitamins and factors related to 1-carbon metabolism help to maintain DNA integrity and regulate gene expression and may affect cancer risk. To investigate if 1-carbon metabolism factors are associated with onset of lung cancer. The European Prospective Investigation into Cancer and Nutrition (EPIC) recruited 519,978 participants from 10 countries between 1992 and 2000, of whom 385,747 donated blood. By 2006, 899 lung cancer cases were identified and 1770 control participants were individually matched by country, sex, date of birth, and date of blood collection. Serum levels were measured for 6 factors of 1-carbon metabolism and cotinine. Odds ratios (ORs) of lung cancer by serum levels of 4 B vitamins (B(2), B(6), folate [B(9)], and B(12)), methionine, and homocysteine. Within the entire EPIC cohort, the age-standardized incidence rates of lung cancer (standardized to the world population, aged 35-79 years) were 6.6, 44.9, and 156.1 per 100,000 person-years among never, former, and current smokers for men, respectively. The corresponding incidence rates for women were 7.1, 23.9, and 100.9 per 100,000 person-years, respectively. After accounting for smoking, a lower risk for lung cancer was seen for elevated serum levels of B(6) (fourth vs first quartile OR, 0.44; 95% confidence interval [CI], 0.33-0.60; P for trend <.000001), as well as for serum methionine (fourth vs first quartile OR, 0.52; 95% CI, 0.39-0.69; P for trend <.000001). Similar and consistent decreases in risk were observed in never, former, and current smokers, indicating that results were not due to confounding by smoking. The magnitude of risk was also constant with increasing length of follow-up, indicating that the associations were not explained by preclinical disease. A lower risk was also seen for serum folate (fourth vs first quartile OR, 0.68; 95% CI, 0.51-0.90; P for trend = .001), although this was apparent only for former and current smokers. When participants were classified by median levels of serum methionine and B(6), having above-median levels of both was associated with a lower lung cancer risk overall (OR, 0.41; 95% CI, 0.31-0.54), as well as separately among never (OR, 0.36; 95% CI, 0.18-0.72), former (OR, 0.51; 95% CI, 0.34-0.76), and current smokers (OR, 0.42; 95% CI, 0.27-0.65). Serum levels of vitamin B(6) and methionine were inversely associated with risk of lung cancer.


5-(2-aminoethyl)dibenzo[c,h][1,6]naphthyridin-6-ones: variation of n-alkyl substituents modulates sensitivity to efflux transporters associated with multidrug resistance.
5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one (ARC-111) has potent TOP1-targeting activity and pronounced antitumor activity. Several analogues of ARC-111 were synthesized with NH2, N-alkyl, N,N-dialkyl, pyrrolidinyl, piperidinyl, and piperazinyl substituents at the 2-position of the 5-ethyl group. The relative TOP1-targeting activity and cytotoxicity of these structural analogues were assessed in RPMI8402 and P388 tumor cells and their camptothecin-resistant variants CPT-K5 and P388/CPT45, respectively. Potent TOP1-targeting activity was retained within a series of mono N-alkyl analogues that included NHCH2CH3, NHCH(CH3)2, and NHC(CH3)3. TOP1-targeting activity was diminished by the presence of a N-benzyl moiety. In a comparison of a series of N-alkyl-N-isopropyl analogues, activity decreased in the order CH3 > CH2CH3 > CH(CH3)2. Cytotoxicity in RPMI8402 and P388 did correlate with TOP1-targeting activity. Cytotoxic activity was also determined in KB3-1 cells and its variants KB/V-1 and KBH5.0. As KB/V-1 cells overexpress MDR1 and KBH5.0 cells overexpress BCRP, decreased cytotoxicity in these cell lines relative to the parent cell line is indicative of compounds that are substrates for these efflux transporters. In view of their diminished cytotoxicity in KB/V-1 cells, it appears that the likely demethylated metabolites of ARC-111, i.e., where NH2 or NHCH3 replaces the N(CH3)2 at the 2-position of the 5-ethyl substituent, are substrates for MDR1. In contrast, no significant difference in cytotoxicity among these three cell lines was observed with other N-alkyl analogues, including NHC2H5, NHCH(CH3)2, NHC(CH3)3, N(CH3)2, N(CH2CH3)2, NCH3(CH(CH3)2), and either the pyrrolidinyl or the piperidinyl analogues. The 2-(piperazinyl) analogues were associated with diminished cytotoxicity in KB/V-1 cells, suggesting that the second basic amino substituent is associated with their recognition as substrates by MDR1. Comparative studies on the antitumor activity of ARC-111 and its N-demethylated derivatives (the NHCH3 and NH2 analogues) against SJ-BT45 medulloblastoma xenografts in scid mice revealed that the secondary amine metabolite is at least as active as ARC-111 in vivo, although the primary amine derivative was significantly less potent.


Pyrexia after transcranial surgery.
Pyrexia after transcranial surgery has been observed regularly in clinical practice but does not usually herald any subsequent pathologic process. However, the significance and incidence of this phenomenon remain uncertain. The aim of this study was to evaluate the incidence and timing of any pyrexia after transcranial surgery for craniosynostosis correction and correlate this with the clinical outcome to assess its significance. Retrospective review of sequential case notes collected over a 10 year period identified 136 transcranial operations undertaken for 122 cases of nonsyndromic craniosynostosis. The incidence of postoperative pyrexia of 38 degrees or more in the first 5 days was 76%, whereas that greater than 39 degrees was 11%. Pyrexia was noticed during the first 48 hours and had a bimodal distribution. Only a single case in this series subsequently developed a clinically significant complication, that is, a minor wound infection of the skin, which was treated by antibiotics and dressings. The occurrence of pyrexia did not appear to be related either to sex or to any affected suture but occurred less frequently in those who were under 6 months old. We conclude that this pyrexia should be considered to be a part of the normal physiological response to craniofacial surgery.


Color changes in post-cure heat-treated resin composites.
The purpose of this study was to determine the color changes that arise from post-cure heat treatment of selected light-cured resin composites by using colorimetric as well as observational methods. Brands of composite were selected that were solely Bis-GMA-based and Bis-GMA/urethane based. These materials also represented a range of filler content (low, medium, and high). The RGB values of cured resin discs were obtained immediately after light-curing as well as after a 5-minute post-cure heat exposure. The range of post-cure temperature was from 100-300 degrees C in 25 degrees C increments. The mean delta L*, delta a*, delta b* and delta E* were determined from red, green and blue data using triplicate replications for each heating condition. Twenty-one observers were asked to determine if the randomly arranged post-cure heated specimens differed in color from the unheated, cured control specimen for each brand. The results indicate that a delta E* value of approximately 3 resulted in greater than 50% of the observers noting a color difference between the post-cure heated specimen and the unheated control. The degree of color change was influenced more by the amount of resin content in the composite systems rather than by the particular resin composition. Microfill resins showed greater potential for color change than did the other types of materials. If clinicians are considering using conventional light-cured composite materials for inlays, the choice of material as well as the post-cure temperature will influence the ability to match the inlay with the original shade of composite selected.


Feedback control of unsupported standing.
This paper presents the results of continuing work on feedback control of unsupported standing in paraplegia. Our experimental setup considers a situation in which all joints above the ankle are braced, and stabilising torque at the ankle is generated by stimulation of the plantarflexors. A previous study showed that short periods of unsupported standing with paraplegic subjects could be achieved. In order to improve consistency and reliability of unsupported standing we are currently investigating several modifications to the control strategy. The paper reports progress towards this goal.


CCL21 induces extensive intratumoral immune cell infiltration and specific anti-tumor cellular immunity.
Chemokines are vital messengers that regulate immune cell activity. The chemokine CCL21 is normally expressed in secondary lymphoid organs and acts as a chemoattractant for several populations of immune cells. Herein, we report that intratumoral CCL21 administration recruited significant numbers of immune cells into murine pancreatic tumors and inhibited tumor growth. Detailed flow cytometric and confocal analysis of CCL21-treated tumor cell isolates revealed increased lymphoid-related dendritic cells (lDC) and myeloid DC (mDC), naïve and mature T cells, natural killer (NK) cells, and NKT cells infiltrating the tumor mass. Furthermore, CCL21 intratumoral treatments resulted in significant tumor growth inhibition in wild-type (WT) C57BL/6 mice, but no therapeutic benefit was observed in C57BL/6 RAG2-/-Pfp-/- mice, suggesting that the growth inhibition observed was immunologically mediated. CCL21 intratumoral injections generated immune responses that were tumor-specific and that could be transferred to naïve animals via splenocytes. In addition, intratumoral injection of CCL21 into pancreatic tumors reduced the growth of distant tumors as well as treated tumors. Thus, these data demonstrate in a pancreatic tumor model that intratumoral administration of CCL21 can cause significant immune cell infiltration of the tumor mass, delay growth of treated tumors, and generate a tumor-specific cellular immune response.


Efficiency of complex production in changing environment.
Cell function necessitates the assemblage of proteins into complexes, a process which requires further regulation on top of the fairly understood mechanisms used to control the transcription and translation of a single protein. However, not much is known about how protein levels are controlled to realize that regulation. We integrated data on the composition of yeast protein complexes and the dynamics of their protein building-blocks concentrations to show how the cell regulates protein levels to optimize complex formation. We find that proteins which are subunits of the same complex tend to have similar levels which change similarly following a change in growth conditions, and that abundant proteins undergo larger decrease in their copy number when grown in minimal media. We also study the fluctuations in protein levels and find them to be significantly smaller in large complexes, and in the least abundant subunit of each complex. We use a mathematical model of complex synthesis to explain how all these observations increase the efficiency of complex synthesis, in terms of better utilization of the available molecules and better resilience to stochastic variations. In conclusion, these results indicate an intricate regulation at all levels of protein production for the purpose of optimizing complex formation.


The Relationship Between Body Image and Sexual Function in Middle-Aged Women.
An individual's social and marital function, interpersonal relationships, and quality of life may, sometimes be affected by negative body image. This study is aimed at determining the relationship between body image and sexual function in middle-aged women. In this cross-sectional study, 437 middle-aged women, who were referred to various public healthcare centers in Ahvaz, Iran during 2014-2015, were selected. The Female Sexual Function Index (FSFI) and Body Shape Questionnaire (BSQ) were used for data collection. Chi-square, one-way analysis of variance, Spearman's correlation test, and logistic regression analysis were performed for statistical analysis. Approximately 58% of the participants expressed satisfaction with their body image, 35% were mildly dissatisfied, and 7% were moderately dissatisfied with their body image. Body image had a significant negative relationship with sexual satisfaction and sexual function (p=0.005). Furthermore, there was a significant relationship between body image and sexual desire (p=0.022), pain (p=0.001), sexual arousal (p<0.0005), sexual orgasm (p=0.001), and sexual satisfaction (p<0.0005). As the results indicated, body image is an important aspect of sexual health. In this study, women with a positive body image had higher sexual function valuation, compared to women with a negative body image. Also, body shape satisfaction was a predictor of sexual function.


Changes in the properties of the modulatory cerebral giant cells contribute to aging in the feeding system of Lymnaea.
This study examined whether electrophysiological changes in the endogenous properties and connectivity of the modulatory serotonergic cerebral giant cells (CGCs) contributed to the age-related changes in feeding behavior of the pond snail, Lymnaea. With increasing age there was a decrease in spontaneous CGC firing rates and decreased excitability of the CGCs to both chemosensory stimulation (0.05M sucrose applied to the lips) and direct intracellular current injection. These changes could be accounted for by a decrease in the input resistance of the neuron and an increase in the amplitude and the duration of the after-hyperpolarization. Decreases were also seen in the % of CGC pairs that were electrically coupled causing asynchronous firing. Together these changes would tend to reduce the ability of the CGCs to gate and control the frequency of the feeding behavior. Part of the ability of the CGCs to gate and frequency control the feeding network is to provide a background level of excitation to the feeding motor neurons. Recordings from B1 and B4 motor neurons showed an age-related hyperpolarization of the resting membrane potential consistent with a deficit in CGC function. Increases were seen in the strength of the evoked CGC-->B1 connection, however, this increase failed to compensate for the deficits in CGC excitability. In summary, age-related changes in the properties of the CGCs were consistent with them contributing to the age-related changes in feeding behavior seen in Lymnaea.


Mental health associations with eczema, asthma and hay fever in children: a cross-sectional survey.
This study aimed to examine the association of eczema, asthma and hay fever with mental health in a general child population and to assess the influence of parental socioeconomic position on these associations. We conducted a cross-sectional health survey of children aged 3, 6, 11 and 15 years in the City of Copenhagen, Denmark. Individual questionnaire data on eczema, asthma, and hay fever and mental health problems assessed using the Strengths and Difficulties Questionnaire (SDQ) was linked to register data on demographics and parental socioeconomic position. 9215 (47.9%) children were included in the analyses. Linear regression analyses showed that children with current eczema symptoms had higher SDQ scores (mean difference, 95% CI) of emotional problems (0.26, 0.12 to 0.39), conduct problems (0.19, 0.09 to 0.29) and hyperactivity problems (0.32, 0.16 to 0.48); children with current asthma symptoms had higher SDQ scores of emotional problems (0.45, 0.32 to 0.58), conduct problems (0.28, 0.18 to 0.38) and hyperactivity problems (0.52, 0.35 to 0.69); and children with current hay fever symptoms had higher SDQ scores of emotional problems (0.57, 0.42 to 0.72), conduct problems (0.22, 0.11 to 0.33), hyperactivity problems (0.44, 0.26 to 0.61) and peer problems (0.14, 0.01 to 0.26), compared with children without current symptoms of the relevant disease. For most associations, parental socioeconomic position did not modify the effect. Children with eczema, asthma or hay fever had more emotional, conduct and hyperactivity problems, but not peer problems, compared with children without these diseases. Atopic diseases added equally to the burden of mental health problems independent of socioeconomic position.


Transcription factors Mesp2 and Paraxis have critical roles in axial musculoskeletal formation.
Mesp2 and Paraxis are basic helix-loop-helix (bHLH) -type transcription factors coexpressed in the presomitic mesoderm (PSM) and are required for normal somite formation. Here, we show that Mesp2/Paraxis double-null mice exhibit a distinct phenotype unexpected from either Mesp2 or Paraxis single-null mice. In the posterior region of the body, most of the skeletal components of both the vertebral body and neural arches are severely reduced and only a rudimental lamina and ribs remain, indicating a strong genetic interaction in the sclerotomal cell lineage. However, yeast two-hybrid analyses revealed no direct interaction between Mesp2 and Paraxis. The Mesp2/Paraxis double-null embryo has caudalized somites, revealed by expanded Uncx4.1 expression pattern observed in the Mesp2-null embryo, but the expression level of Uncx4.1 was significantly decreased in mature somites, indicative of hypoplasia of lateral sclerotome derivatives. By focusing on vertebral column formation, we found that expressions of Pax1, Nkx3.1, and Bapx1 are regulated by Paraxis and that Pax9 expression was severely affected in the Mesp2/Paraxis double-null embryo. Furthermore, the expression of Pax3, a crucial factor for hypaxial muscle differentiation, is regulated by both Mesp2 and Paraxis in the anteriormost PSM and nascent somite region. The present data strongly suggest that patterning events by bHLH-type transcription factors have deep impacts on regional chondrogenic and myogenic differentiation of somitic cells, mainly by means of control of Pax genes.


Responding to GPs' information resource needs: implementation and evaluation of a complementary medicines information resource in Queensland general practice.
Australian General Practitioners (GPs) are in the forefront of primary health care and in an excellent position to communicate with their patients and educate them about Complementary Medicines (CMs) use. However previous studies have demonstrated that GPs lack the knowledge required about CMs to effectively communicate with patients about their CMs use and they perceive a need for information resources on CMs to use in their clinical practice. This study aimed to develop, implement, and evaluate a CMs information resource in Queensland (Qld) general practice. The results of the needs assessment survey of Qld general practitioners (GPs) informed the development of a CMs information resource which was then put through an implementation and evaluation cycle in Qld general practice. The CMs information resource was a set of evidence-based herbal medicine fact sheets. This resource was utilised by 100 Qld GPs in their clinical practice for four weeks and was then evaluated. The evaluation assessed GPs' (1) utilisation of the resource (2) perceived quality, usefulness and satisfaction with the resource and (3) perceived impact of the resource on their knowledge, attitudes, and practice of CMs. Ninety two out of the 100 GPs completed the four week evaluation of the fact sheets and returned the post-intervention survey. The herbal medicine fact sheets produced by this study were well accepted and utilised by Qld GPs. The majority of GPs perceived that the fact sheets were a useful resource for their clinical practice. The fact sheets improved GPs' attitudes towards CMs, increased their knowledge of those herbal medicines and improved their communication with their patients about those specific herbs. Eighty-six percent of GPs agreed that if they had adequate resources on CMs, like the herbal medicine fact sheets, then they would communicate more to their patients about their use of CMs. Further educational interventions on CMs need to be provided to GPs to increase their knowledge of CMs and to improve their communication with patients about their CMs use.


Characterization of the degradation mechanisms of lysine-derived aliphatic poly(ester urethane) scaffolds.
Characterization of the degradation mechanism of polymeric scaffolds and delivery systems for regenerative medicine is essential to assess their clinical applicability. Key performance criteria include induction of a minimal, transient inflammatory response and controlled degradation to soluble non-cytotoxic breakdown products that are cleared from the body by physiological processes. Scaffolds fabricated from biodegradable poly(ester urethane)s (PEURs) undergo controlled degradation to non-cytotoxic breakdown products and support the ingrowth of new tissue in preclinical models of tissue regeneration. While previous studies have shown that PEUR scaffolds prepared from lysine-derived polyisocyanates degrade faster under in vivo compared to in vitro conditions, the degradation mechanism is not well understood. In this study, we have shown that PEUR scaffolds prepared from lysine triisocyanate (LTI) or a trimer of hexamethylene diisocyanate (HDIt) undergo hydrolytic, esterolytic, and oxidative degradation. Hydrolysis of ester bonds to yield α-hydroxy acids is the dominant mechanism in buffer, and esterolytic media modestly increase the degradation rate. While HDIt scaffolds show a modest (<20%) increase in degradation rate in oxidative medium, LTI scaffolds degrade six times faster in oxidative medium. Furthermore, the in vitro rate of degradation of LTI scaffolds in oxidative medium approximates the in vivo rate in rat excisional wounds, and histological sections show macrophages expressing myeloperoxidase at the material surface. While recent preclinical studies have underscored the potential of injectable PEUR scaffolds and delivery systems for tissue regeneration, this promising class of biomaterials has a limited regulatory history. Elucidation of the macrophage-mediated oxidative mechanism by which LTI scaffolds degrade in vivo provides key insights into the ultimate fate of these materials when injected into the body.


Preoperative beta-blocker usage: is it really worthy of being a quality indicator?
Since 2007, the use of preoperative β-blockers has been used as a quality standard for patients undergoing coronary artery bypass graft surgery. Recent studies have called into question of the benefit of empiric preoperative β-blocker use. Data were extracted from our Society of Thoracic Surgeons certified database for patients undergoing isolated coronary artery bypass graft surgery from 2000 to 2008. We compared the outcomes for patients who received preoperative β-blockers with those of patients who did not. The study group had 12,855 patients, of whom 7,967 (62.0%) were treated preoperatively with β-blockers. Using propensity matching, we selected two matched groups of 4,474 patients with preoperative β-blocker use and 4,474 not using preoperative β-blockers. In the unmatched cohort, only deep sternal infection (0.3% versus 0.5% without β-blockers; p=0.032), pneumonia (1.9% versus 2.4% without β-blockers; p=0.039), and intraoperative blood usage (37.2% versus 34.1% without β-blockers; p<0.001) reached statistically significant difference. In the matched groups, there was no difference between adverse event rates in patients treated with β-blockers and those who were not. The number of patients requiring intraoperative blood product use was significantly higher among β-blocker-treated patients (p=0.004). Calculating the adjusted odds ratios showed that in the matched groups, the preoperative use of β-blockers was not an independent predictor of mortality. A rational for preoperative β-blockade exists. However, as with any medical intervention, its application should be tailored to specific clinical scenarios. With no differences in mortality or morbidity, our findings do not support preoperative β-blockade as a useful quality indicator for coronary artery bypass graft surgery.


Mass rearing history and irradiation affect mating performance of the male fruit fly, Anastrepha obliqua.
As an initial step to improve the efficiency of the sterile insect technique applied to eradicate, suppress, and control wild Anastrepha obliqua (Macquart) (Diptera: Tephritidae) in mango producing areas of Mexico, the effect of radiation dose and mass rearing history on male mating performance was examined. Field cage tests in which both male and female laboratory flies were irradiated at different doses (0, 40, and 80 Gy) were released with cohorts of wild flies of both sexes, revealing that both mass rearing history and irradiation affected male mating performance. Laboratory males were accepted for copulation by wild females less frequently than wild males. Copulations involving laboratory males were shorter than those involving wild males. Irradiated males mated less frequently with wild females than wild males, and irradiated females appeared to be less able to reject courting males of both origins. High levels of fertility for untreated laboratory females crossed with males irradiated at different doses may reflect problems in mass rearing affecting homogeneity of pupal age before irradiation, and possibly masked a dose effect. Proposed remedial measures to improve male mating performance are discussed.


Classification of surface epithelial neoplasms of the ovary.
Surface epithelial neoplasms of the ovary, which represent about two-thirds of all primary ovarian neoplasms and almost 90% of all malignant ovarian tumors, are a variegated and heterogeneous collection of proliferations. The standard classification of ovarian neoplasms is the system developed by the World Health Organization in 1973; various studies, however, have found that observer variability for problematic cases is substantial. Prognosis and quality assurance make this variability a major concern. The authors examine the reasons behind this variability, the theories behind classification systems in general, problems of taxonomy, and the significance of confidence intervals. Appendices develop more fully the authors' approach to problems of classification and interobserver agreement, with notes on specific differentiated types of ovarian neoplasms.


BCG vaccination in patients with severe combined immunodeficiency: complications, risks, and vaccination policies.
Severe combined immunodeficiency (SCID) is a syndrome characterized by profound T-cell deficiency. BCG vaccine is contraindicated in patients with SCID. Because most countries encourage BCG vaccination at birth, a high percentage of patients with SCID are vaccinated before their immune defect is detected. We sought to describe the complications and risks associated with BCG vaccination in patients with SCID. An extensive standardized questionnaire evaluating complications, therapeutics, and outcomes regarding BCG vaccination in patients given a diagnosis of SCID was widely distributed. Summary statistics and association analysis was performed. Data on 349 BCG-vaccinated patients with SCID from 28 centers in 17 countries were analyzed. Fifty-one percent of the patients had BCG-associated complications, 34% disseminated and 17% localized (a 33,000- and 400-fold increase, respectively, over the general population). Patients receiving early vaccination (≤1 month) showed an increased prevalence of complications (P = .006) and death caused by BCG-associated complications (P < .0001). The odds of experiencing complications among patients with T-cell numbers of 250/μL or less at diagnosis was 2.1 times higher (95% CI, 1.4-3.4 times higher; P = .001) than among those with T-cell numbers of greater than 250/μL. BCG-associated complications were reported in 2 of 78 patients who received antimycobacterial therapy while asymptomatic, and no deaths caused by BCG-associated complications occurred in this group. In contrast, 46 BCG-associated deaths were reported among 160 patients treated with antimycobacterial therapy for a symptomatic BCG infection (P < .0001). BCG vaccine has a very high rate of complications in patients with SCID, which increase morbidity and mortality rates. Until safer and more efficient antituberculosis vaccines become available, delay in BCG vaccination should be considered to protect highly vulnerable populations from preventable complications.


Phenotype-associated sequence variation in the third variable domain of the human immunodeficiency virus type 1 gp120 molecule.
The third variable (V3) domain has been implicated in determining the human immunodeficiency virus (HIV) phenotype, including fusion capacity and monocytotropism. In a large set of primary HIV type 1 (HIV-1) isolates, V3 sequence analysis revealed that fast-replicating, syncytium-inducing isolates contained V3 sequences with a significantly higher positive charge than those of slow-replicating, non-syncytium-inducing monocytotropic isolates. It appeared that these differences in charge could be attributed to highly variable amino acid residues located on either side of the V3 loop, midway between the cysteine residues and the central GPG motif. In non-syncytium-inducing monocytotropic isolates, these residues were negatively charged or uncharged, whereas in syncytium-inducing nonmonocytotropic isolates, either one or both were positively charged. The substitutions at these positions result in changes in the predicted secondary structure of the V3 loop. Our data suggest that two amino acid residues in the highly variable V3 domain are responsible for phenotype differences and point to conformational differences in V3 loops from phenotypically distinct HIV-1 isolates.


THE DIFFERENTIATION OF CELLS AS A CRITERION FOR CELL IDENTIFICATION, CONSIDERED IN RELATION TO THE SMALL CORTICAL CELLS OF THE THYMUS.
The main problem which has been considered in this paper is the identification of the small thymus cells. Cells resembling ?A infiltrate the cortical layer of the thymus. Whether these cells are true lymph cells, or whether they merely represent a disguised epithelial cell, could not be solved either by purely histological or by histo- and embryogenetic studies. Text-fig. 1 gives a scheme for the differentiation of the small thymus cells and the small lymphocytes, which led to a conception of the lymphoid nature of the small thymus cells. On the left of the figure is shown the origin and the normal differentiation of the small lymphocytes and their mother cells in birds. The source of the lymphoid cells is the loose mesenchyme. The small lymphocytes (S. Lmc.), normally situated in the spleen, in the connective tissue, and in the bone marrow, appear as differentiation products of the lymphoid hemocytoblasts (L. Hbl.), especially when the latter multiply intensely in a limited space, become smaller (S. L. Hbl.), and finally change their morphological structure. The small lymphocytes may themselves under definite conditions undergo further differentiation and develop into plasma cells (Plc.) and into granular lymphocytes (Gr. Lmc.), specific for birds. The mother cells of the small lymphocytes, the lymphoid hemocytoblasts, on the other hand, differentiate in granulopoietic organs (spleen, bone marrow) into granulocytoblasts (Grbl.) and granulocytes (Grc. (Lkc.) ). The histogenetic study of cell ?A shows that its nearest stem cells are represented by the cells ?B and ?C (page 93). The striking similarity in the structure of cell ?A with that of the small lymphocyte (on the left of the text-figure), as well as the analogy of the process of its differentiation, at the expense of cells ?B and ?C, with the normal origin of the small lymphocytes, has led many investigators to accept the mesenchymal origin of the small thymus cells. According to this view, cell ?A becomes a true small lymphocyte. In addition to this is the observation of an invasion of the epithelial thymus anlage by mesenchymal elements. According to the transformation theory cell ?A has become a disguised epithelial cell. The same was admitted for their stem cells ?B and ?C. As mentioned above, many characteristic morphological features of cell structure were shown to be not as essential as previously admitted. Nerve cells and epithelial and connective tissue cells may all assume a spherical shape in a liquid medium. How then are we to regard the small thymus cell ?A ? If the mother cell of the thymus cell ?A is really a lymphoid hemocytoblast, it must possess the differentiation potentialities of a true lymphoid hemocytoblast; it must have the faculty of differentiating not only into small lymphocytes but also into granulocytoblasts (Grbl.'') and further into granulocytes (Grc. (Lkc.)''). If the small thymus cell ?A is a small lymphocyte it must under definite conditions be able to differentiate in the directions characteristic of true small lymphocytes; namely, into plasma cells (Plc.'') and into granular lymphocytes (Gr. Lmc.''). The existence of these possibilities for differentiation of the small thymus cells ?A and their stem cells ?C have been experimentally proved by this study. It has been shown that the mother cell ?C may under certain conditions proliferate intensely and differentiate into granulocytoblasts and granular leukocytes. This is probably due to the stimulating action of certain metabolic products of the grafted spleen cells. It has been also shown that the small thymus cell ?A may differentiate physiologically into a granular lymphocyte, and under administration of x-ray into a plasma cell. All the changes observed on the small thymus cells and their mother cells apply under equal conditions to the lymphoid hemocytoblasts and to the true small lymphocytes in the regions of the organism where these cells are present.


Environmentally toxicant exposures induced intragenerational transmission of liver abnormalities in mice.
Environmental toxicants such as chemicals, heavy metals, and pesticides have been shown to promote transgenerational inheritance of abnormal phenotypes and/or diseases to multiple subsequent generations following parental and/or ancestral exposures. This study was designed to examine the potential transgenerational action of the environmental toxicant trichloroethane (TCE) on transmission of liver abnormality, and to elucidate the molecular etiology of hepatocyte cell damage. A total of thirty two healthy immature female albino mice were randomly divided into three equal groups as follows: a sham group, which did not receive any treatment; a vehicle group, which received corn oil alone, and TCE treated group (3 weeks, 100 μg/kg i.p., every 4th day). The F0 and F1 generation control and TCE populations were sacrificed at the age of four months, and various abnormalities histpathologically investigated. Cell death and oxidative stress indices were also measured. The present study provides experimental evidence for the inheritance of environmentally induced liver abnormalities in mice. The results of this study show that exposure to the TCE promoted adult onset liver abnormalities in F0 female mice as well as unexposed F1 generation offspring. It is the first study to report a transgenerational liver abnormalities in the F1 generation mice through maternal line prior to gestation. This finding was based on careful evaluation of liver histopathological abnormalities, apoptosis of hepatocytes, and measurements of oxidative stress biomarkers (lipid peroxidation, protein carbonylation, and nitric oxide) in control and TCE populations. There was an increase in liver histopathological abnormalities, cell death, and oxidative lipid damage in F0 and F1 hepatic tissues of TCE treated group. In conclusion, this study showed that the biological and health impacts of environmental toxicant TCE do not end in maternal adults, but are passed on to offspring generations. Hence, linking observed liver abnormality in the offspring to environmental exposure of their parental line. This study also illustrated that oxidative stress and apoptosis appear to be a molecular component of the hepatocyte cell injury.


Imaging the Respiratory Effects of Opioids in the Human Brain.
Opioid analgesia is limited by the potentially fatal side effect of respiratory depression. In humans the brain mechanisms of opioid-induced respiratory depression are poorly understood. Investigating pharmacological influences upon breathing helps us to understand better the brain's respiratory control networks. Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (FMRI) maps neuronal activity in the brain, and is therefore a potentially useful, noninvasive technique to investigate the functional neuroanatomy of respiratory control in humans. Contrast in FMRI is derived from the vascular response to brain activity (neurovascular coupling). Therefore, FMRI studies of the neuronal effects of opioids are rendered more complex by the nonneuronal effects of opioids including those on systemic physiology, cerebral blood flow, and direct effects on the cerebral vasculature such as altered vascular reactivity. Here we review our series of studies that dissect the vascular and neuronal breathing-related effects of opioids in the brain. These methodological considerations have enabled successful FMRI studies revealing the brain networks responsible for opioid effects upon respiratory awareness. Similar considerations would be necessary for FMRI studies in hypoxia or in disease states that affect the physiological state of the brain.


Caffeic acid phenethyl ester (CAPE) reverses fibrosis caused by chronic colon inflammation in murine model of colitis.
Fibrosis is known to be the hallmarks of chronic inflammation of the bowel. Epithelial damage due to inflammation compromises the barrier function of the gastrointestinal tract. This barrier dysfunction leads to further spread of inflammation resulting in a chronic state of inflammation. This chronic inflammation leads to development of fibrosis, which has very limited therapeutic options and usually requires surgical removal of the affected tissue. Our previous work has shown that Caffeic acid phenethyl ester (CAPE) is a naturally occurring anti-inflammatory agent, found in propolis, has been found to be protective in experimental colitis via enhancement of epithelial barrier function. However, the impact of CAPE on resolution of fibrosis in the long-term is unknown. The aim of this follow up study was to investigate the effect of CAPE on colon fibrosis in a chronic model of Dextran sulphate sodium induced colitis in mice. Dextran sulphate sodium (DSS) 2.5% w/v was administered in drinking water to induce colitis in C57/BL6 mice for 5 days on the 6th day DSS was stopped and test group mice were treated with intraperitoneal administration of CAPE (30 mg kg-1 day-1) for a further 7 days. Disease activity index (DAI) score, colon length and tissue histology and level of tissue fibrosis was observed. CAPE-treated mice had significantly lower levels of DAI, tissue inflammation scores and fibrosis as compared with control group. Our results show that CAPE is effective in resolving colon fibrosis in chronic inflammation. Thus, we can conclude CAPE could be a potential therapeutic agent for further clinical investigations for treatment of fibrosis in inflammatory bowel diseases in humans.


What research evidence is there for the use of art therapy in the management of symptoms in adults with cancer? A systematic review.
Common psychosocial difficulties experienced by cancer patients are fatigue, depression, anxiety, and existential and relational concerns. Art therapy is one intervention being developed to address these difficulties. The purpose of this research was to assess and synthesize the available research evidence for the use of art therapy in the management of symptoms in adults with cancer. A literature search of electronic databases, 'grey' literature, hand searching of key journals, and personal contacts was undertaken. Keywords searched were 'art therapy' and 'cancer' or 'neoplasm'. The inclusion criteria were: research studies of any design; adult cancer population; and art therapy intervention. There were no language or date restrictions. Data extraction occurred and quality appraisal was undertaken. Data were analyzed using narrative synthesis. Fourteen papers reporting 12 studies met the inclusion criteria. Symptoms investigated spanned emotional, physical, social and global functioning, and existential/spiritual concerns. Measures used were questionnaires, in-depth interviews, patients' artwork, therapists' narratives of sessions, and stress markers in salivary samples. No overall effect size was determined owing to heterogeneity of studies. Narrative synthesis of the studies shows art therapy is used at all stages of the cancer trajectory, most frequently by women, the most common cancer site in participants being breast. Art therapy is a psychotherapeutic approach that is being used by adults with cancer to manage a spectrum of treatment-related symptoms and facilitate the process of psychological readjustment to the loss, change, and uncertainty characteristic of cancer survivorship. Research in this area is still in its infancy.


Long-range ordered carbon clusters: a crystalline material with amorphous building blocks.
Solid-state materials can be categorized by their structures into crystalline (having periodic translation symmetry), amorphous (no periodic and orientational symmetry), and quasi-crystalline (having orientational but not periodic translation symmetry) phases. Hybridization of crystalline and amorphous structures at the atomic level has not been experimentally observed. We report the discovery of a long-range ordered material constructed from units of amorphous carbon clusters that was synthesized by compressing solvated fullerenes. Using x-ray diffraction, Raman spectroscopy, and quantum molecular dynamics simulation, we observed that, although carbon-60 cages were crushed and became amorphous, the solvent molecules remained intact, playing a crucial role in maintaining the long-range periodicity. Once formed, the high-pressure phase is quenchable back to ambient conditions and is ultra-incompressible, with the ability to indent diamond.


The N and C-termini of SPCA2 regulate differently Kv10.1 function: role in the collagen 1-induced breast cancer cell survival.
It's now clearly established that the tumor microenvironment participates to tumor development. Among the different actors contributing to these processes, ion channels, located at the cancer cell surface, play a major role. We recently demonstrated that the association of Kv10.1, Orai1 and SPCA2 is crucial to promote the collagen-induced survival of MCF-7 breast cancer cells. By using siRNA directed against SPCA2, we shown that this protein is involved in the regulation of the activity, the expression and the sub-cellular localization of Kv10.1. In addition, it has been demonstrated that SPCA2 is involved in SICE in MCF-7 cells and that the N- and the C-terminal parts of this protein are necessary to interact and to produce Ca2+ entry. However, no information is available about the necessary SPCA2's important region to regulate Kv10.1. The aim of our work is to evaluate how SPCA2 could interact with Kv10.1 channel to induce survival promotion. By using different SPCA2 mutants, we evaluate the role of the N- and C-terminal sections on the expression and the activity of Kv10.1 channels. In addition, we analyzed the impact of these deletions on the collagen 1-induced cell survival. Our results bring out new information about the regulation of Kv10.1 channel through SPCA2. More specifically how the N- and C-terminus of this Ca2+ transporter regulate Kv10.1 expression, trafficking, and function suggesting new opportunities to target Kv10.1 channels in cancer progression.


The use of European shag pellets as indicators of microplastic fibers in the marine environment.
Microplastic particles are abundant marine pollutants that are ingested by many seabirds. Some seabirds regurgitate non-digestible materials in the form of pellets and their analysis may be useful to study the abundance of plastic debris at the local scale. Here, we aimed to provide baseline data for the presence of microplastics in pellets regurgitated by European shags (Phalacrocorax aristotelis) (n = 41) in the Iberia peninsula (NW Spain). We found microplastic fibers in 63% of pellets, suggesting that this type of plastic pollution is prevalent in the study area. According to Fourier Transform Infrared spectrometry, nylon fibers were the most abundant, followed by polyester. We also found that the presence of microplastics was higher in pellets containing remains of benthic fishes. Our results suggest that shag pellets may be useful to monitor microplastic pollution in coastal waters.


Development of fatness, fitness, and lifestyle from adolescence to the age of 36 years: determinants of the metabolic syndrome in young adults: the amsterdam growth and health longitudinal study.
Among young adults, the metabolic syndrome is an increasingly frequent risk factor for cardiovascular disease. Its determinants are, however, incompletely understood. We investigated the time course, from adolescence (age, 13 years) to young adulthood (age, 36 years), of important potential determinants (body fatness and fat distribution, cardiopulmonary fitness, and lifestyle) in 364 individuals (189 women). Data were derived from the Amsterdam Growth and Health Longitudinal Study and analyzed with the use of generalized estimating equations. The prevalence of the metabolic syndrome at the age of 36 years, as identified with a modified National Cholesterol Education Program definition of the syndrome, was 10.4%. Subjects with the metabolic syndrome at the age of 36 years, compared with those without the syndrome, had (from adolescence to the age of 36 years) the following: (1) a more marked increase in total body fatness and in subcutaneous trunk fat; (2) a more marked decrease in cardiopulmonary fitness levels; (3) a more marked increase in physical activities of light-to-moderate intensity, but a more marked decrease in hard physical activities; (4) a trend toward a higher energy intake throughout the years; and (5) a decreased likelihood of drinking alcoholic beverages. Fatness, fitness, and lifestyle are important determinants of the metabolic syndrome in young adults. More important, these associations were independent of each other and, therefore, represent separate potential targets for the prevention of the metabolic syndrome. Our study further suggests that intervening early in life (eg, in the period of transition from adolescence to adulthood) may be a fruitful area for prevention of the metabolic syndrome.


New Graduate Nurses' Developmental Trajectories for Capability Beliefs Concerning Core Competencies for Healthcare Professionals: A National Cohort Study on Patient-Centered Care, Teamwork, and Evidence-based Practice.
This study aimed to describe the developmental trajectories of registered nurses' capability beliefs during their first 3 years of practice. The focus was on three core competencies for health professionals-patient-centered care, teamwork, and evidence-based practice. A national cohort of registered nurses (n = 1,205) was recruited during their nursing education and subsequently surveyed yearly during the first 3 years of working life. The survey included 16 items on capability beliefs divided into three subscales for the assessment of patient-centered care, teamwork, and evidence-based practice, and the data were analyzed with linear latent growth modeling. The nurses' capability beliefs for patient-centered care increased over the three first years of working life, their capability beliefs for evidence-based practice were stable over the 3 years, and their capability beliefs for teamwork showed a downward trend. Through collaboration between nursing education and clinical practice, the transition to work life could be supported and competence development in newly graduated nurses could be enhanced to help them master the core competencies. Future research should focus on determining which factors impact the development of capability beliefs in new nurses and how these factors can be developed by testing interventions.


MYC as Therapeutic Target for Embryonal Tumors: Potential and Challenges.
The MYC family plays essential roles during brain development and their oncogenic deregulation is implicated in the formation of embryonal neural tumors such as medulloblastomas (MB) and neuroblastoma (NB). Amplification of the MYCN is the predominant marker for aggressive NB and correlates with poor prognosis, while c-MYC overexpression is a defining feature of MB subgroups inflected with aggressive biological behavior and increased likelihood of metastasis. Not surprisingly MYC has emerged as an attractive target for pediatric neural cancer therapy. However despite three decades of intensive research in MYC biology and an impressive number of 30,000 publications, inhibition of MYC as therapeutic strategy remains an elusive goal in cancer medicine. This review discusses the potential and challenges of targeting the oncogenic effects of MYC as therapeutic strategy for MYC over-expressing embryonal neural tumors where current therapies are inadequate.


The effect of various types of motorcycle helmets on cervical spine injury in head injury patients: a multicenter study in Taiwan.
The relationship between cervical spine injury (CSI) and helmet in head injury (HI) patients following motorcycle crashes is crucial. Controversy still exists; therefore we evaluated the effect of various types of helmets on CSI in HI patients following motorcycle crashes and researched the mechanism of this effect. A total of 5225 patients of motorcycle crashes between 2000 and 2009 were extracted from the Head Injury Registry in Taiwan. These patients were divided into case and control groups according to the presence of concomitant CSI. Helmet use and types were separately compared between the two groups and the odds ratio of CSI was obtained by using multiple logistic regression analysis. We observed that 173 (3.3%) of the HI patients were associated with CSI. The HI patients using a helmet (odds ratio (OR) = 0.31, 95% confidence interval (CI) = 0.19-0.49), full-coverage helmet (0.19, 0.10-0.36), and partial-coverage helmet (0.35, 0.21-0.56) exhibited a significantly decreased rate of CSI compared with those without a helmet. Wearing full-coverage and partial-coverage helmets significantly reduced the risk of CSI among HI patients following motorcycle crashes. This effect may be due to the smooth surface and hard padding materials of helmet.


Medical management and the decline in mortality from coronary heart disease.
The contribution of resuscitation before admission to hospital, coronary care units, treatment with beta blockers after myocardial infarction, coronary artery bypass surgery, and the treatment of hypertension to the decline in mortality from coronary heart disease in Auckland between 1974 and 1981 was assessed by using data from several population based studies. There were 126 fewer deaths from coronary heart disease in Auckland in 1981 than expected from the 1974 rates among people less than 70 years. The specific medical interventions probably accounted for about 51 (40%) of the 126 fewer deaths. Local data indicate that resuscitation before admission to hospital was responsible for 20 (16%) of the 126 fewer deaths. Projections based on local data and trials carried out overseas suggest that up to 15 (12%) of the 126 fewer deaths were due to the treatment of hypertension. Coronary care units and the use of beta blockers after myocardial infarction were estimated to be responsible for six (5%) and three (2%) of the 126 fewer deaths, respectively. The impact of coronary surgery was especially difficult to determine in the absence of appropriate randomised controlled trial data. Estimates of its contribution ranged from seven to 23 (5% to 18%) of the 126 fewer deaths.


Accuracy of commercially available c-reactive protein rapid tests in the context of undifferentiated fevers in rural Laos.
C-Reactive Protein (CRP) has been shown to be an accurate biomarker for discriminating bacterial from viral infections in febrile patients in Southeast Asia. Here we investigate the accuracy of existing rapid qualitative and semi-quantitative tests as compared with a quantitative reference test to assess their potential for use in remote tropical settings. Blood samples were obtained from consecutive patients recruited to a prospective fever study at three sites in rural Laos. At each site, one of three rapid qualitative or semi-quantitative tests was performed, as well as a corresponding quantitative NycoCard Reader II as a reference test. We estimate the sensitivity and specificity of the three tests against a threshold of 10 mg/L and kappa values for the agreement of the two semi-quantitative tests with the results of the reference test. All three tests showed high sensitivity, specificity and kappa values as compared with the NycoCard Reader II. With a threshold of 10 mg/L the sensitivity of the tests ranged from 87-98 % and the specificity from 91-98 %. The weighted kappa values for the semi-quantitative tests were 0.7 and 0.8. The use of CRP rapid tests could offer an inexpensive and effective approach to improve the targeting of antibiotics in remote settings where health facilities are basic and laboratories are absent. This study demonstrates that accurate CRP rapid tests are commercially available; evaluations of their clinical impact and cost-effectiveness at point of care is warranted.


Positional cloning of the wheat vernalization gene VRN1.
Winter wheats require several weeks at low temperature to flower. This process, vernalization, is controlled mainly by the VRN1 gene. Using 6,190 gametes, we found VRN1 to be completely linked to MADS-box genes AP1 and AGLG1 in a 0.03-centimorgan interval flanked by genes Cysteine and Cytochrome B5. No additional genes were found between the last two genes in the 324-kb Triticum monococcum sequence or in the colinear regions in rice and sorghum. Wheat AP1 and AGLG1 genes were similar to Arabidopsis meristem identity genes AP1 and AGL2, respectively. AP1 transcription was regulated by vernalization in both apices and leaves, and the progressive increase of AP1 transcription was consistent with the progressive effect of vernalization on flowering time. Vernalization was required for AP1 transcription in apices and leaves in winter wheat but not in spring wheat. AGLG1 transcripts were detected during spike differentiation but not in vernalized apices or leaves, suggesting that AP1 acts upstream of AGLG1. No differences were detected between genotypes with different VRN1 alleles in the AP1 and AGLG1 coding regions, but three independent deletions were found in the promoter region of AP1. These results suggest that AP1 is a better candidate for VRN1 than AGLG1. The epistatic interactions between vernalization genes VRN1 and VRN2 suggested a model in which VRN2 would repress directly or indirectly the expression of AP1. A mutation in the promoter region of AP1 would result in the lack of recognition of the repressor and in a dominant spring growth habit.


Yoga for Teens With Irritable Bowel Syndrome: Results From a Mixed-Methods Pilot Study.
Irritable bowel syndrome (IBS) is a common condition associated with recurrent abdominal pain and altered bowel habits. It is particularly pernicious to youth, who may withdraw from life tasks due to pain, diarrhea, and/or fear of symptoms. Emotional stress exacerbates IBS symptoms, and mind-body interventions may be beneficial. In this mixed-methods study of 18 teens aged 14 to 17 years undertaking a 6-week Iyengar yoga intervention, we aimed to identify treatment responders and to explore differences between responders and nonresponders on a range of quantitative outcomes and qualitative themes related to yoga impact, goodness of fit, and barriers to treatment. Half of the teens responded successfully to yoga, defined as a clinically meaningful reduction in abdominal pain. Responders differed from nonresponders on postintervention quantitative outcomes, including reduced abdominal pain, improved sleep, and increased visceral sensitivity. Qualitative outcomes revealed that responders reported generalized benefits early in treatment and that their parents were supportive and committed to the intervention. Responders and nonresponders alike noted the importance of home practice to achieve maximal, sustained benefits. This study reveals the need for developmentally sensitive yoga programs that increase accessibility of yoga for all patients.


Controller Medication Use and Exacerbations for Children and Adults With Asthma in High-Deductible Health Plans.
High-deductible health plans (HDHPs) are increasingly common and associated with decreased medication use in some adult populations. How children are affected is less certain. To examine the association between HDHP enrollment and asthma controller medication use and exacerbations. For this longitudinal cohort study with a difference-in-differences design, data were obtained from a large, national, commercial (and Medicare Advantage) administrative claims database between January 1, 2002, and December 31, 2014. Children aged 4 to 17 years and adults aged 18 to 64 years with persistent asthma who switched from traditional plans to HDHPs or remained in traditional plans (control group) by employer choice during a 24-month period were identified. A coarsened exact matching technique was used to balance the groups on characteristics including employer and enrollee propensity to have HDHPs. In most HDHPs, asthma medications were exempt from the deductible and subject to copayments. Statistical analyses were conducted from August 13, 2019, to January 19, 2021. Employer-mandated HDHP transition. Thirty-day fill rates and adherence (based on proportion of days covered [PDC]) were measured for asthma controller medications (inhaled corticosteroid [ICS], leukotriene inhibitors, and ICS long-acting β-agonists [ICS-LABAs]). Asthma exacerbations were measured by rates of oral corticosteroid bursts and asthma-related emergency department visits among controller medication users. The HDHP group included 7275 children (mean [SD] age, 10.8 [3.3] years; 4402 boys [60.5%]; and 5172 non-Hispanic White children [71.1%]) and 17 614 adults (mean [SD] age, 41.1 [13.4] years; 10 464 women [59.4%]; and 12 548 non-Hispanic White adults [71.2%]). The matched control group included 45 549 children and 114 141 adults. Compared with controls, children switching to HDHPs experienced significant absolute decreases in annual 30-day fills only for ICS-LABA medications (absolute change, -0.04; 95% CI, -0.07 to -0.01). Adults switching to HDHPs did not have significant reductions in 30-day fills for any controllers. There were no statistically significant differences in PDC, oral steroid bursts, or asthma-related emergency department visits for children or adults. For the 9.9% of HDHP enrollees with health savings account-eligible HDHPs that subjected medications to the deductible, there was a significant absolute decrease in PDC for ICS-LABA compared with controls (-4.8%; 95% CI, -7.7% to -1.9%). This cohort study found that in a population where medications were exempt from the deductible for most enrollees, HDHP enrollment was associated with minimal or no reductions in controller medication use for children and adults and no change in asthma exacerbations. These findings suggest a potential benefit from exempting asthma medications from the deductible in HDHPs.


Dysregulated Arl1, a regulator of post-Golgi vesicle tethering, can inhibit endosomal transport and cell proliferation in yeast.
Small monomeric G proteins regulated in part by GTPase-activating proteins (GAPs) are molecular switches for several aspects of vesicular transport. The yeast Gcs1 protein is a dual-specificity GAP for ADP-ribosylation factor (Arf) and Arf-like (Arl)1 G proteins, and also has GAP-independent activities. The absence of Gcs1 imposes cold sensitivity for growth and endosomal transport; here we present evidence that dysregulated Arl1 may cause these impairments. We show that gene deletions affecting the Arl1 or Ypt6 vesicle-tethering pathways prevent Arl1 activation and membrane localization, and restore growth and trafficking in the absence of Gcs1. A mutant version of Gcs1 deficient for both ArfGAP and Arl1GAP activity in vitro still allows growth and endosomal transport, suggesting that the function of Gcs1 that is required for these processes is independent of GAP activity. We propose that, in the absence of this GAP-independent regulation by Gcs1, the resulting dysregulated Arl1 prevents growth and impairs endosomal transport at low temperatures. In cells with dysregulated Arl1, an increased abundance of the Arl1 effector Imh1 restores growth and trafficking, and does so through Arl1 binding. Protein sequestration at the trans-Golgi membrane by dysregulated, active Arl1 may therefore be the mechanism of inhibition.


Host-seeking stimulant for parasite of corn earworm: isolation, identification, and synthesis.
13-Methylhentriacontane has been identified in the feces and larvae of the corn earworm, Heliothis zea (Boddie), as the major constituent that triggers the short-range host-seeking response of the parasite Microplitis croceipes (Cresson). This chemical, the first found that mediates the complex host-parasite relation, could upgrade present efforts to use parasites for insect control. Bioassay of closely related compounds indicated that the structural requirements for activity are remarkably specific.


Role of Src in C3 transient receptor potential channel function and evidence for a heterogeneous makeup of receptor- and store-operated Ca2+ entry channels.
Receptor-operated Ca2+ entry (ROCE) and store-operated Ca2+ entry (SOCE) are known to be inhibited by tyrosine kinase inhibitors and activation of C-type transient receptor potential channel (TRPC) isoform 3 (TRPC3), a cation channel thought to be involved in SOCE and/or ROCE, was recently shown to depend on src tyrosine kinase activity. What is not known is the step at which src acts on TRPC3 and whether the role for tyrosine kinases in ROCE or SOCE is a general phenomenon. Using in vitro and in cell protein-protein interaction assays we now report that src phosphorylates TRPC3 at Y226 and that formation of phospho-Y226 is essential for TRPC3 activation. This requirement is unique for TRPC3 because (i) mutation of the cognate tyrosines of the closely related TRPC6 and TRPC7 had no effect; (ii) TRPC6 and TRPC7 were activated in src-, yes-, and fyn-deficient cells; and (iii) src, but not yes or fyn, rescued TRPC3 activation in src-, yes-, and fyn-deficient cells. The Src homology 2 domain of src was found to interact with either the N or the C termini of all TRPCs, suggesting that other tyrosine kinases may play a role in ion fluxes mediated by TRPCs other than TRPC3. A side-by-side comparison of the effects of genistein (a general tyrosine kinase inhibitor) on endogenous ROCE and SOCE in mouse fibroblasts, HEK and COS-7 cells, and ROCE in HEK cells mediated by TRPC3, TRPC6, TRPC7, and TRPC5 showed differences that argue for ROCE and SOCE channels to be heterogeneous.


A complete set of human telomeric probes and their clinical application. National Institutes of Health and Institute of Molecular Medicine collaboration.
Human chromosomes terminate with specialized telomeric structures including the simple tandem repeat (TTAGGG)n and additional complex subtelomeric repeats. Unique sequence DNA for each telomere is located 100-300 kilobases (kb) from the end of most chromosomes. A high concentration of genes and a number of candidate genes for recognizable syndromes are known to be present in telomeric regions. The human telomeric regions represent a major diagnostic challenge in clinical cytogenetics, because most of the terminal bands are G negative, and cryptic deletions and translocations in the telomeric regions are therefore difficult to detect by conventional cytogenetic methods. In fact, several submicroscopic chromosomal abnormalities in patients with undiagnosed mental retardation or multiple congenital anomalies have been identified by other molecular methods such as DNA polymorphism analysis. To improve the sensitivity for deletion detection and to determine whether such cryptic rearrangements represent a significant source of human pathology that has not been previously appreciated, it would be valuable to have specific FISH probes for all human telomeres. We report here the isolation and characterization of a complete set of specific FISH probes representing each human telomere. As most of these clones are at a known distance of within 100-300 kb from the end of the chromosome arm, this provides a 10-fold improvement in deletion detection sensitivity compared with high-resolution cytogenetics (2-3 Mb resolution). While testing these probes, we serendipitously identified a family with multiple members carrying a cryptic 1q;11p rearrangement in the balanced or unbalanced state.


HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer.
Purpose: Resistance to anti-HER2 therapies in HER2+ breast cancer can occur through activation of alternative survival pathways or reactivation of the HER signaling network. Here we employed BT474 parental and treatment-resistant cell line models to investigate a mechanism by which HER2+ breast cancer can reactivate the HER network under potent HER2-targeted therapies.Experimental Design: Resistant derivatives to lapatinib (L), trastuzumab (T), or the combination (LR/TR/LTR) were developed independently from two independent estrogen receptor ER+/HER2+ BT474 cell lines (AZ/ATCC). Two derivatives resistant to the lapatinib-containing regimens (BT474/AZ-LR and BT474/ATCC-LTR lines) that showed HER2 reactivation at the time of resistance were subjected to massive parallel sequencing and compared with parental lines. Ectopic expression and mutant-specific siRNA interference were applied to analyze the mutation functionally. In vitro and in vivo experiments were performed to test alternative therapies for mutant HER2 inhibition.Results: Genomic analyses revealed that the HER2L755S mutation was the only common somatic mutation gained in the BT474/AZ-LR and BT474/ATCC-LTR lines. Ectopic expression of HER2L755S induced acquired lapatinib resistance in the BT474/AZ, SK-BR-3, and AU565 parental cell lines. HER2L755S-specific siRNA knockdown reversed the resistance in BT474/AZ-LR and BT474/ATCC-LTR lines. The HER1/2-irreversible inhibitors afatinib and neratinib substantially inhibited both resistant cell growth and the HER2 and downstream AKT/MAPK signaling driven by HER2L755S in vitro and in vivoConclusions: HER2 reactivation through acquisition of the HER2L755S mutation was identified as a mechanism of acquired resistance to lapatinib-containing HER2-targeted therapy in preclinical HER2-amplified breast cancer models, which can be overcome by irreversible HER1/2 inhibitors. Clin Cancer Res; 23(17); 5123-34. ©2017 AACR.


Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes.
Background Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. Methods The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). Although on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal. Conclusions In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal. (Funded by Janssen Research and Development; CANVAS and CANVAS-R ClinicalTrials.gov numbers, NCT01032629 and NCT01989754 , respectively.).


Epilepsy surveillance in normocephalic children with and without prenatal Zika virus exposure.
Children with Congenital Zika Syndrome and microcephaly are at high risk for epilepsy; however, the risk is unclear in normocephalic children with prenatal Zika virus (ZIKV) exposure [Exposed Children (EC)]. In this prospective cohort study, we performed epilepsy screening in normocephalic EC alongside a parallel group of normocephalic unexposed children [Unexposed Children (UC)]. We compared the incidence rate of epilepsy among EC and UC at one year of life to global incidence rates. Pregnant women were recruited from public health centers during the ZIKV outbreak in Grenada, West Indies and assessed for prior ZIKV infection using a plasmonic-gold platform that measures IgG antibodies in serum. Normocephalic children born to mothers with positive ZIKV results during pregnancy were classified as EC and those born to mothers with negative ZIKV results during and after pregnancy were classified as UC. Epilepsy screening procedures included a pediatric epilepsy screening questionnaire and video electroencephalography (vEEG). vEEG was collected using a multi-channel microEEG® system for a minimum of 20 minutes along with video recording of participant behavior time-locked to the EEG. vEEGs were interpreted independently by two pediatric epileptologists, who were blinded to ZIKV status, via telemedicine platform. Positive screening cases were referred to a local pediatrician for an epilepsy diagnostic evaluation. Epilepsy screens were positive in 2/71 EC (IR: 0.028; 95% CI: 0.003-0.098) and 0/71 UC. In both epilepsy-positive cases, questionnaire responses and interictal vEEGs were consistent with focal, rather than generalized, seizures. Both children met criteria for a clinical diagnosis of epilepsy and good seizure control was achieved with carbamazepine. Our results indicate that epilepsy rates are modestly elevated in EC. Given our small sample size, results should be considered preliminary. They support the use of epilepsy screening procedures in larger epidemiological studies of children with congenital ZIKV exposure, even in the absence of microcephaly, and provide guidance for conducting epilepsy surveillance in resource limited settings.


Atypical social modulation of imitation in autism spectrum conditions.
Appropriate modulation of imitation according to social context is important for successful social interaction. In the present study we subliminally primed high-functioning adults with ASC and age- and IQ-matched controls with either a pro- or non- social attitude. Following priming, an automatic imitation paradigm was used to acquire an index of imitation. Whereas imitation levels were higher for pro-socially primed relative to non-socially primed control participants, there was no difference between pro- and non- socially primed individuals with ASC. We conclude that high-functioning adults with ASC demonstrate atypical social modulation of imitation. Given the importance of imitation in social interaction we speculate that difficulties with the modulation of imitation may contribute to the social problems characteristic of ASC.


Measurements of the electric field of zero-point optical phonons in GaAs quantum wells support the Urbach rule for zero-temperature lifetime broadening.
We study a specific type of lifetime broadening resulting in the well-known exponential "Urbach tail" density of states within the energy gap of an insulator. After establishing the frequency and temperature dependence of the Urbach edge in GaAs quantum wells, we show that the broadening due to the zero-point optical phonons is the fundamental limit to the Urbach slope in high-quality samples. In rough analogy with Welton's heuristic interpretation of the Lamb shift, the zero-temperature contribution to the Urbach slope can be thought of as arising from the electric field of the zero-point longitudinal-optical phonons. The value of this electric field is experimentally measured to be 3 kV cm-1, in excellent agreement with the theoretical estimate.


Detailed T1-Weighted Profiles from the Human Cortex Measured in Vivo at 3 Tesla MRI.
Studies into cortical thickness in psychiatric diseases based on T1-weighted MRI frequently report on aberrations in the cerebral cortex. Due to limitations in image resolution for studies conducted at conventional MRI field strengths (e.g. 3 Tesla (T)) this information cannot be used to establish which of the cortical layers may be implicated. Here we propose a new analysis method that computes one high-resolution average cortical profile per brain region extracting myeloarchitectural information from T1-weighted MRI scans that are routinely acquired at a conventional field strength. To assess this new method, we acquired standard T1-weighted scans at 3 T and compared them with state-of-the-art ultra-high resolution T1-weighted scans optimised for intracortical myelin contrast acquired at 7 T. Average cortical profiles were computed for seven different brain regions. Besides a qualitative comparison between the 3 T scans, 7 T scans, and results from literature, we tested if the results from dynamic time warping-based clustering are similar for the cortical profiles computed from 7 T and 3 T data. In addition, we quantitatively compared cortical profiles computed for V1, V2 and V7 for both 7 T and 3 T data using a priori information on their relative myelin concentration. Although qualitative comparisons show that at an individual level average profiles computed for 7 T have more pronounced features than 3 T profiles the results from the quantitative analyses suggest that average cortical profiles computed from T1-weighted scans acquired at 3 T indeed contain myeloarchitectural information similar to profiles computed from the scans acquired at 7 T. The proposed method therefore provides a step forward to study cortical myeloarchitecture in vivo at conventional magnetic field strength both in health and disease.


Identification of molecular compartments and genetic circuitry in the developing mammalian kidney.
Lengthy developmental programs generate cell diversity within an organotypic framework, enabling the later physiological actions of each organ system. Cell identity, cell diversity and cell function are determined by cell type-specific transcriptional programs; consequently, transcriptional regulatory factors are useful markers of emerging cellular complexity, and their expression patterns provide insights into the regulatory mechanisms at play. We performed a comprehensive genome-scale in situ expression screen of 921 transcriptional regulators in the developing mammalian urogenital system. Focusing on the kidney, analysis of regional-specific expression patterns identified novel markers and cell types associated with development and patterning of the urinary system. Furthermore, promoter analysis of synexpressed genes predicts transcriptional control mechanisms that regulate cell differentiation. The annotated informational resource (www.gudmap.org) will facilitate functional analysis of the mammalian kidney and provides useful information for the generation of novel genetic tools to manipulate emerging cell populations.


Validation of the MUSIC Model of Academic Motivation Inventory: Evidence for Use With Veterinary Medicine Students.
The MUSIC® Model of Motivation is used to help instructors select strategies that can increase students' motivation and engagement in courses. The MUSIC model is comprised of five categories of strategies titled: empowerment, usefulness, success, interest, and caring. The purpose of this study was to examine the extent to which the MUSIC® Model of Academic Motivation Inventory (College Student version, short-form), demonstrates acceptable psychometric properties when used with students enrolled in a College of Veterinary Medicine. The inventory is comprised of five scales that correspond to the five MUSIC model components, and it measures the extent to which students perceive that: they have control in the course (empowerment); the activities in the course are useful to their future (usefulness); they can succeed in the course (success); the teaching activities and coursework are interesting (interest); and the instructor cares about students' learning and well-being (caring). The inventory has been validated for use with many different student populations, including students in different countries and of different ages (e.g., college students, middle and high school students, elementary school students). However, the inventory has not been validated for use with veterinary medicine students. We analyzed the data from 578 questionnaires that were obtained from students in six different courses at a College of Veterinary Medicine. We examined the psychometric properties of the MUSIC inventory by: (a) computing the internal consistency reliabilities for the scales; (b) calculating the fit indices and factor loadings obtained from confirmatory factor analyses; and (c) computing correlation coefficients between the inventory scales and students' self-reported effort in the course. The results provide evidence that the inventory demonstrates acceptable psychometric properties for use with veterinary medicine students. Consequently, the MUSIC Inventory can be used by researchers and instructors to assess students' motivation-related perceptions of courses.


Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial.
The alpha4beta2 nicotinic acetylcholine receptors (nAChRs) are linked to the reinforcing effects of nicotine and maintaining smoking behavior. Varenicline, a novel alpha4beta2 nAChR partial agonist, may be beneficial for smoking cessation. To assess efficacy and safety of varenicline for smoking cessation compared with sustained-release bupropion (bupropion SR) and placebo. Randomized, double-blind, parallel-group, placebo- and active-treatment-controlled, phase 3 clinical trial conducted at 19 US centers from June 19, 2003, to April 22, 2005. Participants were 1025 generally healthy smokers (> or =10 cigarettes/d) with fewer than 3 months of smoking abstinence in the past year, 18 to 75 years old, recruited via advertising. Participants were randomly assigned in a 1:1:1 ratio to receive brief counseling and varenicline titrated to 1 mg twice per day (n = 352), bupropion SR titrated to 150 mg twice per day (n = 329), or placebo (n = 344) orally for 12 weeks, with 40 weeks of nondrug follow-up. Primary outcome was the exhaled carbon monoxide-confirmed 4-week rate of continuous abstinence from smoking for weeks 9 through 12. A secondary outcome was the continuous abstinence rate for weeks 9 through 24 and weeks 9 through 52. For weeks 9 through 12, the 4-week continuous abstinence rates were 44.0% for varenicline vs 17.7% for placebo (odds ratio [OR], 3.85; 95% confidence interval [CI], 2.70-5.50; P<.001) and vs 29.5% for bupropion SR (OR, 1.93; 95% CI, 1.40-2.68; P<.001). Bupropion SR was also significantly more efficacious than placebo (OR, 2.00; 95% CI, 1.38-2.89; P<.001). For weeks 9 through 52, the continuous abstinence rates were 21.9% for varenicline vs 8.4% for placebo (OR, 3.09; 95% CI, 1.95-4.91; P<.001) and vs 16.1% for bupropion SR (OR, 1.46; 95% CI, 0.99-2.17; P = .057). Varenicline reduced craving and withdrawal and, for those who smoked while receiving study drug, smoking satisfaction. No sex differences in efficacy for varenicline were observed. Varenicline was safe and generally well tolerated, with study drug discontinuation rates similar to those for placebo. The most common adverse events for participants receiving active-drug treatment were nausea (98 participants receiving varenicline [28.1%]) and insomnia (72 receiving bupropion SR [21.9%]). Varenicline was significantly more efficacious than placebo for smoking cessation at all time points and significantly more efficacious than bupropion SR at the end of 12 weeks of drug treatment and at 24 weeks. clinicaltrials.gov Identifier: NCT00141206.


Analyses of IgA1 hinge glycopeptides in IgA nephropathy by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
This study was performed to analyze the structural variety of O-glycans on the IgA1 hinge in IgA nephropathy (IgAN). The IgA1 fragments containing the hinge glycopeptide (33-mer hinge peptide core (HP) + O-glycans) were separated from 13 IgAN patients, eight healthy control subjects, and 11 patients with other primary glomerulonephritides by pyridylethylation, trypsin treatment, and Jacalin affinity chromatography. Because of the use of Jacalin, only the Gal beta 1-3GalNAc residue containing IgA was analyzed. The molecular weights (MW) of the IgA1 fragments treated by the following sequential treatment by exoglycosidases were estimated using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry: (1) Sialidase treatment: the MW of the two observed peaks A and B were compatible with (A) HP + 4GalNAc + 4Gal and (B) HP + 5GalNAc + 4Gal. (2) Sialidase and galactosidase: the MW of the two identified peaks a and b were consistent with (a) HP + 4GalNAc and (b) HP + 5GalNAc. (3) Sialidase, galactosidase, and alpha-N-acetylgalactosaminidase. All subjects revealed one peak, indicating the 33-mer IgA1 hinge peptide core. The intensity rate of peak B/A was significantly decreased in the IgAN group (mean +/- SD, 1.01 +/- 0.08) compared with the negative control subjects (healthy group, 1.15 +/- 0.06, P = 0.0048; other glomerulonephritis group, 1.13 +/- 0.10, P = 0.0049; Scheffe's F test). These results suggested the presence of a defect in the Gal and/or GalNAc residues in the IgA1 hinge glycopeptides in IgAN.


Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein.
bcl-2, the prototypic cellular antiapoptotic gene, decreases Sindbis virus replication and Sindbis virus-induced apoptosis in mouse brains, resulting in protection against lethal encephalitis. To investigate potential mechanisms by which Bcl-2 protects against central nervous system Sindbis virus infection, we performed a yeast two-hybrid screen to identify Bcl-2-interacting gene products in an adult mouse brain library. We identified a novel 60-kDa coiled-coil protein, Beclin, which we confirmed interacts with Bcl-2 in mammalian cells, using fluorescence resonance energy transfer microscopy. To examine the role of Beclin in Sindbis virus pathogenesis, we constructed recombinant Sindbis virus chimeras that express full-length human Beclin (SIN/beclin), Beclin lacking the putative Bcl-2-binding domain (SIN/beclinDeltaBcl-2BD), or Beclin containing a premature stop codon near the 5' terminus (SIN/beclinstop). The survival of mice infected with SIN/beclin was significantly higher (71%) than the survival of mice infected with SIN/beclinDeltaBcl-2BD (9%) or SIN/beclinstop (7%) (P < 0.001). The brains of mice infected with SIN/beclin had fewer Sindbis virus RNA-positive cells, fewer apoptotic cells, and lower viral titers than the brains of mice infected with SIN/beclinDeltaBcl-2BD or SIN/beclinstop. These findings demonstrate that Beclin is a novel Bcl-2-interacting cellular protein that may play a role in antiviral host defense.


Nanometer-resolution electron microscopy through micrometers-thick water layers.
Scanning transmission electron microscopy (STEM) was used to image gold nanoparticles on top of and below saline water layers of several micrometers thickness. The smallest gold nanoparticles studied had diameters of 1.4 nm and were visible for a liquid thickness of up to 3.3 microm. The imaging of gold nanoparticles below several micrometers of liquid was limited by broadening of the electron probe caused by scattering of the electron beam in the liquid. The experimental data corresponded to analytical models of the resolution and of the electron probe broadening as function of the liquid thickness. The results were also compared with Monte Carlo simulations of the STEM imaging on modeled specimens of similar geometry and composition as used for the experiments. Applications of STEM imaging in liquid can be found in cell biology, e.g., to study tagged proteins in whole eukaryotic cells in liquid and in materials science to study the interaction of solid:liquid interfaces at the nanoscale.


Sustainable Food Security in the Mountains of Pakistan: Towards a Policy Framework.
The nature and causes of food and livelihood security in mountain areas are quite different to those in the plains. Rapid socioeconomic and environmental changes added to the topographical constraints have exacerbated the problem of food insecurity in the Hindu Kush-Himalayan (HKH) region. In Pakistan, food insecurity is significantly higher in the mountain areas than in the plains as a result of a range of biophysical and socioeconomic factors. The potential of mountain niche products such as fruit, nuts, and livestock has remained underutilized. Moreover, the opportunities offered by globalization, market integration, remittances, and non-farm income have not been fully tapped. This paper analyzes the opportunities and challenges of food security in Pakistan's mountain areas, and outlines a framework for addressing the specific issues in terms of four different types of area differentiated by agro-ecological potential and access to markets, information, and institutional services.