Drug-refractory aggression, self-injurious behavior, and severe tantrums in autism spectrum disorders: a chart review study.
Aggression, self-injurious behavior, and severe tantrums are impairing symptoms frequently experienced by individuals with autism spectrum disorders. Despite US Food and Drug Administration approval of two atypical antipsychotics targeting these symptoms in youth with autistic disorder, they remain frequently drug refractory. We define drug-refractory aggression, self-injurious behavior, and severe tantrums in people with autism spectrum disorders as behavioral symptoms requiring medication adjustment despite previous trials of risperidone and aripiprazole or previous trials of three psychotropic drugs targeting the symptom cluster, one of which was risperidone or aripiprazole. We reviewed the medical records of individuals of all ages referred to our clinic for autism spectrum disorder diagnostic evaluation, as well as pharmacotherapy follow-up notes for all people meeting autism spectrum disorder criteria, for drug-refractory symptoms. Among 250 consecutively referred individuals, 135 met autism spectrum disorder and enrollment criteria, and 53 of these individuals met drug-refractory symptom criteria. Factors associated with drug-refractory symptoms included age 12 years or older (p < 0.0001), diagnosis of autistic disorder (p = 0.0139), and presence of intellectual disability (p = 0.0273). This pilot report underscores the significance of drug-refractory aggression, self-injurious behavior, and severe tantrums; suggests the need for future study clarifying factors related to symptom development; and identifies the need for focused treatment study of this impairing symptom domain.


Antibiotic prescribing in public and private practice: a cross-sectional study in primary care clinics in Malaysia.
Antibiotic overuse is driving the emergence of antibiotic resistance worldwide. Good data on prescribing behaviours of healthcare providers are needed to support antimicrobial stewardship initiatives. This study examined the differences in antibiotic prescribing rates of public and private primary care clinics in Malaysia. We used data from the National Medical Care Survey (NMCS), a nationwide cluster sample of Malaysian public and private primary care clinics in 2014. NMCS contained demographic, diagnoses and prescribing from 129 public clinics and 416 private clinics. We identified all encounters who were prescribed antibiotic and analyse the prescribing rate, types of antibiotics, and diagnoses that resulted in antibiotic. Five thousand eight hundred ten encounters were prescribed antibiotics; antibiotic prescribing rate was 21.1 % (public clinics 6.8 %, private clinics 30.8 %). Antibiotic prescribing was higher in private clinics where they contributed almost 87 % of antibiotics prescribed in primary care. Upper respiratory tract infection (URTI) was the most frequent diagnosis in patients receiving antibiotic therapy and accounted for 49.2 % of prescriptions. Of the patients diagnosed with URTI, 46.2 % received antibiotic treatment (public 16.8 %, private 57.7 %). Penicillins, cephalosporins and macrolides were the most commonly prescribed antibiotics and accounted for 30.7, 23.6 and 16.0 % of all antibiotics, respectively. More recently available broad-spectrum antibiotics such as azithromycin and quinolones were more frequently prescribed in private clinics. Antibiotic prescribing rates are high in both public and private primary care settings in Malaysia, especially in the latter. This study provides evidence of excessive and inappropriate antibiotic prescribing for self-limiting conditions. These data highlights the needs for more concerted interventions targeting both prescribers and public. Improvement strategies should focus on reducing inappropriate prescribing.


The major histocompatibility complex haplotypes dictate and the background genes fine-tune the dominant versus the cryptic response profile of a T-cell determinant within a native antigen: relevance to disease susceptibility and vaccination.
The immune system of a healthy individual responds vigorously to foreign microbial antigens. However, all potentially immunogenic regions (determinants) within an antigen are not functionally of equal relevance in mediating host immunity against the pathogen. Moreover, some of these antigenic determinants are well processed and presented (immunodominant), while others are not revealed (cryptic) from the native antigen. Nevertheless, cryptic determinants are good immunogens in the pre-processed peptide form. Defining the factors influencing the dominance versus the crypticity of antigenic determinants is critical to advancing our understanding of the individual variations in host immunity to infection, autoantigens and vaccination. In this study based on a model antigen, hen eggwhite lysozyme (HEL), we describe that the major histocompatibility complex (MHC) haplotypes imprint and the non-MHC genes modify the dominance versus the crypticity of a specific antigenic determinant. Both the H-2(q)- and the H-2(d)-bearing mice raised potent response to native HEL, but responded differently to its determinant region 57-78, which was dominant in the H-2(q) but cryptic in the H-2(d) mice. The H-2(q)- but not the H-2(d)-bearing mice of three different genetic backgrounds yielded patterns of graded reactivity to epitope 57-78 showing the fine-tuning effect of the non-MHC genes. Interestingly, the F1 (H-2(q) x H-2(d)) mice retained the dominant response profile of the H-2(q) parent regardless of the contributing gender, and also responded to a new sub-determinant 61-75. These results highlight the genetic factors influencing the dominance/crypticity of a specific antigenic determinant.


Predictors of red cell folate level in women attempting pregnancy.
To identify predictors of red cell folate level in women attempting to become pregnant. Cohort study. A health maintenance organization serving the Minneapolis-St Paul, Minn, area. A total of 189 healthy, primarily white women aged 22 to 35 years enrolled in the Diana Project, a population-based prospective study of preconceptional and prenatal risks to reproductive outcomes. The sample represents 189 of 219 enrolled women who were sequentially selected from the total Diana Project sample to receive additional laboratory analyses. Red cell folate level. Folic acid supplements, folic acid intake from fortified cereals, vitamin C supplements, and serum zinc level (inverse) were found to predict red cell folate levels. Previous research has shown that red cell folate levels higher than 906 nmol/L (400 ng/mL) may be optimal for the prevention of folate-responsive neural tube defects. For folic acid supplement users, folate intakes of 450 microg per day and higher corresponded to these protective levels of red cell folate. In nonusers of supplements, intakes of more than 500 microg of folate per day from foods and folic acid-fortified cereals may be needed to attain red cell folate levels higher than 906 nmol/L (400 ng/mL). Red cell folate levels higher than 906 nmol/L (400 ng/mL) were primarily found in women who took folic acid supplements. Only 1 in 4 women had red cell folate levels higher than 906 nmol/L (400 ng/mL), while 1 in 8 had red cell folate levels indicative of a negative folate balance. Addition of a daily, 400-microg folic acid supplement to the usual diet would result in red cell folate levels over 906 nmol/L (400 ng/mL) in a majority of women in this study. Supplementation of diets of women of childbearing potential with 400 microg of folic acid per day would effectively raise red cell folate to levels associated with a low risk of folate-responsive neural tube defects. Protective levels of red cell folate may also be obtained by ample consumption of vegetables, fruits, and folic acid-fortified breakfast cereals. Efforts to increase folic acid supplement use and folate consumption among women of childbearing potential must go beyond fortification of refined cereal and grain products and reach women within all educational and income groups.


Fathers Matter: Involving and Engaging Fathers in the Child Welfare System Process.
Research suggests that children with involved and engaged fathers tend to have more positive outcomes relative to physical, cognitive, and social emotional health. Of children who become involved in the child welfare system, involving multiple parents in the case (e.g. mother and father) often results in a greater chance of a child returning home, fewer placement episodes, and reduced trauma that may be caused by separation anxiety. With the rise of single parenting homes (which are mostly maternal) in the United States, child welfare agencies are examining the efficacy of engaging multiple caregivers (esp. fathers) in the child welfare process. Research suggests that in order to involve fathers in child welfare processes, practices and policies must be intentional in implementing systems and protocols that encourage involvement of all parents regardless of relationship status of the parents. However, few child welfare agencies are required to inquire about fathers or involve fathers in the child's case. The purpose of this paper is to highlight efforts of the Connecticut Comprehensive Outcome Review (CCOR) process and discuss challenges and lessons learned from interviews and listening forums/focus groups that included social workers and fathers who are involved in the child welfare system in the state of Connecticut. Recommendations and considerations on engaging and involving fathers are discussed.


How common are long-lasting, intensely itching vaccination granulomas and contact allergy to aluminium induced by currently used pediatric vaccines? A prospective cohort study.
The frequency of long-lasting, intensely itching subcutaneous nodules at the injection site for aluminium (Al)-adsorbed vaccines (vaccination granulomas) was investigated in a prospective cohort study comprising 4,758 children who received either a diphtheria-tetanus-pertussis-polio-Haemophilus influenzae type b vaccine (Infanrix®, Pentavac®) alone or concomitant with a pneumococcal conjugate (Prevenar). Both vaccines were adsorbed to an Al adjuvant. Altogether 38 children (0.83 %) with itching granulomas were identified, epicutaneously tested for Al sensitisation and followed yearly. Contact allergy to Al was verified in 85 %. The median duration of symptoms was 22 months in those hitherto recovered. The frequency of granulomas induced by Infanrix® was >0.66 % and by Prevenar >0.35 %. The risk for granulomas increased from 0.63 to 1.18 % when a second Al-adsorbed vaccine was added to the schedule. Long-lasting itching vaccination granulomas are poorly understood but more frequent than previously known after infant vaccination with commonly used diphtheria-tetanus-pertussis-polio-Haemophilus influenzae type b and pneumococcal conjugate vaccines. The risk increases with the number of vaccines given. Most children with itching granulomas become contact allergic to aluminium. Itching vaccination granulomas are benign but may be troublesome and should be recognised early in primary health care to avoid unnecessary investigations, anxiety and mistrust.


A multinational outbreak of histoplasmosis following a biology field trip in the Ugandan rainforest.
Outbreaks of histoplasmosis have been increasingly reported in association with travel to endemic areas. Multiple outbreaks have been reported following travel to the Americas, but reports of pulmonary histoplasmosis in short-term immunocompetent travelers to Africa are rare. A biology student was referred to our unit with suspected pulmonary histoplasmosis following her return from a field trip in the Ugandan rainforest. The patient informed us that several of her multinational student colleagues on the same expedition had developed a similar illness. Using an alert in ProMED-mail and a questionnaire forwarded to each of the symptomatic students, we accumulated data on the other cases involved in this apparent outbreak of pulmonary histoplasmosis. Thirteen of 24 students developed respiratory symptoms following the expedition. Chest X-ray appearances were often suggestive of miliary tuberculosis but in most cases a final diagnosis of histoplasmosis was made (confirmed with serology in five cases, clinically diagnosed in six, and retrospectively suspected in two). Detailed questioning indicated that the likely source was a large hollow bat-infested tree within the rainforest. This is an unusual outbreak of histoplasmosis following short-term travel to Africa. Pulmonary histoplasmosis should always be considered in the differential diagnosis of an acute febrile respiratory illness in travelers returning from endemic areas or reporting activities suggesting exposure.


Site-Selective Copper-Catalyzed Amination and Azidation of Arenes and Heteroarenes via Deprotonative Zincation.
Arene amination is achieved by site-selective C-H zincation followed by copper-catalyzed coupling with O-benzoylhydroxylamines under mild conditions. Key to this success is ortho-zincation mediated by lithium amidodiethylzincate base that is effective for a wide range of arenes, including nonactivated arenes bearing simple functionalities such as fluoride, chloride, ester, amide, ether, nitrile, and trifluoromethyl groups as well as heteroarenes including indole, thiophene, pyridine, and isoquinoline. An analogous C-H azidation is also accomplished using azidoiodinane for direct introduction of a useful azide group onto a broad scope of arenes and heteroarenes. These new transformations offer rapid access to valuable and diverse chemical space of aminoarenes. Their broad applications in organic synthesis and drug discovery are demonstrated in the synthesis of novel analogues of natural product (-)-nicotine and antidepressant sertraline by late-stage amination and azidation reactions.


Transforming growth factor-beta 2 induces apoptosis of murine T cell clones without down-regulating bcl-2 mRNA expression.
Transforming growth factor-beta (TGF beta) is a potent immunosuppressive cytokine which inhibits the antigen (Ag)-dependent expansion of T cells both in vitro and in vivo by mechanisms not well defined yet. Here we report that exposure of interleukin (IL)-2-dependent T cell lines to TGF beta 2 results in apoptosis defined by morphology, nucleosomal size DNA fragmentation and in situ DNA end labeling. TGF beta 2-induced T cell apoptosis showed the following characteristics: (1) in contrast to the rapid evolution of apoptosis following IL-2 deprivation, apoptosis of T cells triggered by TGF beta 2 was delayed; (2) cycloheximide prevented TGF beta 2-induced apoptosis of CTLL-2 but not of OVA-7 T helper cells; (3) in contrast to apoptosis following IL-2 deprivation, TGF beta 2-mediated T cell apoptosis was not associated with decreased expression of the proto-oncogenes, bcl-2 or c-myc; (4) TGF beta 2-induced apoptosis was not restricted to IL-2-dependent T cell lines since the IL-4-dependent T cell line, CT.4S, as well as EL4 lymphoma cells, which grow independently of exogenous IL-2, were also susceptible to TGF beta 2-mediated apoptosis. Taken together, these data may present a novel mechanism of TGF beta 2-mediated suppression of T cell expansion in response to Ag and IL-2, the activation of the endogenous death program of apoptosis, which appears to operate independently of direct interactions of TGF beta 2 with the IL-2/IL-2 receptor system.


Relationships Between Cortically Mediated Attentional Dysfunction and Social Anxiety, Self-Focused Attention, and External Attention Bias.
Social anxiety disorder is characterized by a marked fear and avoidance of social situations or a fear of being evaluated by others. Although training for top-down attentional control has been an effective treatment for social anxiety disorder, few studies have demonstrated that individuals with social anxiety have top-down attentional dysfunction. This study used dichotic listening (DL) tasks to investigate the relationship between social anxiety and top-down attentional control over relevant brain activities. We also investigated relationships between both social situation-dependent self-focused attention and external attention bias and situation-independent attentional control. Thirty-six healthy participants underwent near-infrared spectroscopy scanning while performing top-down selective and divided attention DL tasks. Then, they undertook a speech task and completed a questionnaire to assess the degrees of their self-focused attention and external attention bias. The results showed that the degree of social fear and self-focused attention during the speech task were negatively correlated with scores on the selective attention task and with the activity of the left pars opercularis during the selective DL task, which were related to each other. These results suggest that a relationship exists between social fear, self-focused attention in a social situation, and top-down selective attentional dysfunction as assessed both behaviorally and by brain activity changes.


Genetic dissection of intermated recombinant inbred lines using a new genetic map of maize.
A new genetic map of maize, ISU-IBM Map4, that integrates 2029 existing markers with 1329 new indel polymorphism (IDP) markers has been developed using intermated recombinant inbred lines (IRILs) from the intermated B73xMo17 (IBM) population. The website http://magi.plantgenomics.iastate.edu provides access to IDP primer sequences, sequences from which IDP primers were designed, optimized marker-specific PCR conditions, and polymorphism data for all IDP markers. This new gene-based genetic map will facilitate a wide variety of genetic and genomic research projects, including map-based genome sequencing and gene cloning. The mosaic structures of the genomes of 91 IRILs, an important resource for identifying and mapping QTL and eQTL, were defined. Analyses of segregation data associated with markers genotyped in three B73/Mo17-derived mapping populations (F2, Syn5, and IBM) demonstrate that allele frequencies were significantly altered during the development of the IBM IRILs. The observations that two segregation distortion regions overlap with maize flowering-time QTL suggest that the altered allele frequencies were a consequence of inadvertent selection. Detection of two-locus gamete disequilibrium provides another means to extract functional genomic data from well-characterized plant RILs.


Dynamics of Cough Frequency in Adults Undergoing Treatment for Pulmonary Tuberculosis.
Cough is the major determinant of tuberculosis transmission. Despite this, there is a paucity of information regarding characteristics of cough frequency throughout the day and in response to tuberculosis therapy. Here we evaluate the circadian cycle of cough, cough frequency risk factors, and the impact of appropriate treatment on cough and bacillary load. We prospectively evaluated human immunodeficiency virus-negative adults (n = 64) with a new diagnosis of culture-proven, drug-susceptible pulmonary tuberculosis immediately prior to treatment and repeatedly until treatment day 62. At each time point, participant cough was recorded (n = 670) and analyzed using the Cayetano Cough Monitor. Consecutive coughs at least 2 seconds apart were counted as separate cough episodes. Sputum samples (n = 426) were tested with microscopic-observation drug susceptibility broth culture, and in culture-positive samples (n = 252), the time to culture positivity was used to estimate bacillary load. The highest cough frequency occurred from 1 pm to 2 pm, and the lowest from 1 am to 2 am (2.4 vs 1.1 cough episodes/hour, respectively). Cough frequency was higher among participants who had higher sputum bacillary load (P < .01). Pretreatment median cough episodes/hour was 2.3 (interquartile range [IQR], 1.2-4.1), which at 14 treatment days decreased to 0.48 (IQR, 0.0-1.4) and at the end of the study decreased to 0.18 (IQR, 0.0-0.59) (both reductions P < .001). By 14 treatment days, the probability of culture conversion was 29% (95% confidence interval, 19%-41%). Coughs were most frequent during daytime. Two weeks of appropriate treatment significantly reduced cough frequency and resulted in one-third of participants achieving culture conversion. Thus, treatment by 2 weeks considerably diminishes, but does not eliminate, the potential for airborne tuberculosis transmission.


Characterization of Mycobacterium tuberculosis diaminopimelic acid epimerase: paired cysteine residues are crucial for racemization.
Recently, the overproduction of Mycobacterium tuberculosis diaminopimelic acid (DAP) epimerase MtDapF in Escherichia coli using a novel codon alteration cloning strategy and the characterization of the purified enzyme was reported. In the present study, the effect of sulphydryl alkylating agents on the in vitro activity of M. tuberculosis DapF was tested. The complete inhibition of the enzyme by 2-nitro-5-thiocyanatobenzoate, 5,5'-dithio-bis(2-nitrobenzoic acid) and 1,2-benzisothiazolidine-3-one at nanomolar concentrations suggested that these sulphydryl alkylating agents modify functionally significant cysteine residues at or near the active site of the epimerase. Consequently, the authors extended the characterization of MtDapF by studying the role of the two strictly conserved cysteine residues. The putative catalytic residues Cys87 and Cys226 of MtDapF were replaced individually with both serine and alanine. Residual epimerase activity was detected for both the serine replacement mutants C87S and C226S in vitro. Kinetic analyses revealed that, despite a decrease in the K(M) value of the C87S mutant for DAP that presumably indicates an increase in nonproductive substrate binding, the catalytic efficiency of both serine substitution mutants was severely compromised. When either C87 or C226 were substituted with alanine, epimerase activity was not detected emphasizing the importance of both of these cysteine residues in catalysis.


Supplementation with eicosapentaenoic acid and docosahexaenoic acid reduces high levels of circulating proinflammatory cytokines in aging adults: A randomized, controlled study.
High levels of circulating proinflammatory cytokines are characteristic of inflammaging, a term coined to describe age-related chronic systemic inflammation involved in the etiology of many age-related disorders including nonhealing wounds. Some studies have shown that supplementing diets with n-3 polyunsaturated fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) lowers systemic levels of key proinflammatory cytokines associated with inflammaging. However, findings from the few studies that have focused exclusively on older adults are inconclusive. As such, the objective of this randomized controlled study was to test the effects of EPA+DHA therapy on circulating levels of proinflammatory cytokines in adults in middle to late adulthood. Plasma levels of fatty acids and interleukin (IL)-6, IL-1β and tumor necrosis factor-α (TNF-α) were measured in 35 participants with chronic venous leg ulcers (mean age: 60.6 years) randomnly assigned to 8 weeks of EPA+DHA therapy (2.5 g/d) or placebo therapy. EPA+DHA therapy had a significant lowering effect on levels of IL-6, IL-1β and TNF-α after 4 weeks of therapy and an even greater lowering effect after 8 weeks of therapy. Further, after adjusting for baseline difference, the treatment group had significantly lower levels of IL-6 (p = 0.008), IL-1β (p < 0.001), and TNF-α (p < 0.001) at Week 4 and at Week 8 [IL-6 (p = 0.007), IL-1β (p < 0.001), and TNF-α (p < 0.001)] compared to the control group. Adults in middle to late adulthood receiving EPA+DHA therapy demonstrated significantly greater reductions in circulating levels of proinflammatory cytokines compared with those receiving placebo therapy. EPA+DHA therapy may be an effective low-risk dietary intervention for assuaging the harmful effects of inflammaging.


When things do not go as expected: scenario life savers.
In this paper we discuss scenario life savers - interventions before and during simulation scenarios that allow to create and use relevant learning opportunities, even if unexpected events happen during the conduction of the scenario. Scenario life savers are needed, when the comprehension or acceptance of the scenario by the participants is at stake, thus compromising learning opportunities. Scenario life savers can principally work by bringing participants back on track of the planned scenario or by adapting the conduction to their actions on the fly. Interventions can be within the logic of the scenario or from the "outside," not being part of the scenario itself. Scenario life savers should be anticipated during the design of scenarios and used carefully during their conduction, aiming to maximize the learning for participants.


Cost-Effectiveness of Antihypertensive Deprescribing in Primary Care: a Markov Modelling Study Using Data From the OPTiMISE Trial.
Deprescribing of antihypertensive medications for older patients with normal blood pressure is recommended by some clinical guidelines, where the potential harms of treatment may outweigh the benefits. This study aimed to assess the cost-effectiveness of this approach. A Markov patient-level simulation was undertaken to model the effect of withdrawing one antihypertensive compared with usual care, over a life-time horizon. Model population characteristics were estimated using data from the OPTiMISE antihypertensive deprescribing trial, and the effects of blood pressure changes on outcomes were derived from the literature. Health-related quality of life was modeled in Quality-Adjusted Life Years (QALYs) and presented as costs per QALY gained. In the base-case analysis, medication reduction resulted in lower costs than usual care (mean difference £185), but also lower QALYs (mean difference 0.062) per patient over a life-time horizon. Usual care was cost-effective at £2975 per QALY gained (more costly, but more effective). Medication reduction resulted more heart failure and stroke/TIA events but fewer adverse events. Medication reduction may be the preferred strategy at a willingness-to-pay of £20 000/QALY, where the baseline absolute risk of serious drug-related adverse events was ≥7.7% a year (compared with 1.7% in the base-case). Although there was uncertainty around many of the assumptions underpinning this model, these findings suggest that antihypertensive medication reduction should not be attempted in many older patients with controlled systolic blood pressure. For populations at high risk of adverse effects, deprescribing may be beneficial, but a targeted approach would be required in routine practice.


Diffusion dynamics of the Keap1-Cullin3 interaction in single live cells.
Transcription factor NF-E2 p45-related factor 2 (Nrf2) regulates the expression of a network of genes encoding drug-detoxification, anti-inflammatory, and metabolic enzymes, as well as proteins involved in the regulation of cellular redox homeostasis. Under basal conditions, Kelch-like ECH associated protein 1 (Keap1) targets Nrf2 for ubiquitination and proteasomal degradation via association with Cullin3 (Cul3)-based Rbx1 E3 ubiquitin ligase. Various small molecules (inducers) activate Nrf2 leading to upregulation of cytoprotective gene expression. Inducers chemically modify specific cysteine residues of Keap1 which ultimately loses its ability to target Nrf2 for degradation. Dissociation of the Keap1-Cul3 complex by inducers is one possible mechanism, but evidence in single live cells is lacking. To investigate the diffusion dynamics of the Keap1-Cul3 interaction and the effect of inducers, we developed a quantitative fluorescence recovery after photobleaching (FRAP)-based system using Keap1-EGFP and mCherry-Cul3 fusion proteins. We show that Keap1-EGFP and mCherry-Cul3 interact in single live cells. Exposure for 1h to small-molecule inducers of 4 different types, the oleanane triterpenoid CDDO, the isothiocyanate sulforaphane, the sulfoxythiocarbamate STCA, and the oxidant hydrogen peroxide which target distinct cysteine sensors within Keap1 with potencies which differ by nearly 4000-fold, does not dissociate the Keap1-Cul3 complex. As inducers cause conformational changes in Keap1, we conclude that changes in conformation rather than dissociation from Cul3 inactivate the repressor function of Keap1 leading to Nrf2 stabilization.


Revisiting Treatment Options for Depressed Patients with Generalised Anxiety Disorder.
Symptoms of anxiety and depression often coexist, and evidence suggests that this has a genetic basis, among other possible causes. However, the current classification of comorbid generalised anxiety disorder (GAD) and depression (anxious depression) in the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition; DSM-5) does not fully reflect the high prevalence of anxiety symptoms in people with depression and the International Classification of Diseases (10th and 11th revisions) has tended to identify anxious depression with minor disorders seen in primary care. As a result, few dedicated therapeutic trials have been conducted in patients with anxious depression, and specific treatment guidelines and recommendations are lacking. Fortunately, there is considerable therapeutic overlap between anxiety and depression, such that many agents with antidepressant efficacy are also effective for symptoms of GAD. The initial treatment of a patient with depression and symptoms of anxiety should be with an agent that is approved for both major depressive disorder and GAD, such as a selective serotonin reuptake inhibitor. There is an obvious need for greater recognition of anxious depression in order to boost the volume of high-quality clinical data, which should translate over time into better, more specific treatment recommendations and improved outcomes.


Phase II marker lesion study with intravesical instillation of apaziquone for superficial bladder cancer: toxicity and marker response.
We studied the ablative activity of intravesical apaziquone (EOquin) on a papillary marker tumor and determined the incidence of side effects. A total of 46 patients with multiple pTa or pT1 bladder tumors underwent visible lesion resection except for 1 marker tumor. Patients were then treated with 6 instillations of apaziquone at weekly intervals. The response was determined 2 to 4 weeks after the last instillation. One patient withdrew informed consent and refused the last treatment due to side effects. A histologically proven complete response was seen in 30 patients. Progression to invasive stage was not observed. Local side effects in this study were comparable to those due to other chemotherapy instillations, such as mitomycin C and epirubicin, but less severe and less frequent compared to those of bacillus Calmette-Guerin instillations. The histological complete response rate after 6 consecutive instillations of apaziquone in patients with superficial bladder cancer was 67% (95% CI 51 to 80). Local side effects were comparable to side effects due to other chemotherapy instillations.


HSP105 prevents depression-like behavior by increasing hippocampal brain-derived neurotrophic factor levels in mice.
Heat shock proteins (HSPs) are stress-induced chaperones that are involved in neurological disease. Although increasingly implicated in behavioral disorders, the mechanisms of HSP action, and the relevant functional pathways, are still unclear. We examined whether oral administration of geranylgeranylacetone (GGA), a known HSP inducer, produced an antidepressant effect in a social defeat stress model of depression in mice. We also investigated the possible molecular mechanisms involved, particularly focusing on hippocampal neurogenesis and neurotrophic factor expression. In stressed mice, hippocampal HSP105 expression decreased. However, administration of GGA increased HSP105 expression and improved depression-like behavior, induced hippocampal cell proliferation, and elevated brain-derived neurotrophic factor (BDNF) levels in mouse hippocampus. Co-treatment with GGA and the BDNF receptor inhibitor K252a suppressed the antidepressant effects of GGA. HSP105 knockdown decreased BDNF mRNA levels in HT22 hippocampal cell lines and hippocampal tissue and inhibited the GGA-mediated antidepressant effect. These observations suggest that GGA administration is a therapeutic candidate for depressive diseases by increasing hippocampal BDNF levels via HSP105 expression.


An electromyographic study of the effect of hand grip sizes on forearm muscle activity and golf performance.
The study describes the differences in surface electromyography (EMG) activity of two forearm muscles in the lead and trail arm at specific phases of the golf swing using a 7-iron with three different grip sizes among amateur and professional golfers. Fifteen right-handed male golfers performed five golf swings using golf clubs with three different grip sizes. Surface EMG was used to measure muscle activity of the extensor carpi radialis brevis (ECRB) and flexor digitorum superficialis (FDS) on both forearms. There were no significant differences in forearm muscle activity when using the three golf grips within the group of 15 golfers (p > 0.05). When using the undersize grip, club head speed significantly increased (p = 0.044). During the backswing and downswing phases, amateurs produced significantly greater forearm muscle activity with all three grip sizes (p < 0.05). In conclusion, forearm muscle activity is not affected by grip sizes. However, club head speed increases when using undersize grips.


Who are the Pioneers? A Critical Analysis of Innovation and Expertise in Cutaneous Noninvasive and Minimally Invasive Cosmetic and Surgical Procedures.
Few studies illustrate the contributions made by various specialties in pioneering commonly performed noninvasive and minimally invasive cosmetic and surgical procedures. To evaluate the contributions made by various specialties in pioneering noninvasive and minimally invasive cosmetic and surgical procedures. Key words using the Medical Search Headings Database were used to query in the Thomson Reuters Web of Science Database. The 25 most highly cited studies were sorted according to the citation number. The author specialty was identified and assigned scores based on the number of citations. Dermatology was identified as the specialty with the greatest contribution to botulinum toxin treatments for rhytides, injectable fillers, laser treatments, chemical peels, and noninvasive body contouring. Neurology was identified as the leading specialty in botulinum toxin treatments for hyperhidrosis, and vascular surgery was identified as leading specialty in sclerotherapy. Plastic surgery was identified as having made the greatest contribution to hair transplantation, and liposuction. Dermatology was identified as the leading specialty for the majority of noninvasive and minimally invasive cosmetic procedures. Other specialties have also contributed important literature to this area.


Early treatment with prednisolone or acyclovir in Bell's palsy.
Corticosteroids and antiviral agents are widely used to treat the early stages of idiopathic facial paralysis (i.e., Bell's palsy), but their effectiveness is uncertain. We conducted a double-blind, placebo-controlled, randomized, factorial trial involving patients with Bell's palsy who were recruited within 72 hours after the onset of symptoms. Patients were randomly assigned to receive 10 days of treatment with prednisolone, acyclovir, both agents, or placebo. The primary outcome was recovery of facial function, as rated on the House-Brackmann scale. Secondary outcomes included quality of life, appearance, and pain. Final outcomes were assessed for 496 of 551 patients who underwent randomization. At 3 months, the proportions of patients who had recovered facial function were 83.0% in the prednisolone group as compared with 63.6% among patients who did not receive prednisolone (P<0.001) and 71.2% in the acyclovir group as compared with 75.7% among patients who did not receive acyclovir (adjusted P=0.50). After 9 months, these proportions were 94.4% for prednisolone and 81.6% for no prednisolone (P<0.001) and 85.4% for acyclovir and 90.8% for no acyclovir (adjusted P=0.10). For patients treated with both drugs, the proportions were 79.7% at 3 months (P<0.001) and 92.7% at 9 months (P<0.001). There were no clinically significant differences between the treatment groups in secondary outcomes. There were no serious adverse events in any group. In patients with Bell's palsy, early treatment with prednisolone significantly improves the chances of complete recovery at 3 and 9 months. There is no evidence of a benefit of acyclovir given alone or an additional benefit of acyclovir in combination with prednisolone. (Current Controlled Trials number, ISRCTN71548196 [controlled-trials.com].).


Hepatoprotective Property of Oral Silymarin is Comparable to N-Acetyl Cysteine in Acetaminophen Poisoning.
N-Acetyl Cysteine (NAC) is usually used as antidote for prevention of acetaminophen-induced hepatotoxicity. In present study we have evaluated efficacy of oral silymarin in its prevention in rats intoxicated with lethal dose of acetaminophen. A total of 50 Male Sprague-Dawley rats were randomly divided into five groups. The first group received only vehicle of acetaminophen and served as control. The second group was given 800 mg/kg acetaminophen by gavage with an orogastric canula. The third, fourth and fifth groups were given 300 mg/kg NAC and 150 and 300 mg/kg silymarin respectively. Analysis of serum AST, ALT, and ALP and liver histopathology were employed for assessment of hepatotoxicity. Mean serum ALT levels were significantly increased in the APAP group rats. The mean serum ALT levels returned to normal in both NAC treated and silymarin treated groups. Silymarin (150 mg/kg) had prevented hepatocytes necrosis similar to NAC. No severe hepatotoxicity were seen in groups 3 and 4; while it is seen in 70% of animals in group 2. We found that a single dose of orally administered silymarin (150 mg/kg) significantly attenuated acetaminophen-induced liver damage in rat. Oral silymarin can be used in these patients instead of NAC.


Adverse events associated with hospitalization or detected through the RAI-HC assessment among Canadian home care clients.
The occurrence of adverse events (AEs) in care settings is a patient safety concern that has significant consequences across healthcare systems. Patient safety problems have been well documented in acute care settings; however, similar data for clients in home care (HC) settings in Canada are limited. The purpose of this Canadian study was to investigate AEs in HC, specifically those associated with hospitalization or detected through the Resident Assessment Instrument for Home Care (RAI-HC). A retrospective cohort design was used. The cohort consisted of HC clients from the provinces of Nova Scotia, Ontario, British Columbia and the Winnipeg Regional Health Authority. The overall incidence rate of AEs associated with hospitalization ranged from 6% to 9%. The incidence rate of AEs determined from the RAI-HC was 4%. Injurious falls, injuries from other than fall and medication-related events were the most frequent AEs associated with hospitalization, whereas new caregiver distress was the most frequent AE identified through the RAI-HC. The incidence of AEs from all sources of data ranged from 4% to 9%. More resources are needed to target strategies for addressing safety risks in HC in a broader context. Tools such as the RAI-HC and its Clinical Assessment Protocols, already available in Canada, could be very useful in the assessment and management of HC clients who are at safety risk.


On-chip stimulated Brillouin scattering.
We demonstrate on-chip stimulated Brillouin scattering (SBS) in an As2S3 chalcogenide rib waveguide. SBS was characterized in a cm long waveguide with a cross-section 4 μm x 850 nm using the backscattered signal and pump-probe technique. The measured Brillouin shift and its full-width at half-maximum (FWHM) linewidth were ~7.7 GHz and 34 MHz, respectively. Probe vs. pump power measurements at the Brillouin shift were used to obtain the gain coefficient from an exponential fit. The Brillouin gain coefficient obtained was 0.715 x 10(-9) m/W. A probe gain of 16 dB was obtained for a CW pump power of ~300 mW.


Light-induced deposits in Bruch's membrane of protoporphyric mice.
Photosensitization of choriocapillary endothelium with blood-borne photosensitizers, such as protoporphyrin IX, has been proposed as a mechanism for the choriocapillary sclerosis and Bruch's membrane deposits seen in age-related macular degeneration. Utilizing a mouse model of protoporphyria with approximately a 10-fold increase in protoporphyrin IX level and exposure to blue light (14 microW/cm2; bandwidth, 390 to 430 nm), a time- and light-dependent increase in choriocapillary and sub-retinal pigment epithelium basal laminar-like deposits could be demonstrated at 7 months by transmission electron microscopy. Thickening of the choriocapillary endothelial basement membrane with a homogeneous electron-dense material was first noted in protoporphyric mice exposed to blue light for 13 weeks. At 28 weeks the experimental animals exhibited a thick band of homogeneous deposits at the level of the choriocapillary basement membrane and electron-dense fibrillogranular deposits of varying sizes along the inner aspect of Bruch's membrane, with fibrils measuring up to 16 nm, with a periodicity of 13 nm. These deposits contributed to an overall thickening of Bruch's membrane with narrowing of the choriocapillaris. The morphologic appearance and localization of these deposits within Bruch's membrane of this animal model are similar to previously described deposits noted in the aging Bruch's membrane prior to the development of age-related macular degeneration.


Experiences and outcomes of maternal Ramadan fasting during pregnancy: results from a sub-cohort of the Born in Bradford birth cohort study.
Observing the fast during the holy month of Ramadan is one of the five pillars of Islam. Although pregnant women and those with pre-existing illness are exempted from fasting many still choose to fast during this time. The fasting behaviours of pregnant Muslim women resident in Western countries remain largely unexplored and relationships between fasting behaviour and offspring health outcomes remain contentious. This study was undertaken to assess the prevalence, characteristics of fasting behaviours and offspring health outcomes in Asian and Asian British Muslim women within a UK birth cohort. Prospective cohort study conducted at the Bradford Royal Infirmary UK from October to December 2010 comprising 310 pregnant Muslim women of Asian or Asian British ethnicity that had a live singleton birth at the Bradford Royal Infirmary. The main outcome of the study was the decision to fast or not during Ramadan. Secondary outcomes were preterm births and mean birthweight. Logistic regression analyses were used to investigate the relationship between covariables of interest and women's decision to fast or not fast. Logistic regression was also used to investigate the relationship between covariables and preterm birth as well as low birth weight. Mutually adjusted analysis showed that the odds of any fasting were higher for women with an obese BMI at booking compared to women with a normal BMI, (OR 2.78 (95% C.I. 1.29-5.97)), for multiparous compared to nulliparous women(OR 3.69 (95% C.I. 1.38-9.86)), and for Bangladeshi origin women compared to Pakistani origin women (OR 3.77 (95% C.I. 1.04-13.65)). Odds of fasting were lower in women with higher levels of education (OR 0.40 (95% C.I. 0.18-0.91)) and with increasing maternal age (OR 0.87 (95% C.I. 0.80-0.94). No associations were observed between fasting and health outcomes in the offspring. Pregnant Muslim women residing in the UK who fasted during Ramadan differed by social, demographic and lifestyle characteristics compared to their non-fasting peers. Fasting was not found to be associated with adverse birth outcomes in this sample although these results require confirmation using reported fasting data in a larger sample before the safety of fasting during pregnancy can be established.


Recent advances in avian egg science: A review.
Eggs and egg products form an integral part of the food chain. As such, research into egg structure, function, and production has made an important contribution to the field of poultry science. The past decade has seen significant advances in avian egg science research, with work supplementing our understanding of the nature of the avian egg, and its biological, chemical, and physical properties. Eggshell color, strength, and chemical composition, poultry nutrition, and genetics have all been intensively studied recently, with significant progress being made in a number of these areas. Indeed, with the prevalence of robust theoretical techniques, it is now commonplace to combine experimental investigations with theory, providing a balanced and interdisciplinary perspective.


Activation of Wnt signaling in hematopoietic regeneration.
Hematopoietic stem cells (HSCs) respond to injury by rapidly proliferating and regenerating the hematopoietic system. Little is known about the intracellular programs that are activated within HSCs during this regenerative process and how this response may be influenced by alterations in signals from the injured microenvironment. Here we have examined the regenerating microenvironment and find that following injury it has an enhanced ability to support HSCs. During this regenerative phase, both hematopoietic and stromal cell elements within the bone marrow microenvironment show increased expression of Wnt10b, which can function to enhance growth of hematopoietic precursors. In addition, regenerating HSCs show increased activation of Wnt signaling, suggesting that microenvironmental changes in Wnt expression after injury may be integrated with the responses of the hematopoietic progenitors. Cumulatively, our data reveal that growth signals in the hematopoietic system are re-activated during injury, and provide novel insight into the influence of the microenvironment during regeneration.


Use of different concentrations of carbamide peroxide for bleaching teeth: an in vitro study.
This in vitro study compared the shade changes in extracted teeth during 2 weeks' whitening with 5%, 10%, or 16% carbamide peroxide. After color calibration, the sole examiner selected 110 extracted unrestored, noncarious teeth, shade A3 or darker on a value-oriented guide. The teeth were randomly distributed into equal color groups. The control group (11 teeth) was treated with 0.9% saline, while the experimental groups (33 teeth each) were treated with 5%, 10%, or 16% carbamide peroxide. The solutions remained on the teeth for 8 hours. The teeth and tray were rinsed with tap water for 2 minutes, then rehydrated in 0.9% saline for 16 hours in the humidifier. The shade was assessed, and the process was repeated daily for 2 weeks. Repeated-measures analysis of variance indicated a significant difference in overall shade values between the control and all carbamide peroxide-treated groups at days 8 and 15. A Kaplan-Meier Survival Analysis indicated a quicker two-tab color change for the 10% and 16% groups than the 5% group. However, continuation of the 5% treatment to 3 weeks resulted in shades that approached the 2-week 10% and 16% values. Lower concentrations of carbamide peroxide take longer to whitening teeth but eventually achieve the same result as higher concentrations. Higher concentrations may cause increased sensitivity.


Xenopus axis formation: induction of goosecoid by injected Xwnt-8 and activin mRNAs.
In this study, we compare the effects of three mRNAs-goosecoid, activin and Xwnt-8- that are able to induce partial or complete secondary axes when injected into Xenopus embryos. Xwnt-8 injection produces complete secondary axes including head structures whereas activin and goosecoid injection produce partial secondary axes at high frequency that lack head structures anterior to the auditory vesicle and often lack notochord. Xwnt-8 can activate goosecoid only in the deep marginal zone, i.e., in the region in which this organizer-specific homeobox gene is normally expressed on the dorsal side. Activin B mRNA, however, can turn on goosecoid in all regions of the embryo. We also tested the capacity of these gene products to restore axis formation in embryos in which the cortical rotation was blocked by UV irradiation. Whereas Xwnt-8 gives complete rescue of anterior structures, both goosecoid and activin give partial rescue. Rescued axes including hindbrain structures up to level of the auditory vesicle can be obtained at high frequency even in the absence of notochord structures. The possible functions of Wnt-like and activin-like signals and of the goosecoid homeobox gene, and their order of action in the formation of Spemann's organizer are discussed.


Morphology, morphogenesis and molecular phylogeny of a novel soil ciliate, Pseudouroleptus plestiensis n. sp. (Ciliophora, Oxytrichidae), from the uplands of Colfiorito, Italy.
The terrestrial oxytrichid ciliate Pseudouroleptus plestiensis n. sp., isolated from soil samples collected from the uplands of Colfiorito (Umbria region, Italy), was investigated using live observation and protargol impregnation. The morphology, morphogenesis and molecular phylogeny inferred from small-subunit (SSU) rRNA gene sequences were studied. The novel species is mainly characterized by the following: a cell size of about 145×35 µm in vivo; two ellipsoidal macronuclear nodules and two to four micronuclei; adoral zone about 26% of body length with a mean of 30 membranelles; about 40 cirri in the right marginal row and 38 in the left marginal row; left fronto-ventral row consisting of about 27-40 cirri, right fronto-ventral row of about three to seven cirri forming a short row to the right of the rear portion of the left fronto-ventral row; one parabuccal cirrus ( = III/2), one buccal and one post-peristomial cirrus; and four dorsal kineties with caudal cirri at the end of kineties 1 and 2. The morphogenesis of the novel species is similar to that of Pseudouroleptus caudatus. Phylogenetic analyses based on SSU rRNA gene sequences consistently placed the novel species within the family Oxytrichidae Ehrenberg, 1838, clustering with P. caudatus and the genus Strongylidium. The results from the present study contribute to the expanding knowledge of the diversity of ciliates in Italian soil.


Hyponatremia among runners in the Zurich Marathon.
Hyperhydration and exercise-associated hyponatremia (EAH) are critical issues during endurance events. We studied a cohort of marathon runners to examine EAH's prevalence in a marathon with a short time limit and to investigate underlying mechanisms that may be responsible for its development. Observational cohort study. 2006 Zurich Marathon (cool and rainy weather, time limit of 5 hours). 167 marathon runners were recruited the month before the race. Body mass, plasma sodium, and osmolality were measured just before the start and immediately after the race. Fluid intake during the race was ascertained by a recall questionnaire. Five subjects (3 %) developed asymptomatic EAH, and no symptomatic EAH was found. Body mass change during the race correlated similarly with postrace sodium levels (r = -0.72, P < 0.0001) and with sodium change during the race (r = -0.66, P < 0.0001). Postrace sodium levels correlated significantly with sodium change during the race (r = 0.74, P < 0.0001). Fluid intake correlated significantly (r = -0.43, P < 0.0001) with plasma sodium change between the start and finish of the race. Postrace sodium levels and postrace osmolality were significantly correlated (r = 0.68, P < 0.0001). In this study we observed a relatively low incidence of EAH in subjects running the marathon in around 2.5 to 5 hours and in a cool environment. Plasma sodium change during the race and postrace sodium levels correlated with body mass change. There was also a direct correlation between fluid intake and plasma sodium change during the race.


Molecular characterization of a cell wall-associated beta(1-3)endoglucanase of Aspergillus fumigatus.
A 74 kDa beta(1-3)endoglucanase of Aspergillus fumigatus was recently isolated from a cell wall autolysate and biochemically characterized. In this study, we report the cloning and the disruption of the ENGL1 gene encoding this beta(1-3)endoglucanase. ENGL1 contains an open reading frame of 2181 bp encoding a polypeptide of 727 amino acids. Sequence analysis showed that ENGL1 is the first characterized member of a new family of beta(1-3)glucanases. Disruption of ENGL1, however, did not lead to a phenotype distinct from the parental strain, indicating that this cell wall-associated beta(1-3)endoglucanase does not play an essential role in constitutive cell growth.


Paget's disease of the nipple in a population based cohort.
Paget's disease of the nipple is a rare form of breast cancer characterised by the presence of intraepidermal tumour cells. It is often associated with ductal carcinoma in situ (DCIS) and/or invasive cancer in the breast parenchyma. We have studied the presentation and symptoms of Paget's disease, local control and breast cancer corrected survival following breast conserving surgery or mastectomy. The study is based on 223 women with histological verified Paget's disease of the nipple diagnosed between 1976 and 2001 at 13 Swedish hospitals. All women s charts were reviewed. All recurrences and deaths were registered. A comparison was made for differences in breast cancer-corrected survival (BCS) and disease-free survival (DFS) in univariate analyses. The median follow-up was 12 (4-28) years. In a vast majority (98%), the main presenting symptom was eczema or ulceration of the nipple. The diagnosis of an underlying breast malignancy was established in 79% of the women before surgery. A cone excision of the nipple-areola complex was performed in 43 women and 169 women had a mastectomy. Eleven elderly women were not operated. One hundred and seventeen women had a non-invasive Paget of which 40 had an underlying DCIS. Invasive cancer was seen in 68 women. In 38 cases the histopathological report did not state if the tumour was invasive or not. Thirty-three women died from breast cancer. In operated women BCS and DFS at 10 years were 87% and 82%, respectively. The 10-year BCS for non-operated patients (n = 11) was 34%. At 10 years, the cumulative local recurrence rate was 9%, 8% among women undergoing mastectomy and 16% among those treated with breast conserving surgery. In univariate analysis the type of surgery, cone excision or mastectomy, had no statistically significant impact on BCS or DFS. Risk factors for breast cancer death and recurrence were having an underlying invasive cancer compared with an in situ carcinoma and having a palpable tumour in the breast. The main presenting symptoms were eczema or ulceration of the nipple. Patients with non invasive Pagets disease of the nipple had an excellent cancer outcome. Selected patients with Paget's disease of the nipple were treated with breast conserving surgery with survival rates similar to those achieved with mastectomy.


Gas6 and the receptor tyrosine kinase Axl in clear cell renal cell carcinoma.
The molecular biology of renal cell carcinoma (RCC) is complex and not fully understood. We have recently found that the expression of the receptor tyrosine kinase Axl in the RCC tumors independently correlates with survival of the patients. Here, we have investigated the role of Axl and its ligand Gas6, the vitamin-K dependent protein product of the growth arrest-specific gene 6, in clear cell RCC (ccRCC) derived cells. The Axl protein was highly expressed in ccRCC cells deficient in functional von Hippel-Lindau (VHL) protein, a tumor suppressor gene often inactivated in ccRCC. VHL reconstituted cells expressed decreased levels of Axl protein, but not Axl mRNA, suggesting VHL to regulate Axl expression. Gas6-mediated activation of Axl in ccRCC cells resulted in Axl phosphorylation, receptor down-regulation, decreased cell-viability and migratory capacity. No effects of the Gas6/Axl system could be detected on invasion. Moreover, in ccRCC tumor tissues, Axl was phosphorylated and Gas6 gamma-carboxylated, suggesting these molecules to be active in vivo. These results provide novel information regarding the complex function of the Gas6/Axl system in ccRCC.


Hierarchies of Attention and Experimental Designs: Effects of Spatial and Intermodal Attention Revisited.
When attention is directed to stimuli in a given modality and location, information processing in other irrelevant modalities at this location is affected too. This spread of attention to irrelevant stimuli is often interpreted as superiority of location selection over modality selection. However, this conclusion is based on experimental paradigms in which spatial attention was transient whereas intermodal attention was sustained. Furthermore, whether modality selection affects processing in the task-relevant modality at irrelevant locations remains an open question. Here, we addressed effects of simultaneous spatial and intermodal attention in an EEG study using a balanced design where spatial attention was transient and intermodal attention sustained or vice versa. Effects of spatial attention were not affected by which modality was attended and effects of intermodal attention were not affected by whether the stimuli were at the attended location or not. This suggests not only spread of spatial attention to task-irrelevant modalities but also spread of intermodal attention to task-irrelevant locations. Whether spatial attention was transient or sustained did not alter the effect of spatial attention on visual N1 and Nd1 responses. Prestimulus preparatory occipital alpha band responses were affected by both transient and sustained spatial cueing, whereas late post-stimulus responses were more strongly affected by sustained than by transient spatial attention. Sustained but not transient intermodal attention affected late responses (>200 msec) to visual stimuli. Together, the results undermine the universal superiority of spatial attention and suggest that the mode of attention manipulation is an important factor determining attention effects.


Generation and characterization of two novel monoclonal antibodies produced against human TLT-2 molecule.
Trem-like transcript 2 (TLT-2), one of the TREM family members, which is expressed on B cells, T cells, and macrophages, plays a critical role in immune response mechanism. In this study, two novel mouse anti-human TLT-2 monoclonal antibodies (MAbs) were prepared using hybridoma technology and their immunological characteristics were determined. The results showed that the two MAbs (clones 10F5 and 8C10) were both IgG1 (κ) and bound specifically to human TLT-2. Furthermore, 10F5 and 8C10 seemed to recognize a different site (epitope) of TLT-2 by competition assay. MAb 10F5 was proven in Western blot analysis to specifically bind to denatured TLT-2 protein while both MAbs were proven in dot blot analyses and immunofluorescence to specifically bind to natural TLT-2 protein. In addition, crosslinking of TLT-2 with MAb 8C10 markedly blocked TLT-2 positive signal and T cell proliferation. Taken together, these two monoclonal antibodies might be of great value as tools for further exploration of the expression and function of TLT-2.


A conserved mechanism for replication origin recognition and binding in archaea.
To date, methanogens are the only group within the archaea where firing DNA replication origins have not been demonstrated in vivo. In the present study we show that a previously identified cluster of ORB (origin recognition box) sequences do indeed function as an origin of replication in vivo in the archaeon Methanothermobacter thermautotrophicus. Although the consensus sequence of ORBs in M. thermautotrophicus is somewhat conserved when compared with ORB sequences in other archaea, the Cdc6-1 protein from M. thermautotrophicus (termed MthCdc6-1) displays sequence-specific binding that is selective for the MthORB sequence and does not recognize ORBs from other archaeal species. Stabilization of in vitro MthORB DNA binding by MthCdc6-1 requires additional conserved sequences 3' to those originally described for M. thermautotrophicus. By testing synthetic sequences bearing mutations in the MthORB consensus sequence, we show that Cdc6/ORB binding is critically dependent on the presence of an invariant guanine found in all archaeal ORB sequences. Mutation of a universally conserved arginine residue in the recognition helix of the winged helix domain of archaeal Cdc6-1 shows that specific origin sequence recognition is dependent on the interaction of this arginine residue with the invariant guanine. Recognition of a mutated origin sequence can be achieved by mutation of the conserved arginine residue to a lysine or glutamine residue. Thus despite a number of differences in protein and DNA sequences between species, the mechanism of origin recognition and binding appears to be conserved throughout the archaea.


Cosmic rays, clouds, and climate.
It has been proposed that Earth's climate could be affected by changes in cloudiness caused by variations in the intensity of galactic cosmic rays in the atmosphere. This proposal stems from an observed correlation between cosmic ray intensity and Earth's average cloud cover over the course of one solar cycle. Some scientists question the reliability of the observations, whereas others, who accept them as reliable, suggest that the correlation may be caused by other physical phenomena with decadal periods or by a response to volcanic activity or El Niño. Nevertheless, the observation has raised the intriguing possibility that a cosmic ray-cloud interaction may help explain how a relatively small change in solar output can produce much larger changes in Earth's climate. Physical mechanisms have been proposed to explain how cosmic rays could affect clouds, but they need to be investigated further if the observation is to become more than just another correlation among geophysical variables.


Taxonomy-free molecular diatom index for high-throughput eDNA biomonitoring.
Current biodiversity assessment and biomonitoring are largely based on the morphological identification of selected bioindicator taxa. Recently, several attempts have been made to use eDNA metabarcoding as an alternative tool. However, until now, most applied metabarcoding studies have been based on the taxonomic assignment of sequences that provides reference to morphospecies ecology. Usually, only a small portion of metabarcoding data can be used due to a limited reference database and a lack of phylogenetic resolution. Here, we investigate the possibility to overcome these limitations using a taxonomy-free approach that allows the computing of a molecular index directly from eDNA data without any reference to morphotaxonomy. As a case study, we use the benthic diatoms index, commonly used for monitoring the biological quality of rivers and streams. We analysed 87 epilithic samples from Swiss rivers, the ecological status of which was established based on the microscopic identification of diatom species. We compared the diatom index derived from eDNA data obtained with or without taxonomic assignment. Our taxonomy-free approach yields promising results by providing a correct assessment for 77% of examined sites. The main advantage of this method is that almost 95% of OTUs could be used for index calculation, compared to 35% in the case of the taxonomic assignment approach. Its main limitations are under-sampling and the need to calibrate the index based on the microscopic assessment of diatoms communities. However, once calibrated, the taxonomy-free molecular index can be easily standardized and applied in routine biomonitoring, as a complementary tool allowing fast and cost-effective assessment of the biological quality of watercourses.


Studying the role of ApoE in Alzheimer's disease pathogenesis using a systems biology model.
Alzheimer's disease (AD) is the most common form of dementia. Even with its well-known symptoms of memory loss and well-characterized pathology of beta amyloid (Aβ) plaques and neurofibrillary tangles, the disease pathogenesis and initiating factors are still not well understood. To tackle this problem, a systems biology model has been developed and used to study the varying effects of variations in the ApoE allele present, as well as the effects of short term and periodic inflammation at low to moderate levels. Simulations showed a late onset peak of Aβ in the ApoE4 case that lead to localized neuron loss which could be ameliorated in part by application of short-term pro-inflammatory mediators. The model that has been developed herein represents one of the first attempts to model AD from a systems approach to study physiologically relevant parameters that may prove useful to physicians in the future.


Preeclampsia and the systemic inflammatory response.
Normal pregnancy is associated with a systemic inflammatory response. The response is exacerbated in preeclampsia and can account for its clinical features. Many of the physiologic changes of normal pregnancy are part of an acute-phase reaction, which is generated by an inflammatory response. The placenta is the proximal cause of these problems. There are several possible placental factors that may evoke the inflammatory responses that currently are being investigated. The special susceptibility of obese women, or those with diabetes or chronic hypertension, to preeclampsia is explained by the chronic systemic inflammatory responses that these women have. The clinical implications of these concepts are discussed.


[Development of Autogenic Training Clinical Effectiveness Scale (ATCES)].
The purpose of the present study was to develop a scale measuring clinical effectiveness of autogenic training. In Study 1, 167 undergraduates completed a survey of items concerning physical and mental states, which were thought to vary in the course of autogenic training. With item and factor analyses, 20 items were selected, and the resulting scale (ATCES) had high discrimination and clear factor structure. In Study 2, reliability and concurrent and clinical validity of the scale were examined with three groups of respondents: 85 mentally healthy, 31 control, 13 clinical persons. The scale showed a high test-retest correlation (r = .83) and alpha coefficient (alpha = .86). ATCES had a Pearson correlation coefficient of r = .56 with General Health Questionnaire (GHQ-12), and r = .73 with trait anxiety (STAI-T). And ATCES successfully discriminated the mentally healthy and clinical groups in terms of clinical effectiveness. These results demonstrated high reliability and sufficient concurrent and clinical validity of the new scale.


Declining length of stay for patients hospitalized with AMI: impact on mortality and readmissions.
Length of hospital stay after acute myocardial infarction decreased significantly in the 1980s and 1990s. Whether length of stay has continued to decrease during the 2000s, and the impact of decreasing length of stay on rehospitalization and mortality, is unclear. We describe decade-long (1995-2005) trends in length of stay after acute myocardial infarction, and examine whether declining length of stay has impacted early rehospitalization and postdischarge mortality in a population-based sample of hospitalized patients. The study sample consisted of 4184 patients hospitalized with acute myocardial infarction in a central New England metropolitan area during 6 annual periods (1995, 1997, 1999, 2001, 2003, 2005). The average age of the study sample was 71 years, and 54% were men. The average length of stay decreased by nearly one third over the 10-year study period, from 7.2 days in 1995 to 5.0 days in 2005 (P <.001). Younger patients (<65 years), men, and patients with an uncomplicated hospital stay had significantly shorter lengths of stay than respective comparison groups. Lengths of stay shorter than the median were not associated with significantly higher odds of hospital readmission at 7 or 30 days postdischarge, or with mortality in the year after discharge. In contrast, longer lengths of stay were associated with significantly higher odds of short-term mortality. These findings did not vary by year under study. Length of stay in patients hospitalized for acute myocardial infarction decreased significantly between 1995 and 2005. Declining length of stay is not associated with an increased risk for early readmission or all-cause mortality.


Cost-effectiveness of fibronectin testing in a triage in women with threatened preterm labor: alleviation of pregnancy outcome by suspending tocolysis in early labor (APOSTEL-I trial).
At present, women with threatened preterm labor before 32 weeks of gestation are, after transfer to a perinatal center, treated with tocolytics and corticosteroids. Many of these women are treated unnecessarily. Fibronectin is an accurate predictor for the occurrence of preterm birth among women with threatened preterm labor. We will assess whether triage of these women with fibronectin testing, cervical length or their combination is cost-effective. We will investigate a prospective cohort of women referred to a perinatal centre for spontaneous threatened preterm labor between 24 and 34 weeks with intact membranes. All women will be tested for fibronectin and cervical length. Women with a cervical length <10 mm and women with a cervical length between 10-30 mm in combination with a positive fibronectin test will be treated with tocolytics according to local protocol. Women with a cervical length between 10-30 mm in combination with a negative fibronectin test will be randomised between treatment with nifedipine (intervention) and placebo (control) for 48 hours. Women with a cervical length > 30 mm will be managed according to local protocol. Corticosteroids may be given to all women at the discretion of the attending physician. Primary outcome measure will be delivery within 7 days. Secondary outcome measures will be neonatal morbidity and mortality, complications of tocolytics, costs and health related quality of life. The analysis will be according to the intention to treat principle. We anticipate the probability on preterm birth within 7 days in the group of women with a negative fibronectine test to be 5%. Two groups of 110 women will be needed to assure that in case of non-inferiority the difference in the proportion of preterm deliveries < 7 days will be within a prespecified boundary of 7.5% (one sided test, beta 0.2, alpha 0.05). Data obtained from women with a positive and negative fibronectin tests in both the cohort study and the trial will be integrated in a cost-effectiveness analysis that will assess economic consequences of the use of fibronectin. This study will provide evidence for the use of fibronectin testing as safe and cost-effective method in a triage for threatened preterm labor. Nederlands Trial Register (NTR) number 1857, http://www.trialregister.nl.


Continuously tunable pulsed Ti:Sa laser self-seeded by an extended grating cavity.
A continuously tunable titanium:sapphire (Ti:Sa) laser self-seeded by an extended grating cavity was demonstrated and characterized. By inserting a partially reflecting mirror inside the cavity of a classic single-cavity grating laser, two oscillators are created: a broadband power oscillator and a narrowband oscillator with a prism beam expander and a diffraction grating in Littrow configuration. By coupling the grating cavity oscillation into the power oscillator, a power-enhanced narrow-linewidth laser oscillation is achieved. Compared to the classic grating laser, this simple modification significantly increases the laser output power without considerably broadening the linewidth. With most of the oscillating laser power confined inside the broadband power cavity and lower power incident onto the grating, the new configuration also allows higher pump power, which is typically limited by the thermal deformation of the grating coating at high oscillation power.


Partial thermal imidization of polyelectrolyte multilayer cell tethering surfaces (TetherChip) enables efficient cell capture and microtentacle fixation for circulating tumor cell analysis.
The technical challenges of imaging non-adherent tumor cells pose a critical barrier to understanding tumor cell responses to the non-adherent microenvironments of metastasis, like the bloodstream or lymphatics. In this study, we optimized a microfluidic device (TetherChip) engineered to prevent cell adhesion with an optically-clear, thermal-crosslinked polyelectrolyte multilayer nanosurface and a terminal lipid layer that simultaneously tethers the cell membrane for improved spatial immobilization. Thermal imidization of the TetherChip nanosurface on commercially-available microfluidic slides allows up to 98% of tumor cell capture by the lipid tethers. Importantly, time-lapse microscopy demonstrates that unique microtentacles on non-adherent tumor cells are rapidly destroyed during chemical fixation, but tethering microtentacles to the TetherChip surface efficiently preserves microtentacle structure post-fixation and post-blood isolation. TetherChips remain stable for more than 6 months, enabling shipment to distant sites. The broad retention capability of TetherChips allows comparison of multiple tumor cell types, revealing for the first time that carcinomas beyond breast cancer form microtentacles in suspension. Direct integration of TetherChips into the Vortex VTX-1 CTC isolation instrument shows that live CTCs from blood samples are efficiently captured on TetherChips for rapid fixation and same-day immunofluorescence analysis. Highly efficient and unbiased label-free capture of CTCs on a surface that allows rapid chemical fixation also establishes a streamlined clinical workflow to stabilize patient tumor cell samples and minimize analytical variables. While current studies focus primarily on CTC enumeration, this microfluidic device provides a novel platform for functional phenotype testing in CTCs with the ultimate goal of identifying anti-metastatic, patient-specific therapies.


Hospital-based surveillance for rotavirus gastroenteritis in children younger than 5 years of age in Ethiopia: 2007-2012.
Rotavirus surveillance was initiated in Ethiopia to estimate the burden of rotavirus gastroenteritis in children <5 years of age, to generate data to assist the policy-making process for new vaccine introduction and to monitor impact of vaccination on disease burden after introduction. Sentinel surveillance was conducted at 3 hospitals in Addis Ababa, Ethiopia using a standardized WHO surveillance protocol from August 2007 to March 2012. Children <5 years of age, hospitalized for the primary reason of treatment for acute gastroenteritis, were enrolled, stool samples were collected and tested for group A rotavirus using an enzyme immunoassay. Confirmed positive specimens were further characterized by rotavirus genotyping. A total of 1841 children were enrolled and 21% were rotavirus positive. Children 6-12 months of age had the highest proportion of rotavirus (36%) followed by children <6 months of age (23%). There was no significant difference between sexes. Significant differences in clinical characteristics, such as vomiting, vomiting episodes, cases with vomiting and diarrhea among rotavirus positive cases, were observed. Rotavirus circulated year round with peak prevalence from October through January. The most prevalent detected genotypes were G1P[8] (20%), G12P[8] (17%) and G3P[6] (15%), respectively. Rotavirus infection is common in Ethiopian children. A safe and effective intervention against the infection is needed to prevent severity of the disease. Rotavirus vaccine introduction is planned before the end of 2013. The established surveillance system and the data generated can be used to monitor the impact of rotavirus vaccination program on severe disease.


Risk of acute kidney injury associated with the use of fluoroquinolones.
Case reports indicate that the use of fluoroquinolones may lead to acute kidney injury. We studied the association between the use of oral fluoroquinolones and acute kidney injury, and we examined interaction with renin-angiotensin-system blockers. We formed a nested cohort of men aged 40-85 enrolled in the United States IMS LifeLink Health Plan Claims Database between 2001 and 2011. We defined cases as men admitted to hospital for acute kidney injury, and controls were admitted to hospital with a different presenting diagnosis. Using risk-set sampling, we matched 10 controls to each case based on hospital admission, calendar time (within 6 wk), cohort entrance (within 6 wk) and age (within 5 yr). We used conditional logistic regression to assess the rate ratio (RR) for acute kidney injury with current, recent and past use of fluoroquinolones, adjusted by potential confounding variables. We repeated this analysis with amoxicillin and azithromycin as controls. We used a case-time-control design for our secondary analysis. We identified 1292 cases and 12 651 matched controls. Current fluoroquinolone use had a 2.18-fold (95% confidence interval [CI] 1.74-2.73) higher adjusted RR of acute kidney injury compared with no use. There was no association between acute kidney injury and recent (adjusted RR 0.87, 95% CI 0.66-1.16) or past (RR 0.86, 95% CI 0.66-1.12) use. The absolute increase in acute kidney injury was 6.5 events per 10 000 person-years. We observed 1 additional case per 1529 patients given fluoroquinolones or per 3287 prescriptions dispensed. The dual use of fluoroquinolones and renin-angiotensin-system blockers had an RR of 4.46 (95% CI 2.84-6.99) for acute kidney injury. Our case-time-control analysis confirmed an increased risk of acute kidney injury with fluoroquinolone use (RR 2.16, 95% CI 1.52-3.18). The use of amoxicillin or azithromycin was not associated with acute kidney injury. We found a small, but significant, increased risk of acute kidney injury among men with the use of oral fluoroquinolones, as well as a significant interaction between the concomitant use of fluoroquinolones and renin-angiotensin-system blockers.


Fast Bayesian scan statistics for multivariate event detection and visualization.
The multivariate Bayesian scan statistic (MBSS) is a recently proposed, general framework for event detection and characterization in multivariate space-time data. MBSS integrates prior information and observations from multiple data streams in a Bayesian framework, computing the posterior probability of each type of event in each space-time region. MBSS has been shown to have many advantages over previous event detection approaches, including improved timeliness and accuracy of detection, easy interpretation and visualization of results, and the ability to model and accurately differentiate between multiple event types. This work extends the MBSS framework to enable detection and visualization of irregularly shaped clusters in multivariate data, by defining a hierarchical prior over all subsets of locations. While a naive search over the exponentially many subsets would be computationally infeasible, we demonstrate that the total posterior probability that each location has been affected can be efficiently computed, enabling rapid detection and visualization of irregular clusters. We compare the run time and detection power of this 'Fast Subset Sums' method to our original MBSS approach (assuming a uniform prior over circular regions) on semi-synthetic outbreaks injected into real-world Emergency Department data from Allegheny County, Pennsylvania. We demonstrate substantial improvements in spatial accuracy and timeliness of detection, while maintaining the scalability and fast run time of the original MBSS method.


Telomere longitudinal shortening as a biomarker for dementia status of adults with Down syndrome.
Previous studies have suggested that Alzheimer's disease (AD) causes an accelerated shortening of telomeres, the ends of chromosomes consisting of highly conserved TTAGGG repeats that, because of unidirectional 5'-3' DNA synthesis, lose end point material with each cell division. Our own previous work suggested that telomere length of T-lymphocytes might be a remarkably accurate biomarker for "mild cognitive impairment" in adults with Down syndrome (MCI-DS), a population at dramatically high risk for AD. To verify that the progression of cognitive and functional losses due to AD produced this observed telomere shortening, we have now examined sequential changes in telomere length in five individuals with Down syndrome (3F, 2M) as they transitioned from preclinical AD to MCI-DS (N = 4) or dementia (N = 1). As in our previous studies, we used PNA (peptide nucleic acid) probes for telomeres and the chromosome 2 centromere (as an "internal standard" expected to be unaffected by aging or dementia status), with samples from the same individuals now collected prior to and following development of MCI-DS or dementia. Consistent shortening of telomere length was observed over time. Further comparisons with our previous cross-sectional findings indicated that telomere lengths prior to clinical decline were similar to those of other adults with Down syndrome (DS) who have not experienced clinical decline while telomere lengths following transition to MCI-DS or dementia in the current study were comparable to those of other adults with DS who have developed MCI-DS or dementia. Taken together, findings indicate that telomere length has significant promise as a biomarker of clinical progression of AD for adults with DS, and further longitudinal studies of a larger sample of individuals with DS are clearly warranted to validate these findings and determine if and how factors affecting AD risk also influence these measures of telomere length.


Characterization of T cell clones from chagasic patients: predominance of CD8 surface phenotype in clones from patients with pathology.
Human Chagas' disease, caused by the protozoan Trypanosoma cruzi, is associated with pathological processes whose mechanisms are not known. To address this question, T cell lines were developed from chronic chagasic patients peripheral blood mononuclear cells (PBMC) and cloned. These T cell clones (TCC) were analyzed phenotypically with monoclonal antibodies by the use of a fluorescence microscope. The surface phenotype of the TCC from the asymptomatic patient were predominantly CD4 positive (86%). On the contrary, the surface phenotype CD8 was predominant in the TCC from the patients suffering from cardiomegaly with right bundle branch block (83%), bradycardia with megacolon (75%) and bradycardia (75%). Future studies will be developed in order to identify the antigens eliciting these T cell subpopulations.


A powerful and adaptive association test for rare variants.
This article focuses on conducting global testing for association between a binary trait and a set of rare variants (RVs), although its application can be much broader to other types of traits, common variants (CVs), and gene set or pathway analysis. We show that many of the existing tests have deteriorating performance in the presence of many nonassociated RVs: their power can dramatically drop as the proportion of nonassociated RVs in the group to be tested increases. We propose a class of so-called sum of powered score (SPU) tests, each of which is based on the score vector from a general regression model and hence can deal with different types of traits and adjust for covariates, e.g., principal components accounting for population stratification. The SPU tests generalize the sum test, a representative burden test based on pooling or collapsing genotypes of RVs, and a sum of squared score (SSU) test that is closely related to several other powerful variance component tests; a previous study (Basu and Pan 2011) has demonstrated good performance of one, but not both, of the Sum and SSU tests in many situations. The SPU tests are versatile in the sense that one of them is often powerful, although its identity varies with the unknown true association parameters. We propose an adaptive SPU (aSPU) test to approximate the most powerful SPU test for a given scenario, consequently maintaining high power and being highly adaptive across various scenarios. We conducted extensive simulations to show superior performance of the aSPU test over several state-of-the-art association tests in the presence of many nonassociated RVs. Finally we applied the SPU and aSPU tests to the GAW17 mini-exome sequence data to compare its practical performance with some existing tests, demonstrating their potential usefulness.


Chromosome assembled and annotated genome sequence of Aspergillus flavus NRRL 3357.
Aspergillus flavus is an opportunistic pathogen of crops, including peanuts and maize, and is the second leading cause of aspergillosis in immunocompromised patients. A. flavus is also a major producer of the mycotoxin, aflatoxin, a potent carcinogen, which results in significant crop losses annually. The A. flavus isolate NRRL 3357 was originally isolated from peanut and has been used as a model organism for understanding the regulation and production of secondary metabolites, such as aflatoxin. A draft genome of NRRL 3357 was previously constructed, enabling the development of molecular tools and for understanding population biology of this particular species. Here, we describe an updated, near complete, telomere-to-telomere assembly and re-annotation of the eight chromosomes of A. flavus NRRL 3357 genome, accomplished via long-read PacBio and Oxford Nanopore technologies combined with Illumina short-read sequencing. A total of 13,715 protein-coding genes were predicted. Using RNA-seq data, a significant improvement was achieved in predicted 5' and 3' untranslated regions, which were incorporated into the new gene models.


Cannabinoids, cannabis, and cannabis-based medicines for pain management: an overview of systematic reviews.
Cannabinoids, cannabis, and cannabis-based medicines (CBM) are increasingly used to manage pain, with limited understanding of their efficacy and safety. We assessed methodological quality, scope, and results of systematic reviews of randomised controlled trials of these treatments. Several search strategies sought self-declared systematic reviews. Methodological quality was assessed using both AMSTAR-2 and techniques important for bias reduction in pain studies. Of the 106 articles read, 57 were self-declared systematic reviews, most published since 2010. They included any type of cannabinoid, cannabis, or CBM, at any dose, however administered, in a broad range of pain conditions. No review examined the effects of a particular cannabinoid, at a particular dose, using a particular route of administration, for a particular pain condition, reporting a particular analgesic outcome. Confidence in the results in the systematic reviews using AMSTAR-2 definitions was critically low (41), low (8), moderate (6), or high (2). Few used criteria important for bias reduction in pain. Cochrane reviews typically provided higher confidence; all industry-conflicted reviews provided critically low confidence. Meta-analyses typically pooled widely disparate studies, and, where assessable, were subject to potential publication bias. Systematic reviews with positive or negative recommendation for use of cannabinoids, cannabis, or CBM in pain typically rated critically low or low (24/25 [96%] positive; 10/12 [83%] negative). Current reviews are mostly lacking in quality and cannot provide a basis for decision-making. A new high-quality systematic review of randomised controlled trials is needed to critically assess the clinical evidence for cannabinoids, cannabis, or CBM in pain.


Comparison of the effect of buspirone and 1-(2-pyrimidinyl)-piperazine on cerebral glucose utilization in the rat.
The novel anxiolytic and antidepressant, buspirone, and its main metabolite 1-(2-pyrimidinyl)-piperazine (1-PP), which is pharmacologically active, were examined for their effect on regional cerebral glucose utilization in awake rats using quantitative 2-deoxyglucose autoradiography. At a dose of 1 mg/kg, buspirone reduced glucose utilization in the hippocampus by approximately 15%, whilst 1-PP at the same dose had no effect. In comparison, at a higher dose, 10 mg/kg of both buspirone and 1-PP decreased glucose utilization in the hippocampus by 20% and 27%, respectively. In addition, widespread reductions in local cerebral glucose utilization were noted with this higher dose of 1-PP; such generalized effects are compatible with those reported for alpha 2 adrenoceptor antagonists. Buspirone at 1 and 10 mg/kg increased glucose utilization by 40% and 65%, respectively, in the lateral habenular nucleus, whilst 1-PP at 1 and 10 mg/kg had no effect. The findings suggest that buspirone's effects on glucose utilization cannot be attributed to 1-PP, unless high doses of buspirone are administered.


Origin and Processing Methods Slightly Affect Allergenic Characteristics of Cashew Nuts (Anacardium occidentale).
The protein content and allergen composition was studied of cashews from 8 different origins (Benin, Brazil, Ghana, India, Ivory Coast, Mozambique, Tanzania, Vietnam), subjected to different in-shell heat treatments (steamed, fried, drum-roasted). On 2D electrophoresis, 9 isoforms of Ana o 1, 29 isoforms of Ana o 2 (11 of the acidic subunit, 18 of the basic subunit), and 8 isoforms of the large subunit of Ana o 3 were tentatively identified. Based on 1D and 2D electrophoresis, no difference in allergen content (Ana o 1, 2, 3) was detected between the cashews of different origins (P > 0.5), some small but significant differences were detected in allergen solubility between differently heated cashews. No major differences in N- and C-terminal microheterogeneity of Ana o 3 were detected between cashews of different origins. Between the different heat treatments, no difference was detected in glycation, pepsin digestibility, or IgE binding of the cashew proteins.


Association Between Myocardial Injury and Cardiovascular Outcomes of Orthopaedic Surgery: A Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) Substudy.
Myocardial injury after noncardiac surgery (MINS) is common and of prognostic importance. Little is known about MINS in orthopaedic surgery. The diagnostic criterion for MINS was a level of ≥0.03 ng/mL on a non-high-sensitivity troponin T (TnT) assay due to myocardial ischemia. We undertook an international, prospective study of 15,103 patients ≥45 years of age who had inpatient noncardiac surgery; 3,092 underwent orthopaedic surgery. Non-high-sensitivity TnT assays were performed on postoperative days 0, 1, 2, and 3. Among orthopaedic patients, we determined (1) the prognostic relevance of the MINS diagnostic criteria, (2) the 30-day mortality rate for those with and without MINS, and (3) the probable proportion of MINS cases that would go undetected without troponin monitoring because of a lack of an ischemic symptom. Three hundred and sixty-seven orthopaedic patients (11.9%) had MINS. MINS was associated independently with 30-day mortality including among those who had had orthopaedic surgery. Orthopaedic patients without and with MINS had a 30-day mortality rate of 1.0% and 9.8%, respectively (odds ratio [OR], 11.28; 95% confidence interval [CI], 6.72 to 18.92). The 30-day mortality rate was increased for patients with MINS who had an ischemic feature (i.e., symptoms, or evidence of ischemia on electrocardiography or imaging) (OR, 18.25; 95% CI, 10.06 to 33.10) and for those who did not have an ischemic feature (OR, 7.35; 95% CI, 3.37 to 16.01). The proportion of orthopaedic patients with MINS who were asymptomatic and in whom the myocardial injury would have probably gone undetected without TnT monitoring was 81.3% (95% CI, 76.3% to 85.4%). One in 8 orthopaedic patients in our study had MINS, and MINS was associated with a higher mortality rate regardless of symptoms. Troponin levels should be measured after surgery in at-risk patients because most MINS cases (>80%) are asymptomatic and would go undetected without routine measurements. Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.


The D614G mutations in the SARS-CoV-2 spike protein: Implications for viral infectivity, disease severity and vaccine design.
The development of the SARS-CoV-2 pandemic has prompted an extensive worldwide sequencing effort to characterise the geographical spread and molecular evolution of the virus. A point mutation in the spike protein, D614G, emerged as the virus spread from Asia into Europe and the USA, and has rapidly become the dominant form worldwide. Here we review how the D614G variant was identified and discuss recent evidence about the effect of the mutation on the characteristics of the virus, clinical outcome of infection and host immune response.


Fit Minded College Edition Pilot Study: Can a Magazine-Based Discussion Group Improve Physical Activity in Female College Freshmen?
Initial efficacy of a magazine-based discussion group for improving physical activity (PA), self-worth, and eating behaviors in female college freshmen. Randomized control trial. A large university in southwestern United States. Thirty-seven female college freshmen were randomized to the intervention (n = 17) and control groups (n = 20) in September 2013. Participants completed an 8-week magazine-based discussion group program, Fit Minded College Edition, adapted from Fit Minded, a previously tested theory-based intervention. Education on PA, self-worth, and nutrition was provided using excerpts from women's health magazines. Participants also had access to a Web site with supplementary health and wellness material. The control group did not attend meetings or have access to the Web site but received the magazines. Interventions focusing on concepts of self-worth with less focus on weight and appearance may promote long term PA participation and healthy eating behaviors in college women. Self-reported PA, global self-worth, knowledge self-worth, self-efficacy, social support, eating behaviors (ie, fruit/veggie/junk food/sugar-sweetened beverage consumption), satisfaction, and Web site usage. Mean age of participants was 18.11 (SD = 0.32) years. Time × Intervention effects were observed for PA minutes per week (Partial η = 0.34), knowledge self-worth (Partial η = 0.02), and daily sugar-sweetened beverage consumption (Partial η = 0.17) (P < .05), with the intervention group reporting greater increases in PA and knowledge self-worth and greater decreases in sugar-sweetened beverage consumption. A magazine-based discussion group may provide a promising platform to improve health behaviors in female college freshmen.


In pursuit of the ideal antifungal agent for Candida infections: high-throughput screening of small molecules.
Candida infections have created a great burden on the public healthcare sector. The situation is worsened by recent epidemiological changes. Furthermore, the current arsenal of antifungal agents is limited and associated with undesirable drawbacks. Therefore, new antifungal agents that surpass the existing ones are urgently needed. High-throughput screening of small molecule libraries enables rapid hit identification and, possibly, increases hit rate. Moreover, the identified hits could be associated with unrecognized or multiple drug targets, which would provide novel insights into the biological processes of the pathogen. Hence, it is proposed that high-throughput screening of small molecules is particularly important in the pursuit of the ideal antifungal agents for Candida infections.


Vaccine-generated lung tissue-resident memory T cells provide heterosubtypic protection to influenza infection.
Tissue-resident memory T cells (TRM) are a recently defined, noncirculating subset with the potential for rapid in situ protective responses, although their generation and role in vaccine-mediated immune responses is unclear. Here, we assessed TRM generation and lung-localized protection following administration of currently licensed influenza vaccines, including injectable inactivated influenza virus (IIV, Fluzone) and i.n. administered live-attenuated influenza virus (LAIV, FluMist) vaccines. We found that, while IIV preferentially induced strain-specific neutralizing antibodies, LAIV generated lung-localized, virus-specific T cell responses. Moreover, LAIV but not IIV generated lung CD4+ TRM and virus-specific CD8+ TRM, similar in phenotype to those generated by influenza virus infection. Importantly, these vaccine-generated TRM mediated cross-strain protection, independent of circulating T cells and neutralizing antibodies, which persisted long-term after vaccination. Interestingly, intranasal administration of IIV or injection of LAIV failed to elicit T cell responses or provide protection against viral infection, demonstrating dual requirements for respiratory targeting and a live-attenuated strain to establish TRM. The ability of LAIV to generate lung TRM capable of providing long-term protection against nonvaccine viral strains, as demonstrated here, has important implications for protecting the population against emergent influenza pandemics by direct fortification of lung-specific immunity.


Fertility and use of cigarettes, alcohol, marijuana, and cocaine.
This study demonstrated that cigarette smoking was associated with an increase in both time to conception (among 2817 fertile women) and risk of primary infertility (among 1818 infertile women and their primiparous control subjects). The average time to conception was 4.3 months for women who never smoked, 4.6 months for those who smoked in the past, and 5.1 months for those who currently smoked. The delay in conception for current smokers remained significant after adjusting for confounders (risk ratio of 0.9 (0.8 to 1.0)). Additionally, current smokers were at increased risk of primary infertility (odd ratios of 1.9 (1.5 to 2.3)). For alcohol use, the average time to conception and risk of primary infertility did not vary by level of consumption. The average time to conception was significantly shorter for women who had used marijuana regularly and for women who had ever used cocaine than for women who had never used these drugs. Because of the increased use of marijuana and cocaine among young adults, further investigations of these associations are needed.