Host metabolite producing endophytic fungi isolated from Hypericum perforatum.
In the present study, endophytic fungi have been isolated from various parts of the medicinal herb Hypericum perforatum (St. John's Wort), which is known as a source of medically important metabolites. The isolated strains were cultured in liquid media and their ability to synthesize hypericin, the secondary metabolite of the host and its suspected precursor, emodin was tested analyzing the extracts of the fermentation broth and the mycelia. The HPLC-UV analysis of the chloroform/methanol extracts of the mycelia revealed that three isolates were able to produce emodin (SZMC 23771, 19.9 ng/mg; SZMC 23772, 20.8 ng/mg; SZMC 23769, 427.9 ng/mg) and one of them also could synthesize hypericin (SZMC 23769, 320.4 ng/mg). These results were also confirmed via UHPLC-HRMS technique both in full scan and MS/MS mode. The strains producing only emodin belong to the section Alternata of the genus Alternaria, while the isolate producing both metabolites was identified as Epicoccum nigrum. The mycelial extracts of E. nigrum and the Alternaria sp. SZMC 23772 showed higher inhibitory activities in the antimicrobial tests against the six selected bacteria compared to the hypericin and emodin standards in the applied concentration (100 μg/mL), while in case of the Alternaria sp. SZMC 23771 lower inhibition activities were observed on Staphylococcus aureus and Streptomyces albus than the pure compounds.


TRANSLATOR Database-A Vision for a Multi-Institutional Research Network.
The formation of the CTSI One Health Alliance (COHA) network has generated the infrastructure necessary to support "Big Data" collaborative comparative and translational research in veterinary medicine. We describe the first step in the design, implementation, and dissemination of a collaborative information technology infrastructure that will serve the public and clinicians (COHA public/member based web site at https://ctsaonehealthalliance.org/) and its research focused COHA Research Workbench application. The core research infrastructure, TRANSLATOR (TRanslational ANimal Shared ColLAboraTive Observational Research), represents the foundation of a federated research-capable network to enable pooling large datasets from both electronic health records and publications. The public facing COHA website is a mechanism for both the dissemination of knowledge to the public and to foster collaborations amongst veterinary clinician scientists and the greater medical research community.


Long-term effects of a parenting preventive intervention on young adults' painful feelings about divorce.
This study examined whether the New Beginnings Program (NBP), a parenting preventive intervention for divorced mothers that was designed to reduce children's postdivorce mental health problems, reduced painful feelings about divorce in young adults whose families had participated 15 years earlier. This study also explored whether NBP participation reduced the relations between young adults' painful feelings about divorce and their concurrent internalizing, externalizing, and substance use problems. Participants (M = 25.6 years; 50% female; 88% Caucasian) were from 240 families that had been recruited into a randomized experimental trial (NBP vs. literature control). Data from the pretest and 15-year follow-up were used. NBP participants reported less feelings of seeing life through a filter of divorce (e.g., thinking about how the divorce causes continued struggles for them) than those in the control condition. Program effects on maternal blame and acceptance of the divorce were moderated by pretest risk, a composite of divorce-related stressors and externalizing problems. NBP participants with elevated risk at program entry had lower levels of maternal blame. Program participation was associated with higher acceptance for those with elevated risk at program entry but lower acceptance for those with low risk at program entry. Program participation decreased the relations between maternal blame, acceptance of the divorce and filter of divorce and some, but not all, of the adjustment outcomes. These findings suggest that programs designed to help families after divorce have benefits in terms of long-term feelings about parental divorce as well as their relations with adjustment problems. (PsycINFO Database Record


Risk factors for preterm delivery: do they add to fetal fibronectin testing and cervical length measurement in the prediction of preterm delivery in symptomatic women?
To assess whether patient characteristics add to the fetal fibronectin test and cervical length measurement in the prediction of preterm delivery in symptomatic women. A nationwide prospective cohort study was conducted in all ten perinatal centres in the Netherlands. Women with symptoms of preterm labour between 24 and 34 weeks gestation with intact membranes were invited. In all women qualitative fibronectin testing (0.050 μg/mL cut-off) and cervical length measurement were performed. Only singleton pregnancies were included in this analysis. Logistic regression was used to construct two multivariable models to predict spontaneously delivery within 7 days: a model including cervical length and fetal fibronectin as predictors, and an extended model including all potential predictors. The models were internally validated using bootstrapping techniques. Predictive performances were assessed as the area under the receiver operator characteristic curve (AUC) and calibration plots. We compared the models' capability to identify women with a low risk to deliver within 7 days. A risk less than 5%, corresponding to the risk for women with a cervical length of at least 25 mm, was considered as low risk. Seventy-three of 600 included women (12%) had delivered spontaneously within 7 days. The extended model included maternal age, parity, previous preterm delivery, vaginal bleeding, C-reactive protein, cervical length, dilatation and fibronectin status. Both models had high discriminative performances (AUC of 0.92 (95% CI 0.88-0.95) and 0.95 (95% CI 0.92-0.97) respectively). Compared to the model with fibronectin and cervical length, our extended model reclassified 38 women (6%) from low risk to high risk and 21 women (4%) from high risk to low risk. Preterm delivery within 7 days occurred once in both the reclassification groups. In women with symptoms of preterm labour before 34 weeks gestation, a model that integrates maternal characteristics, clinical signs and laboratory tests, did not predict delivery within 7 days better than a model with only fibronectin and cervical length.


Dehumanized Perception: A Psychological Means to Facilitate Atrocities, Torture, and Genocide?
Dehumanized perception, a failure to spontaneously consider the mind of another person, may be a psychological mechanism facilitating inhumane acts like torture. Social cognition - considering someone's mind - recognizes the other as a human being subject to moral treatment. Social neuroscience has reliably shown that participants normally activate a social-cognition neural network to pictures and thoughts of other people; our previous work shows that parts of this network uniquely fail to engage for traditionally dehumanized targets (homeless persons or drug addicts; see Harris & Fiske, 2009, for review). This suggests participants may not consider these dehumanized groups' minds. Study 1 demonstrates that participants do fail to spontaneously think about the contents of these targets' minds when imagining a day in their life, and rate them differently on a number of human-perception dimensions. Study 2 shows that these human-perception dimension ratings correlate with activation in brain regions beyond the social-cognition network, including areas implicated in disgust, attention, and cognitive control. These results suggest that disengaging social cognition affects a number of other brain processes and hints at some of the complex psychological mechanisms potentially involved in atrocities against humanity.


Local anesthetics induce apoptosis in human breast tumor cells.
Previous studies have shown that local anesthetics may induce apoptosis in some cell types. In this study, we investigated the apoptotic effects of local anesthetics in human breast tumor cells. Human breast cancer (MCF-7) and mammary epithelial (MCF-10A) cell lines were treated with lidocaine and/or bupivacaine. Cell viability, DNA fragmentation, and annexin V immunofluorescence staining were assessed. The effects on apoptosis-related protein expression were investigated by Western blot analysis. The findings were extended to studies in an in vivo xenograft model. Treatment of breast tumor cells with lidocaine and bupivacaine resulted in inhibition of cell viability via induction of apoptosis. The effects were more prominent in MCF-7 cells than in MCF-10A cells. Treatment with local anesthetics induced caspase 7, 8, 9, and poly ADP-ribose polymerase cleavage. The cleavage of caspase 7 and poly ADP-ribose polymerase induced by local anesthetics were effectively blocked by caspase inhibitors. Furthermore, treatment of MCF-7 xenografts with local anesthetics resulted in higher expression of cleaved caspase 7 and an increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining. Lidocaine and bupivacaine induce apoptosis of breast tumor cells at clinically relevant concentrations. Our results reveal previously unrecognized beneficial actions of local anesthetics and call for further studies to assess the oncologic advantages of their use during breast cancer surgery.


Divergent viral presentation among human tumors and adjacent normal tissues.
We applied a newly developed bioinformatics system called VirusScan to investigate the viral basis of 6,813 human tumors and 559 adjacent normal samples across 23 cancer types and identified 505 virus positive samples with distinctive, organ system- and cancer type-specific distributions. We found that herpes viruses (e.g., subtypes HHV4, HHV5, and HHV6) that are highly prevalent across cancers of the digestive tract showed significantly higher abundances in tumor versus adjacent normal samples, supporting their association with these cancers. We also found three HPV16-positive samples in brain lower grade glioma (LGG). Further, recurrent HBV integration at the KMT2B locus is present in three liver tumors, but absent in their matched adjacent normal samples, indicating that viral integration induced host driver genetic alterations are required on top of viral oncogene expression for initiation and progression of liver hepatocellular carcinoma. Notably, viral integrations were found in many genes, including novel recurrent HPV integrations at PTPN13 in cervical cancer. Finally, we observed a set of HHV4 and HBV variants strongly associated with ethnic groups, likely due to viral sequence evolution under environmental influences. These findings provide important new insights into viral roles of tumor initiation and progression and potential new therapeutic targets.


An Examination of the Effects of Leuprolide Acetate Used in the Treatment of Central Precocious Puberty on Bone Mineral Density and 25-Hydroxy Vitamin D.
Leuprolide acetate is a gonadotropin-releasing hormone (GnRH) analogue frequently used in the treatment of central precocious puberty. Research is currently taking place into its effects on endocrine systems. The aim of this study is to investigate the effect of leuprolide acetate on vitamin D and bone mineral density. Twenty-three children diagnosed with central precocious puberty and receiving leuprolide acetate therapy for at least 12 months, and a control group of 17 healthy children were enrolled. In the study group, calcium, phosphorus, alkaline phosphatase, parathormone and 25-hydroxy vitamin D levels and bone mineral density were measured. The results were compared with those of the control group. 25-Hydroxy vitamin D levels in the study and control groups were 15.17 ± 7 mg/dL and 22.2 ± 6.1 mg/dL, respectively (p < 0.05). In terms of bone mineral density, osteopenia was determined in 13 (56.5%) patients in the study group and osteoporosis in one (4.3%), while osteopenia was identified in seven patients in the control group, with no osteoporosis being identified (p > 0.05). Gonadotropin-releasing hormone agonists may have an adverse effect on bone health. They may exhibit these effects by impacting on vitamin D levels. These levels should be periodically monitored in patients receiving treatment, and vitamin D support should be given in cases where the deficiency is identified.


Evolutionary loss of a signalling colour is linked to increased response to conspecific chemicals.
Behavioural responses to communicative signals combine input from multiple sensory modalities and signal compensation theory predicts that evolutionary shifts in one sensory modality could impact the response to signals in other sensory modalities. Here, we conducted two types of field experiments with 11 species spread across the lizard genus Sceloporus to test the hypothesis that the loss of visual signal elements affects behavioural responses to a chemical signal (conspecific scents) or to a predominantly visual signal (a conspecific lizard), both of which are used in intraspecific communication. We found that three species that have independently lost a visual signal trait, a colourful belly patch, responded to conspecific scents with increased chemosensory behaviour compared to a chemical control, while species with the belly patch did not. However, most species, with and without the belly patch, responded to live conspecifics with increased visual displays of similar magnitude. While aggressive responses to visual stimuli are taxonomically widespread in Sceloporus, our results suggest that increased chemosensory response behaviour is linked to colour patch loss. Thus, interactions across sensory modalities could constrain the evolution of complex signalling phenotypes, thereby influencing signal diversity.


Enhancement of adenovirus vector entry into CD70-positive B-cell Lines by using a bispecific CD70-adenovirus fiber antibody.
Although many recombinant adenovirus vectors (rAd) have been developed, especially by using group C adenoviruses, to transfer and express genes, such rAd do not readily infect B-cell lines due to the lack of the coxsackievirus-adenovirus receptor. Bispecific antibodies have been used in different cell systems to facilitate entry of rAd into otherwise nonpermissive cells. Bispecific antibody is synthesized by covalently linking two monoclonal antibodies with distinct specificities. It has been shown that lymphoproliferative tumors commonly express the cell surface protein CD70, while this receptor is normally expressed on only a small subset of highly activated B cells and T cells. We therefore investigated whether a bispecific antibody with specificities for the adenovirus fiber protein and CD70 can facilitate rAd entry and subsequent expression of rAd-encoded genes in CD70-positive B cells. We found high CD70 expression on Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs), as well as some, but not all, Burkitt lymphoma (BL) lines. We show here that rAd encoding green fluorescent protein (Ad-GFP) infects EBV-transformed LCLs and a CD70-positive BL line 10- to 20-fold more efficiently in the presence of the CD70-fiber bispecific antibody. In contrast, the bispecific antibody does not enhance Ad-GFP infection in CD70-deficient BL cells. Using the CD70-fiber bispecific antibody, we increased the ability of rAd vectors encoding the EBV immediate-early proteins BZLF1 and BRLF1 to induce the lytic form of EBV infection in LCLs. These results indicate that the CD70-fiber bispecific antibody can enhance rAd infection of CD70-positive B cells and suggest the use of this vector to explore EBV-positive LCLs.


Democratic Policing and Officer Well-Being.
Efforts to improve police-community relationships have increased initiatives that aim to build trust and mutual respect between officers and the communities they serve. Existing literature examines the impact of internal departmental dynamics and individual-level characteristics on officers' endorsement of community-oriented policing strategies. Research has indicated that when officers feel fairly treated within their agencies and when they are less psychologically and emotionally distressed, they report stronger support for policing tactics that increase fairness in police processes and decision making. This mixed-method study is the first to examine the reciprocal relationship by asking: How do procedurally just and community-oriented policing strategies impact officer well-being and occupational stress? Sworn officers in a medium-sized California department completed a survey assessing their views on their agency, various police tactics, the communities they serve, and their physical and mental health. Results showed that officers' increased support for community-oriented and procedurally just police strategies are significantly associated with decreased job stress, depression, anxiety, and negative affect, controlling for race, gender, perceived job dangerousness, cynicism, and how many years they had served as a police officer. In-depth interviews with officers in the department revealed three explanatory mechanisms for these statistical relationships. First, the tenets of procedural justice provided officers with tactics that reduce the threat and stress of intergroup interactions. Second, community-oriented policing activities increased opportunities for officers to have positive interactions with the communities they work in, mitigating the distrust, cynicism, and detachment fostered by enforcement activities. Last, procedural justice and community-oriented police strategies empowered officers to counter negative stereotypes about police and reaffirm their self-image. Taken together, these survey and interview findings highlight the mutuality of democratic policing and officer wellness.


Polypeptide self-assemblies: nanostructures and bioapplications.
Polypeptide copolymers can self-assemble into diverse aggregates. The morphology and structure of aggregates can be varied by changing molecular architectures, self-assembling conditions, and introducing secondary components such as polymers and nanoparticles. Polypeptide self-assemblies have gained significant attention because of their potential applications as delivery vehicles for therapeutic payloads and as additives in the biomimetic mineralization of inorganics. This review article provides an overview of recent advances in nanostructures and bioapplications related to polypeptide self-assemblies. We highlight recent contributions to developing strategies for the construction of polypeptide assemblies with increasing complexity and novel functionality that are suitable for bioapplications. The relationship between the structure and properties of the polypeptide aggregates is emphasized. Finally, we briefly outline our perspectives and discuss the challenges in the field.


Age-patterns of malaria vary with severity, transmission intensity and seasonality in sub-Saharan Africa: a systematic review and pooled analysis.
There is evidence that the age-pattern of Plasmodium falciparum malaria varies with transmission intensity. A better understanding of how this varies with the severity of outcome and across a range of transmission settings could enable locally appropriate targeting of interventions to those most at risk. We have, therefore, undertaken a pooled analysis of existing data from multiple sites to enable a comprehensive overview of the age-patterns of malaria outcomes under different epidemiological conditions in sub-Saharan Africa. A systematic review using PubMed and CAB Abstracts (1980-2005), contacts with experts and searching bibliographies identified epidemiological studies with data on the age distribution of children with P. falciparum clinical malaria, hospital admissions with malaria and malaria-diagnosed mortality. Studies were allocated to a 3x2 matrix of intensity and seasonality of malaria transmission. Maximum likelihood methods were used to fit five continuous probability distributions to the percentage of each outcome by age for each of the six transmission scenarios. The best-fitting distributions are presented graphically, together with the estimated median age for each outcome. Clinical malaria incidence was relatively evenly distributed across the first 10 years of life for all transmission scenarios. Hospital admissions with malaria were more concentrated in younger children, with this effect being even more pronounced for malaria-diagnosed deaths. For all outcomes, the burden of malaria shifted towards younger ages with increasing transmission intensity, although marked seasonality moderated this effect. The most severe consequences of P. falciparum malaria were concentrated in the youngest age groups across all settings. Despite recently observed declines in malaria transmission in several countries, which will shift the burden of malaria cases towards older children, it is still appropriate to target strategies for preventing malaria mortality and severe morbidity at very young children who will continue to bear the brunt of malaria deaths in sub-Saharan Africa.


Sleep, death, and the heart.
Obstructive and central sleep apnea have been associated with increased risk of adverse cardiovascular events and mortality. Sympathetic dysregulation occurring as a result of the respiratory disturbance is thought to play a role in this increased risk. Sleep apnea increases the risk of arrhythmias, myocardial ischemia/infarction, stroke, and heart failure, all of which may increase mortality risk. A higher incidence of nocturnal arrhythmias, cardiac ischemia, and sudden death has been noted in subjects with sleep-disordered breathing (SDB). In this review, the association between SDB and each of these conditions is discussed, as well as the potential mechanisms underlying these risks and the effects of treatment of SDB. Particular emphasis is placed on the relationship between SDB and nocturnal atrial and ventricular arrhythmias, myocardial ischemia/infarction and sudden death.


Nodal signaling patterns the organizer.
Spemann's organizer plays an essential role in patterning the vertebrate embryo. During gastrulation, organizer cells involute and form the prechordal plate anteriorly and the notochord more posteriorly. The fate mapping and gene expression analyses in zebrafish presented in this study reveal that this anteroposterior polarity is already initiated in the organizer before gastrulation. Prechordal plate progenitors reside close to the blastoderm margin and express the homeobox gene goosecoid, whereas notochord precursors are located further from the margin and express the homeobox gene floating head. The nodal-related genes cyclops and squint are expressed at the blastoderm margin and are required for prechordal plate and notochord formation. We show that differential activation of the Nodal signaling pathway is essential in establishing anteroposterior pattern in the organizer. First, overexpression of cyclops and squint at different doses leads to the induction of floating head at low doses and the induction of both goosecoid and floating head at higher doses. Second, decreasing Nodal signaling using different concentrations of the antagonist Antivin inhibits goosecoid expression at low doses and blocks expression of both goosecoid and floating head at higher doses. Third, attenuation of Nodal signaling in zygotic mutants for the EGF-CFC gene one-eyed pinhead, an essential cofactor for Nodal signaling, leads to the loss of goosecoid expression and expansion of floating head expression in the organizer. Concomitantly, cells normally fated to become prechordal plate are transformed into notochord progenitors. Finally, activation of Nodal signaling at different times suggests that prechordal plate specification requires sustained Nodal signaling, whereas transient signaling is sufficient for notochord development. Together, these results indicate that differential Nodal signaling patterns the organizer before gastrulation, with the highest level of activity required for anterior fates and lower activity essential for posterior fates.


Attentional modulation of adaptation to illusory lines.
Selective visual attention modulates neuronal activation in various cortical areas. This type of neuronal modulation could happen even in the early stages of visual processing where specific attributes of visual stimuli are processed. It has been shown that different forms of visual aftereffects, such as tilt aftereffect, motion aftereffect, and figural aftereffect, are modulated by attention. In this study, we investigated the effect of visual attention on adaptation to illusory lines. In the first experiment, orientation selective adaptation to a peripheral illusory line was measured in three conditions: (1) poor attention condition in which subjects performed a dual task (even-odd judgment) at the fixation point during the adaptation period, (2) partial attention condition in which subjects only observed successively presented digits at the fixation point and did not perform the task during the adaptation period, and (3) full attention condition in which no visual stimuli were presented at the fixation point. Results showed that the magnitude of adaptation systematically decreased as the attentional load at the fixation point increased. In the second experiment, two transparent illusory contours were presented during the adaptation period, and tilt aftereffects to attended and non-attended illusory lines were compared. The magnitude of tilt aftereffect to the attended illusory line was significantly greater than that to the non-attended illusory line even when non-attended illusory contour was more visually salient. Because visual areas V2 and V1 are the first stage in the processing of illusory contours, we could conclude that visual attention has modulatory effects on the activation of neurons in these areas.


A brief social-belonging intervention in college improves adult outcomes for black Americans.
Could mitigating persistent worries about belonging in the transition to college improve adult life for black Americans? To examine this question, we conducted a long-term follow-up of a randomized social-belonging intervention delivered in the first year of college. This 1-hour exercise represented social and academic adversity early in college as common and temporary. As previously reported in Science, the exercise improved black students' grades and well-being in college. The present study assessed the adult outcomes of these same participants. Examining adult life at an average age of 27, black adults who had received the treatment (versus control) exercise 7 to 11 years earlier reported significantly greater career satisfaction and success, psychological well-being, and community involvement and leadership. Gains were statistically mediated by greater college mentorship. The results suggest that addressing persistent social-psychological concerns via psychological intervention can shape the life course, partly by changing people's social realities.


Diabetes mellitus does not affect jugular bulb oxygen saturation in patients undergoing off-pump coronary artery bypass graft surgery.
Diabetes mellitus (DM) is associated with the impairment of cerebral oxygenation during cardiac surgery. The aim of the present study was to investigate the effects of DM on cerebral oxygenation assessed by jugular bulb oxygen saturation (SjvO2) in patients undergoing off-pump coronary artery bypass graft surgery (OPCAB) in a prospective controlled trial. Twenty-three diabetic patients with glycosylated hemoglobin above 7.0% (DM group) and 23 non-diabetic patients (control group) undergoing OPCAB with no-touch aortic technique were included. A fiberoptic oximetry catheter was inserted into the jugular bulb. The lowest SjvO2 and the number of patients with cerebral desaturation, defined as SjvO2 less than 50% over 5 min, were recorded during coronary grafting. Three neurocognitive tests were done before surgery and at postoperative day 2 and 7. There were no differences in SjvO2 between the groups. Furthermore, the number of patients with cerebral desaturation and all neurocognitive test scores were similar between the 2 groups. None of the patients developed neurocognitive dysfunction. Cerebral oxygenation in diabetic patients was similar to that of non-diabetic patients and well maintained above the critical level without resulting in clinically significant postoperative neurocognitive dysfunction during OPCAB with no-touch aortic technique.


Initial dosimetric experience with mega voltage computed tomography detectors and estimation of pre and post-repair dosimetric parameters of a first Helical Hi-Art II tomotherapy machine in India.
A Helical Tomotherapy (HT) Hi-Art II (TomoTherapy, Inc., Madison, WI, USA) has been one of the important innovations to help deliver IMRT with image guidance. On-board, mega voltage computed tomography (MVCT) detectors are used for imaging and dosimetric purpose. The two objectives of this study are: (i) To estimate the dosimetric and general capability (TomoImage registration, reconstruction, contrast and spatial resolution, artifacts-free image and dose in TomoImage) of on-board MVCT detectors. (ii) To measure the dosimetric parameters (output and energy) following major repair. The MVCT detectors also estimated the rotational output constancy well. During this study, dosimetric tests were repeated after replacing MVCT detectors and the target. fixed-gantry/fixed-couch measurements were measured daily to investigate; the system stability. Thermoluminescense dosimeter (TLD) was used during both the measurements subsequently. The MVCT image quality with old and new detectors was comparable and hence acceptable clinically. The spatial resolution was optimal and the dose during TomoImage was 2 cGy (well within the manufacturer tolerance of 4 cGy). The results of lateral beam profiles showed an excellent agreement between the two normalized plots. The output from the rotational procedure revealed 99.7% while the energy was consistent over a period of twelve months. The Hi-Art II system has maintained its calibration to within +/- 2% and energy to within +/- 1.5% over the initial twelve-month period. Based on the periodic measurements for rotational output and consistency in the lateral beam profile shape, the on-board detector proved to be a viable dosimetric quality assurance tool for IMRT with Tomotherapy. Tomotherapy was stable from the dosimetric point of view during the twelve-month period.


Effects of web-based stress and depression literacy intervention on improving work engagement among workers with low work engagement: An analysis of secondary outcome of a randomized controlled trial.
The purpose of this randomized, controlled trial was to examine the effects of a psychoeducational information website on improving work engagement among individual workers with low work engagement, where work engagement was measured as a secondary outcome. Participants were recruited from registered members of a web survey site in Japan. Participants who fulfilled the eligibility criteria were randomly allocated to intervention or control groups. Immediately after the baseline survey, the intervention group was invited to study a psychoeducational website called the "UTSMed," which provided general mental health literacy and cognitive behavioral skills. Work engagement was assessed by using the Utrecht Work Engagement Scale at baseline, 1-, and 4-month follow-ups for both intervention and control groups. An exploratory analysis was conducted for a subgroup with low (lower than the median scores) work engagement scores at baseline. A total of 1,236 workers completed the baseline survey. In the low work engagement subgroup, a total of 313 and 300 participants were allocated to an intervention and control group, respectively. In the high work engagement subgroup, 305 and 318 participants were allocated to an intervention and control group, respectively. The program showed a significant effect on work engagement (t = 1.98, P = 0.048) at the 4-month follow-up in the low work engagement subgroup, with a small effect size (d = 0.17). A web-based psychoeducation resource of mental health literacy and cognitive behavioral skills may be effective for improving work engagement among individual workers with low work engagement.


Serum cortisol and BDNF in patients with major depression-effect of yoga.
Depression is associated with low serum Brain Derived Neurotrophic Factor (BDNF) and elevated levels of serum cortisol. Yoga practices have been associated with antidepressant effects, increase in serum BDNF, and reduction in serum cortisol. This study examined the association between serum BDNF and cortisol levels in drug-naïve patients with depression treated with antidepressants, yoga therapy, and both. Fifty-four drug-naïve consenting adult outpatients with Major Depression (32 males) received antidepressants only (n = 16), yoga therapy only (n = 19), or yoga with antidepressants (n = 19). Serum BDNF andcortisol levels were obtained before and after 3 months using a sandwich ELISA method. One-way ANOVA, Chi-square test, and Pearson's correlation tests were used for analysis. The groups were comparable at baseline on most parameters. Significant improvement in depression scores and serum BDNF levels, and reduction in serum cortisol in the yoga groups, have been described in previous reports. A significant negative correlation was observed between change in BDNF (pre-post) and cortisol (pre-post) levels in the yoga-only group (r = -0.59, p = 0.008). In conclusion, yoga may facilitate neuroplasticity through stress reduction in depressed patients. Further studies are needed to confirm the findings and delineate the pathways for these effects.


Using tandem mass spectrometry in targeted mode to identify activators of class IA PI3K in cancer.
Phosphatiditylinositide-3-kinase (PI3K) is activated in some cancers by direct mutation, but it is activated more commonly in cancer by mutation of upstream acting receptor tyrosine kinases (TK). At present, there is no systematic method to determine which TK signaling cascades activate PI3K in certain cancers, despite the likely utility of such information to help guide selection of tyrosine kinase inhibitor (TKI) drug strategies for personalized therapy. Here, we present a quantitative liquid chromatography tandem mass spectrometry approach that identifies upstream activators of PI3K both in vitro and in vivo. Using non-small cell lung carcinoma to illustrate this approach, we show a correct identification of the mechanism of PI3K activation in several models, thereby identifying the most appropriate TKI to downregulate PI3K signaling. This approach also determined the molecular mechanisms and adaptors required for PI3K activation following inhibition of the mTOR kinase TORC1. We further validated the approach in breast cancer cells with mutational activation of PIK3CA, where tandem mass spectrometry detected and quantitatively measured the abundance of a helical domain mutant (E545K) of PIK3CA connected to PI3K activation. Overall, our findings establish a mass spectrometric approach to identify functional interactions that govern PI3K regulation in cancer cells. Using this technique to define the pathways that activate PI3K signaling in a given tumor could help inform clinical decision making by helping guide personalized therapeutic strategies for different patients.


Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20,536 high-risk individuals: a randomised controlled trial.
Findings of large randomised trials have shown that lowering LDL cholesterol with statins reduces vascular morbidity and mortality rapidly, but limited evidence exists about the long-term efficacy and safety of statin treatment. The aim of the extended follow-up of the Heart Protection Study (HPS) is to assess long-term efficacy and safety of lowering LDL cholesterol with statins, and here we report cause-specific mortality and major morbidity in the in-trial and post-trial periods. 20,536 patients at high risk of vascular and non-vascular outcomes were allocated either 40 mg simvastatin daily or placebo, using minimised randomisation. Mean in-trial follow-up was 5·3 years (SD 1·2), and post-trial follow-up of surviving patients yielded a mean total duration of 11·0 years (SD 0·6). The primary outcome of the long-term follow-up of HPS was first post-randomisation major vascular event, and analysis was by intention to treat. This trial is registered with ISRCTN, number 48489393. During the in-trial period, allocation to simvastatin yielded an average reduction in LDL cholesterol of 1·0 mmol/L and a proportional decrease in major vascular events of 23% (95% CI 19-28; p<0·0001), with significant divergence each year after the first. During the post-trial period (when statin use and lipid concentrations were similar in both groups), no further significant reductions were noted in either major vascular events (risk ratio [RR] 0·95 [0·89-1·02]) or vascular mortality (0·98 [0·90-1·07]). During the combined in-trial and post-trial periods, no significant differences were recorded in cancer incidence at all sites (0·98 [0·92-1·05]) or any particular site, or in mortality attributed to cancer (1·01 [0·92-1·11]) or to non-vascular causes (0·96 [0·89-1·03]). More prolonged LDL-lowering statin treatment produces larger absolute reductions in vascular events. Moreover, even after study treatment stopped in HPS, benefits persisted for at least 5 years without any evidence of emerging hazards. These findings provide further support for the prompt initiation and long-term continuation of statin treatment. UK Medical Research Council, British Heart Foundation, Merck & Co, Roche Vitamins.


Case report: unusual complication during outpatient continuous regional popliteal analgesia.
Continuous regional anesthesia applied as pain therapy at home is clinically established standard practice after upper and lower limb surgery. Persistent motor block at discharge or after continuous infusion of local anesthetics, however, might lead to complications related to the insensate extremity. We report a rare case of a foot fracture due to stumbling after continuous sciatic nerve block at home and discuss the related clinical implications. After uncomplicated ambulatory foot surgery under regional anesthesia, a patient was discharged with a continuous sciatic popliteal nerve block for pain therapy at home. After stumbling, the patient remained symptom-free even until catheter removal three days after surgery. Radiography done one week after surgery revealed a styloid fracture of the fifth metatarsal bone. Her subsequent recovery was uneventful. The true incidence of complications related to falls at home associated with lower extremity blockade remains unknown, as symptoms of possible complications may be masked by the effects of the local anesthetic. However, with increasing use of postoperative regional anesthesia, it is mandatory to develop and adhere to clinical care maps, and to elaborate and teach strategies to further enhance patient safety.


Oxidation-reduction properties of the cytochrome b found in the plasma-membrane fraction of human neutrophils. A possible oxidase in the respiratory burst.
The oxidation-reduction midpoint potential of the cytochrome b found in the plasma membrane of human neutrophils has been determined at pH 7.0 (Em,7.0) from measurements of absorption spectra at fixed potentials. In both unstimulated and phorbol myristate acetate-stimulated cells Em,7.0 was -245 mV. Changes in pH affected the Em of the cytochrome b, with a slope of approx. 25 mV/pH unit change. The Em,7.0 of the haem group(s) of the membrane-bound myeloperoxidase of human neutrophils was found to be +34 mV. The plasma membranes contained no detectable ubiquinone, and no iron-sulphur compounds were detected by e.p.r. spectroscopy at 5-20 K. No flavins were detected by e.p.r. spectroscopy. The cytochrome b-245 was not reduced by added NADH or NADPH. Dithionite-reduced cytochrome b-245 formed a complex with CO, supplied as a saturated solution, which was dissociated with 26 microseconds illumination from a xenon flash lamp, and the recombination with CO had a half-time of approx. 6 ms. Partly (80%) reduced cytochrome b-245 was oxidized by added air-saturated buffer with a half-time faster than 1 s at 20 degrees C, a resolution limited by mixing time. These results are compatible with cytochrome b-245 acting as an oxidase.


Training needs analysis. A literature review and reappraisal.
Training needs analysis is the initial step in a cyclical process which contributes to the overall training and educational strategy of staff in an organisation or a professional group. The cycle commences with a systematic consultation to identify the learning needs of the population considered, followed by course planning, delivery and evaluation. Although much has been written about training needs analysis in relation to post-registration nursing education, there is disagreement concerning its impact on the training cycle and its potential to influence service delivery. This stimulated the literature review presented below. Initial searches of nursing databases identified 266 works. Twenty three (8.6%) contained empirical findings relating to post-registration nursing education in which assessment of training needs was presented as the major aim. Most of these accounts were concerned with the training needs of nurses in more than one organisation and were classified as macro-level training needs analysis. However, seven studies were concerned with a single, specific organisation (micro-level training needs analysis). Despite their smaller scale and more limited scope, micro-level training needs initiatives demonstrated greater methodological rigour, were more likely to consider the stakeholder perspective, to generate findings which could positively influence the rest of the training cycle and showed the greatest potential for influencing service delivery and quality of patient care. The review drew attention to the similarities between the training cycle and the audit cycle and resulted in the development of a model which could be used to evaluate the effectiveness of the process and outcomes of future training needs analysis initiatives.


Writing abstracts and developing posters for national meetings.
Presenting posters at national meetings can help fellows and junior faculty members develop a national reputation. They often lead to interesting and fruitful networking and collaboration opportunities. They also help with promotion in academic medicine and can reveal new job opportunities. Practically, presenting posters can help justify funding to attend a meeting. Finally, this process can be invaluable in assisting with manuscript preparation. This article provides suggestions and words of wisdom for palliative care fellows and junior faculty members wanting to present a poster at a national meeting describing a case study or original research. It outlines how to pick a topic, decide on collaborators, and choose a meeting for the submission. It also describes how to write the abstract using examples that present a general format as well as writing tips for each section. It then describes how to prepare the poster and do the presentation. Sample poster formats are provided as are talking points to help the reader productively interact with those that visit the poster. Finally, tips are given regarding what to do after the meeting. The article seeks to not only describe the basic steps of this entire process, but also to highlight the hidden curriculum behind the successful abstracts and posters. These tricks of the trade can help the submission stand out and will make sure the reader gets the most out of the hard work that goes into a poster presentation at a national meeting.


Molecular Detection and Quantification of Pythium Species: Evolving Taxonomy, New Tools, and Challenges.
The genus Pythium is one of the most important groups of soilborne plant pathogens, present in almost every agricultural soil and attacking the roots of thousands of hosts, reducing crop yield and quality. Most species are generalists, necrotrophic pathogens that infect young juvenile tissue. In fact, Cook and Veseth have called Pythium the "common cold" of wheat, because of its chronic nature and ubiquitous distribution. Where Pythium spp. are the cause of seedling damping-off or emergence reduction, the causal agent can easily be identified based on symptoms and culturing. In more mature plants, however, infection by Pythium spp. is more difficult to diagnose, because of the nonspecific symptoms that could have abiotic causes such as nutrient deficiencies or be due to other root rotting pathogens. Molecular methods that can accurately identify and quantify this important group are needed for disease diagnosis and management recommendations and to better understand the epidemiology and ecology of this important group. The purpose of this article is to outline the current state-of-the-art in the detection and quantification of this important genus. In addition, we will introduce the reader to new changes in the taxonomy of this group.


Superior vena cava obstruction in small-cell lung cancer.
To identify prognostic or treatment factors influencing the response of superior vena cava obstruction (SVCO), time to SVCO recurrence, and overall survival of SCLC patients with SVCO at presentation; and to assess the role of retreatment in patients with SVCO at recurrent or persistent disease. Between January 1983 and November 1993, 76 consecutive patients who had small-cell lung cancer (SCLC) with SVCO were treated in our institution. Analysis was done according to the disease status at diagnosis of SVCO. The first analysis concerned a group of 50 patients who had SVCO at initial presentation. The second analysis concerned a group who had SVCO as a manifestation of persistent or recurrent disease. In the first analysis, 93% had significant improvement in symptoms of SVCO after chemotherapy and 94% after mediastinal radiation. Response is almost universal despite a wide range of radiation fractionation and total dose used. Seventy percent remained SVCO-free before death. Thirty percent developed recurrence of SVCO symptoms 1-16 months (median 8) after the start of initial treatment. Those who received combined chemotherapy and radiation had a longer time to SVCO recurrence (p = 0.018) compared to those who received chemotherapy alone. This effect is mainly seen in limited-stage patients. The presence of SVCO recurrence tends to have an adverse effect on the overall survival (p = 0.077) irrespective of the time when the recurrences occurred (p = 0.296). The median survival of this whole group of 50 patients in the first analysis was 9.5 months, and the 2-year survival was 10%. Stage was strongly predictive of survival (p < 0.001). Sixteen percent (3 of 19) of the patients with limited-stage diseases were long-term survivors (two patients survived 35 months and one survived 70 months). The early mortality from SVCO was 2%. In the second analysis, 85% had previously been treated with chemotherapy alone. The response rate of SVCO in the analysable patients (n = 39) was 77%. There was no significant difference in the response rate of SVCO to treatment comparing patients treated by chemotherapy first or mediastinal radiation first (p = 0.653), but most patients [82% (32 of 39)] received radiation as the initially treatment of SVCO. Ninety-three percent (38 of 41) received mediastinal radiation as a part of their ultimate retreatment regimen, and 68% (28 of 41) received mediastinal radiation as their sole retreatment regimen. Thirty-two percent (13 of 41) received chemotherapy as a part of their ultimate retreatment regimen, and only 7% received chemotherapy alone as their sole retreatment regimen. Eighty-three percent (25 of 30) of those whose SVCO responded remained free of SVCO before death, with a median survival of 3 months after recurrent or persistent disease documented. Chemotherapy or mediastinal radiation is very effective as an initial treatment in SCLC patients with SVCO at presentation and at recurrent or persistent disease. There is no obvious need to use big radiation fraction sizes for the first few radiation treatment as was previously believed. In patients with recurrent or persistent SCLC with SVCO, especially in those who previously received chemotherapy only, we have more experience in incorporating mediastinal radiation as a major component of the palliative regimen with highly effective and durable palliation achieved.


Primary Percutaneous Coronary Intervention in Elderly Patients With Acute Myocardial Infarction - An Analysis From a Japanese Nationwide Claim-Based Database.
Primary percutaneous coronary intervention (pPCI) is strongly recommended by guidelines for patients presenting with acute myocardial infarction (AMI), but its applications in elderly patients are less clear.Methods and Results:The JROAD-DPC is a Japanese nationwide registry for patients with cardiovascular diseases combined with an administrative claim-based database. Among 2,369,165 records from 2012 to 2015, data for 115,407 AMI patients were extracted for this study. Elderly patients (≥75 years) comprised 45,645 subjects (39.6%), and received pPCI less frequently (62.2%) than younger patients (79.2%, P<0.001). Clinical variables such as higher age, female sex, higher Killip class, and renal dysfunction, but not functional status on admission, were predictors of non-application of pPCI. Endpoint 30-day mortality increased with aging, and was significantly higher in elderly patients (10.7%) than in younger patients (3.8%, P<0.001). Indeed, pPCI was independently associated with lower 30-day mortality only in subgroups of patients aged ≥60 years. Propensity score-matching analysis confirmed a similar reduction in endpoint 30-day mortality with pPCI in elderly patients. Duration of hospitalization was significantly shorter and functional ability on discharge was significantly better in elderly patients who underwent pPCI. Elderly patients with AMI underwent pPCI less frequently, but it was consistently associated with better clinical outcome in these patients. Our findings support the proactive application of pPCI for elderly AMI patients when they are eligible for an invasive strategy.


Natural history of hepatic steatosis: observed outcomes for subsequent liver and cardiovascular complications.
Hepatic steatosis is a common incidental finding at radiologic imaging. The natural history of nonalcoholic fatty liver disease (NAFLD) and its associated risks for cardiovascular complications are not well established in this context. Our purpose was to investigate the clinical outcome of moderate-to-severe hepatic steatosis detected incidentally at CT. Liver attenuation was measured at unenhanced CT in 4412 consecutive adults scanned over a 12-month period. Moderate-to-severe steatosis was diagnosed by liver attenuation less than or equal to 45 HU, which is essentially 100% specific for histologic grading of 30% or more fat content. The control group was defined by a high-normal liver attenuation of 60-65 HU. The main exclusion criteria were preexisting liver disease (beyond asymptomatic NAFLD), alcoholism, or less than 1 year of clinical follow-up. A medical record review assessed for the development of symptomatic liver disease (including nonalcoholic steatohepatitis and cirrhosis) and seminal cardiovascular events (myocardial infarction, cerebrovascular accident, transient ischemic attacks, or coronary bypass or stent). Data for body mass index, diabetes, and liver enzyme levels were also recorded. Five hundred three adults (11.4%) had unenhanced CT liver attenuation of 45 HU or less, yielding a final steatosis cohort of 282 patients after exclusions; the control group consisted of 768 patients after exclusions. The mean (± SD) patient age (51.4 ± 14.7 vs 50.8 ± 17.4 years), sex (53.9% vs 54.7% female), and mean follow-up intervals (7.3 ± 3.2 vs 7.7 ± 3.2 years) were similar between groups. No patient in either group had progression of liver disease beyond incidental steatosis. Subsequent cardiovascular events were more common in the steatosis cohort (9.9% vs 5.9%; p = 0.028), but steatosis was not an independent risk factor after controlling for diabetes and body mass index in multiple logistic regression analysis. This longitudinal study failed to show progression of moderate-to-severe hepatic steatosis to symptomatic forms of fatty liver disease over a 5- to 10-year time horizon. Aggressive workup of hepatic steatosis found incidentally on imaging does not appear to be warranted. Steatosis was a biomarker for subsequent cardiovascular events but not an independent risk factor.


Dopaminergic genes are associated with both directed and random exploration.
In order to maximize long-term rewards, agents must balance exploitation (choosing the option with the highest payoff) and exploration (gathering information about options that might have higher payoffs). Although the optimal solution to this trade-off is intractable, humans make use of two effective strategies: selectively exploring options with high uncertainty (directed exploration), and increasing the randomness of their choices when they are more uncertain (random exploration). Using a task that independently manipulates these two forms of exploration, we show that single nucleotide polymorphisms related to dopamine are associated with individual differences in exploration strategies. Variation in a gene linked to prefrontal dopamine (COMT) predicted the degree of directed exploration, as well as the overall randomness of responding. Variation in a gene linked to striatal dopamine (DARPP-32) predicted the degree of both directed and random exploration. These findings suggest that dopamine makes multiple contributions to exploration, depending on its afferent target.


Text mining resources for the life sciences.
Text mining is a powerful technology for quickly distilling key information from vast quantities of biomedical literature. However, to harness this power the researcher must be well versed in the availability, suitability, adaptability, interoperability and comparative accuracy of current text mining resources. In this survey, we give an overview of the text mining resources that exist in the life sciences to help researchers, especially those employed in biocuration, to engage with text mining in their own work. We categorize the various resources under three sections: Content Discovery looks at where and how to find biomedical publications for text mining; Knowledge Encoding describes the formats used to represent the different levels of information associated with content that enable text mining, including those formats used to carry such information between processes; Tools and Services gives an overview of workflow management systems that can be used to rapidly configure and compare domain- and task-specific processes, via access to a wide range of pre-built tools. We also provide links to relevant repositories in each section to enable the reader to find resources relevant to their own area of interest. Throughout this work we give a special focus to resources that are interoperable-those that have the crucial ability to share information, enabling smooth integration and reusability.


Sub-Chronic Stress Exacerbates the Pro-Thrombotic Phenotype in BDNFVal/Met Mice: Gene-Environment Interaction in the Modulation of Arterial Thrombosis.
Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism has been associated with increased susceptibility to develop mood disorders and recently it has been also linked with cardiovascular disease (CVD). Interestingly, stressful conditions unveil the anxious/depressive-like behavioral phenotype in heterozygous BDNFVal66Met (BDNFVal/Met) mice, suggesting an important relationship in terms of gene-environment interaction (GxE). However, the interplay between stress and BDNFVal/Met in relation to CVD is completely unknown. Here, we showed that BDNFVal/Met mice display a greater propensity to arterial thrombosis than wild type BDNFVal/Val mice after 7 days of restraint stress (RS). RS markedly increased the number of leukocytes and platelets, and induced hyper-responsive platelets as showed by increased circulating platelet/leukocyte aggregates and enhanced expression of P-selectin and GPIIbIIIa in heterozygous mutant mice. In addition, stressed BDNFVal/Met mice had a greater number of large and reticulated platelets but comparable number and maturation profile of bone marrow megakaryocytes compared to BDNFVal/Val mice. Interestingly, RS led to a significant reduction of BDNF expression accompanied by an increased activity of tissue factor in the aorta of both BDNFVal/Val and BDNFVal/Met mice. In conclusion, we provide evidence that sub-chronic stress unveils prothrombotic phenotype in heterozygous BDNF Val66Met mice affecting both the number and functionality of blood circulating cells, and the expression of key thrombotic molecules in aorta. Human studies will be crucial to understand whether this GxE interaction need to be taken into account in risk stratification of coronary artery disease (CAD) patients.


Intramucosal poorly differentiated and signet-ring cell components in patients with ulcerative colitis-associated high-grade dysplasia.
Despite the rarity of colorectal poorly differentiated adenocarcinoma (Por) and signet-ring cell carcinoma (Sig), they are more frequent in patients with ulcerative colitis (UC). However, little is known about these components of early colitis-associated cancer due to the difficulty of detection at an early stage. Here, we reviewed colitis-associated high-grade dysplasia/cancer with Por/Sig components within the submucosa among 103 lesions of 79 UC patients who presented between 1997 and 2017. In total, one Sig in situ, three intramucosal and two submucosal carcinomas (8.7%) were identified among 69 lesions within the submucosa. Depressed appearance, loss of crypt architecture and amorphous surface pattern suggested the presence of Por/Sig, rather than submucosal infiltration. All lesions were located in the rectosigmoid colon and included high-grade dysplasia. While the surrounding noncancerous mucosa expressed E-cadherin and MUC5AC, the expression of E-cadherin was reduced and the expression of MUC5AC was negative in all of the carcinomas except for the Sig in situ. The gastric type metaplasia associated with altered MUC5AC profiles may be a sign of the stepwise accumulation of molecular alterations, including TP53 defects and a reduced expression level of E-cadherin.


Intracellular antigens associated with the cytoplasmic surface of phagolysosomes.
Monoclonal antibodies were prepared to study the cytoplasmic face of latex phagolysosomes isolated from thioglycollate-elicited mouse peritoneal macrophages. Phagolysosomes obtained by sucrose flotation contained latent beta-glucuronidase activity and tightly associated cellular proteins and glycoproteins. Fluorescence-activated cell sorter analysis, scanning and transmission electron microscopy showed that the particle preparation contained greater than 98% monomers and dimers, invested with a smooth layer of membrane and minimally contaminated with cytoplasmic adhesions. Sera for immunized rats bound preferentially to isolated phagolysosomes rather than intact cells and monoclonal antibodies PL-1 and PL-4 were isolated on this basis. Indirect fluorescent, radio- and peroxidase immunobinding assays with intact and methanol-permeabilized cells confirmed that antigens PL-1 and PL-4 were exclusively intracellular and that well-washed phagolysosomes bound both antibodies. These antigens were found in a variety of cells from several species and in macrophages not fed latex. Although the PL-1 antigen could not be immunoprecipitated, intracellular staining was characteristic of intermediate filament distribution, that is, it was in the form of a fine intersecting network, which collapsed, reversibly, in a rim round the nucleus upon treatment with colcemid. The staining pattern was undetectable in cells 1 h after adherence to a substratum, but gradually appeared after 6-12 h. The PL-4 antibody has been shown elsewhere to define a Ca2+-binding protein of approximately 20 000 molecular weight, which is phosphorylated during phagocytosis. This antibody stained stress fibres and revealed a widespread punctate distribution of antigen within cells at all stages after adhesion. The nature of the association between these intracellular antigens and phagolysosomes and their possible role in phagocytosis are not known.


[Medical after-care of laryngectomized patients with voice prosthesis].
The success of prosthetic voice rehabilitation in laryngectomies depends not only upon logopedic training but also upon qualified follow-up care by the otorhinolaryngologist. As the voice prosthesis is increasingly used, this paper discusses specific aspects of medical follow-up care. At present, three types of voice prostheses are in general use in Germany: (1) the non-indwelling, low-pressure voice-prosthesis after Singer and Blom, which can be removed and reinserted by the patient, (2) the non-indwelling ESKA-Herrmann prosthesis as an angled duckbill prosthesis, which can also be maintained by the patient and (3) the indwelling Provox-prosthesis after Hilgers and Schouwenburg, which has to be replaced by the otorhinolaryngologist. Additionally, a tracheostoma valve fixed to the skin with a liquid adhesive (Blom) or inserted after a special tracheostoma plasty (Herrmann) enables the patient to speak free-handed. During the first postoperative weeks the patient has to learn manual occlusion of the stoma, breathing and phonation techniques and, eventually, how to remove, clean and reinsert his non-indwelling prosthesis (Blom-Singer or ESKA-Herrmann). Development of granulation tissue around the prosthesis and/or shunt insufficiencies are relatively rare and are mainly seen in patients after pre- or postoperative radiation therapy. In both cases temporary removal of the prosthesis is required. In case of accidental loss of a non-indwelling prosthesis a new prosthesis has to be inserted immediately; otherwise the shunt may spontaneously close overnight. A sudden increase of phonatory air-flow resistance, which cannot be reduced by insertion of a new prosthesis, may indicate tumor recurrence.


Identification of Novel Acinetobacter baumannii Host Fatty Acid Stress Adaptation Strategies.
Free fatty acids hold important immune-modulatory roles during infection. However, the host's long-chain polyunsaturated fatty acids, not commonly found in the membranes of bacterial pathogens, also have significant broad-spectrum antibacterial potential. Of these, the omega-6 fatty acid arachidonic acid (AA) and the omega-3 fatty acid decosahexaenoic acid (DHA) are highly abundant; hence, we investigated their effects on the multidrug-resistant human pathogen Acinetobacter baumannii Our analyses reveal that AA and DHA incorporate into the A. baumannii bacterial membrane and impact bacterial fitness and membrane integrity, with DHA having a more pronounced effect. Through transcriptional profiling and mutant analyses, we show that the A. baumannii β-oxidation pathway plays a protective role against AA and DHA, by limiting their incorporation into the phospholipids of the bacterial membrane. Furthermore, our study identified a second bacterial membrane protection system mediated by the AdeIJK efflux system, which modulates the lipid content of the membrane via direct efflux of lipids other than AA and DHA, thereby providing a novel function for this major efflux system in A. baumannii This is the first study to examine the antimicrobial effects of host fatty acids on A. baumannii and highlights the potential of AA and DHA to protect against A. baumannii infections.IMPORTANCE A shift in the Western diet since the industrial revolution has resulted in a dramatic increase in the consumption of omega-6 fatty acids, with a concurrent decrease in the consumption of omega-3 fatty acids. This decrease in omega-3 fatty acid consumption has been associated with significant disease burden, including increased susceptibility to infectious diseases. Here we provide evidence that DHA, an omega-3 fatty acid, has superior antimicrobial effects upon the highly drug-resistant pathogen Acinetobacter baumannii, thereby providing insights into one of the potential health benefits of omega-3 fatty acids. The identification and characterization of two novel bacterial membrane protective mechanisms against host fatty acids provide important insights into A. baumannii adaptation during disease. Furthermore, we describe a novel role for the major multidrug efflux system AdeIJK in A. baumannii membrane maintenance and lipid transport. This core function, beyond drug efflux, increases the appeal of AdeIJK as a therapeutic target.


Acute and chronic effects of aquatic treadmill training on land treadmill running kinematics: A cross-over and single-subject design approach.
The aim of this study was to determine if selected kinematic measures (foot strike index [SI], knee contact angle and overstride angle) were different between aquatic treadmill (ATM) and land treadmill (LTM) running, and to determine if these measures were altered during LTM running as a result of 6 weeks of ATM training. Acute effects were tested using 15 competitive distance runners who completed 1 session of running on each treadmill type at 5 different running speeds. Subsequently, three recreational runners completed 6 weeks of ATM training following a single-subject baseline, intervention and withdrawal experiment. Kinematic measures were quantified from digitisation of video. Regardless of speed, SI values during ATM running (61.3 ± 17%) were significantly greater (P = 0.002) than LTM running (42.7 ± 23%). Training on the ATM did not change (pre/post) the SI (26 ± 3.2/27 ± 3.1), knee contact angle (165 ± 0.3/164 ± 0.8) or overstride angle (89 ± 0.4/89 ± 0.1) during LTM running. Although SI values were different between acute ATM and LTM running, 6 weeks of ATM training did not appear to alter LTM running kinematics as evidenced by no change in kinematic values from baseline to post intervention assessments.


Openness to help-seeking for mental illness among Greek-Cypriots.
The aim of this study was to test a model of people's willingness to seek help for mental illness whether currently diagnosed or not. A cross-sectional design was used to test this model in a non-clinical convenience sample of Greek-Cypriots. Participants were 196 Greek-Cypriots living in Cyprus (age M = 34.50 years, SD = 14.16). They provided demographic data on their age, gender, SES and whether diagnosed or not with a mental illness, from whom they have/would seek help for a mental illness, and their willingness to seek help. They completed the Inventory of Attitudes towards Seeking Mental Health Services, the Multidimensional Scale of Perceived Support, and the Practical Barriers in Seeking Mental Health Services Scales, translated into Greek for this study. Approximately 24% of the sample reported being diagnosed with a mental illness within the past 12 months, and around a third of these people were taking prescribed medication. Willingness to seek help across all participants was predicted negatively by stigma and positively by openness to help. The findings of the current study extend our previous limited understanding of the factors affecting people's willingness to seek help or their intentions towards the use of mental health services among Greek-Cypriots. Future research should consider whether there are any differences in help-seeking behaviours and motivations across people experiencing different disorders. Despite this limitation in the current data, these results can, in general terms, be used to inform policy in Cyprus for mental health promotions and interventions especially with respect to fostering an open attitude towards mental illness.


Proteolytic processing of phospholipase Czeta and [Ca2+]i oscillations during mammalian fertilization.
Phospholipase Czeta (PLCzeta) is a sperm-specific PLC capable of causing repetitive intracellular Ca2+ ([Ca2+]i) release ([Ca2+]i oscillations) in mammalian eggs. Accumulating evidence suggests that PLCzeta is the sperm factor responsible for inducing egg activation. Nevertheless, some sperm fractions devoid of 72-kDa PLCzeta showed [Ca2+]i oscillation-inducing and PLCzeta-like PLC activity (Kurokawa et al., (2005) Dev. Biol. 285, 376-392). Here, we report that PLCzeta remains functional after proteolytic cleavage at the X-Y linker region. We found that N-terminal (33 and 37 kDa) and C-terminal fragments (27 kDa), presumably the result of PLCzeta cleavage at the X-Y linker region, were present in fresh sperm as well as in sperm extracts and remained associated as functional complexes. Protease V8 cleaved 72-kDa PLCzeta into 33/37 and 27 kDa fragments, while PLC activity and [Ca2+]i oscillation-inducing activity persisted until degradation of the fragments. Immunodepletion or affinity depletion of these fragments abolished PLC activity and [Ca2+]i oscillation-inducing activity from sperm extracts. Lastly, co-expression of cRNAs encoding residues 1-361 and 362-647 of mouse PLCzeta, mimicking cleavage at the X-Y linker region, induced [Ca2+]i oscillations and embryo development in mouse eggs. Our results support the hypothesis that PLCzeta is the sole mammalian sperm factor and that its linker region may have important regulatory functions during mammalian fertilization.


Power versus stabilization for laser satellite communication.
To establish optical communication between any two satellites, the lines of sight of their optics must be aligned for the duration of the communication. The satellite pointing and tracking systems perform the alignment. The satellite pointing systems vibrate because of tracking noise and mechanical impacts (such as thruster operation, the antenna pointing mechanism, the solar array driver, navigation noise, tracking noise). These vibrations increase the bit error rate (BER) of the communication system. An expression is derived for adaptive transmitter power that compensates for vibration effects in heterodyne laser satellite links. This compensation makes it possible to keep the link BER performance constant for changes in vibration amplitudes. The motivation for constant BER is derived from the requirement for future satellite communication networks with high quality of service. A practical situation of a two-low-Earth-orbit satellite communication link is given. From the results of the example it is seen that the required power for a given BER increases almost exponentially for linear increase in vibration amplitude.


Whole-exome sequencing of pancreatic neoplasms with acinar differentiation.
Pancreatic carcinomas with acinar differentiation, including acinar cell carcinoma, pancreatoblastoma and carcinomas with mixed differentiation, are distinct pancreatic neoplasms with poor prognosis. Although recent whole-exome sequencing analyses have defined the somatic mutations that characterize the other major neoplasms of the pancreas, the molecular alterations underlying pancreatic carcinomas with acinar differentiation remain largely unknown. In the current study, we sequenced the exomes of 23 surgically resected pancreatic carcinomas with acinar differentiation. These analyses revealed a relatively large number of genetic alterations at both the individual base pair and chromosomal levels. There was an average of 119 somatic mutations/carcinoma. When three outliers were excluded, there was an average of 64 somatic mutations/tumour (range 12-189). The mean fractional allelic loss (FAL) was 0.27 (range 0-0.89) and heterogeneity at the chromosome level was confirmed in selected cases using fluorescence in situ hybridization (FISH). No gene was mutated in >30% of the cancers. Genes altered in other neoplasms of the pancreas were occasionally targeted in carcinomas with acinar differentiation; SMAD4 was mutated in six tumours (26%), TP53 in three (13%), GNAS in two (9%), RNF43 in one (4%) and MEN1 in one (4%). Somatic mutations were identified in genes in which constitutional alterations are associated with familial pancreatic ductal adenocarcinoma, such as ATM, BRCA2 and PALB2 (one tumour each), as well as in genes altered in extra-pancreatic neoplasms, such as JAK1 in four tumours (17%), BRAF in three (13%), RB1 in three (13%), APC in two (9%), PTEN in two (9%), ARID1A in two (9%), MLL3 in two (9%) and BAP1 in one (4%). Perhaps most importantly, we found that more than one-third of these carcinomas have potentially targetable genetic alterations, including mutations in BRCA2, PALB2, ATM, BAP1, BRAF and JAK1.


Factors associated with HIV testing among male injecting drug users: findings from a cross-sectional behavioural and biological survey in Manipur and Nagaland, India.
Although targeted interventions in India require all high-risk groups, including injecting drug users (IDUs), to test for HIV every 6 months, testing uptake among IDUs remains far from universal. Our study estimates the proportion of IDUs who have taken an HIV test and identifies the factors associated with HIV testing uptake in Nagaland and Manipur, two high HIV prevalence states in India where the epidemic is driven by injecting drug use. Data are drawn from the cross-sectional Integrated Behavioural and Biological Assessment (2009) of 1650 male IDUs from two districts each of Manipur and Nagaland. Participants were recruited using respondent-driven sampling (RDS). Descriptive data were analysed using RDSAT 7.1. Multivariate logistic regression analysis was undertaken using STATA 11 to examine the association between HIV testing and socio-demographic, behavioural and programme exposure variables. One third of IDUs reported prior HIV testing, of whom 8 % had tested HIV-positive. Among those without prior testing, 6.2 % tested HIV-positive in the current survey. IDUs aged 25-34 years (adjusted odds ratio (OR) = 1.41; 95 % confidence interval (CI) = 1.03-1.93), married (Adjusted OR = 1.56; 95 % CI = 1.15-2.12), had a paid sexual partner (Adjusted OR = 1.64; 95 % CI = 1.24-2.18), injected drugs for more than 36 months (Adjusted OR = 1.38; 95 % CI = 1.06-1.81), injected frequently (Adjusted OR = 1.49; 95 % CI = 1.12-1.98) and had high-risk perception (Adjusted OR = 1.68; 95 % CI = 1.32-2.14) were more likely than others to test for HIV. Compared to those with no programme exposure, IDUs who received counselling, or counselling and needle/syringe services, were more likely to test for HIV. HIV testing uptake among IDUs is low in Manipur and Nagaland, and a critical group of HIV-positive IDUs who have never tested for HIV are being missed by current programmes. This study identifies key sub-groups-including early initiators, short duration and less frequent injectors, perceived to be at low risk-for promoting HIV testing. Providing needles/syringes alone is not adequate to increase HIV testing; additionally, interventions must provide counselling services to inform all IDUs about HIV testing benefits, facilitate visits to testing centres and link those testing positive to timely treatment and care.


Signal strength regulates antigen-mediated T-cell deceleration by distinct mechanisms to promote local exploration or arrest.
T lymphocytes are highly motile cells that decelerate upon antigen recognition. These cells can either completely stop or maintain a low level of motility, forming contacts referred to as synapses or kinapses, respectively. Whether similar or distinct molecular mechanisms regulate T-cell deceleration during synapses or kinapses is unclear. Here, we used microfabricated channels and intravital imaging to observe and manipulate T-cell kinapses and synapses. We report that high-affinity antigen induced a pronounced deceleration selectively dependent on Ca(2+) signals and actin-related protein 2/3 complex (Arp2/3) activity. In contrast, low-affinity antigens induced a switch of migration mode that promotes T-cell exploratory behavior, characterized by partial deceleration and frequent direction changes. This switch depended on T-cell receptor binding but was largely independent of downstream signaling. We propose that distinct mechanisms of T-cell deceleration can be triggered during antigenic recognition to favor local exploration and signal integration upon suboptimal stimulus and complete arrest on the best antigen-presenting cells.


Iris morphologic changes related to alpha(1)-adrenergic receptor antagonists implications for intraoperative floppy iris syndrome.
To identify iris structural alterations associated with intraoperative floppy iris syndrome (IFIS) in patients using systemic alpha(1)-adrenergic receptor antagonists (alpha-1ARA). Cross-sectional study. Twenty-nine patients with current or past treatment with any systemic alpha-1ARA and 22 untreated controls. Consecutive eligible patients underwent slit-lamp-adapted optical coherence tomography in a masked fashion under standardized lighting conditions. Iris thickness at the dilator muscle region (DMR; measured at half of the distance between the scleral spur and the pupillary margin) and at the sphincter muscle region (SMR; 0.75 mm from the pupillary margin), the ratio between the DMR/SMR (to compensate for possible intersubject variability), and pupillary diameter. Most treated patients were on tamsulosin (27/29). Mean age was similar in study and control groups (70.6+/-7.6 vs 67.1+/-9.1 years; P = 0.061). Photopic pupil diameter was reduced in the study group (2.06+/-0.5 vs 2.5+/-0.6 mm; P = 0.001). The SMR was similar between groups (P = 0.53). Significantly lower values were found in treated subjects for the DMR and the DMR/SMR ratio (P<0.001). These differences remained significant after adjusting for pupil diameter (P<0.001). Multiple regression analysis showed that a longer duration of alpha-1ARA treatment correlated to a reduced DMR/SMR ratio (P = 0.001; r = 0.47). Age and eye color were not significant in this model. Patients using systemic alpha-1ARA have significantly lower values of DMR thickness and DMR/SMR ratio and smaller pupil diameter when compared with age-matched controls. These differences seem to be related to the duration of drug exposure and provide evidence of structural alterations to the iris dilator muscle from this class of agents in IFIS. Proprietary or commercial disclosure may be found after the references.


l-Carnitine l-tartrate supplementation favorably affects biochemical markers of recovery from physical exertion in middle-aged men and women.
The purpose of this study was to examine the effects of Carnipure tartrate (Lonza, Allendale, NJ) supplementation (total dose of 2 g/d of l-carnitine) on markers of performance and recovery from physical exertion in middle-aged men and women. Normally active and healthy men (n = 9, 45.4 +/- 5.3 years old) and women (n = 9, 51.9 +/- 5.0 years old) volunteered to participate in the investigation. Double-blind, placebo, balanced treatment presentation and crossover design were used with 3 weeks and 3 days of supplementation followed by a 1-week washout period before the other counterbalanced treatment was initiated. After 3 weeks of each supplementation protocol, each participant then performed an acute resistance exercise challenge of 4 sets of 15 repetitions of squat/leg press at 50% 1-repetition maximum and continued supplementation over the recovery period that was evaluated. Blood samples were obtained at preexercise and at 0, 15, 30, and 120 minutes postexercise during the acute resistance exercise challenge and during 4 recovery days as well. Two grams of l-carnitine supplementation had positive effects and significantly (P < or = .05) attenuated biochemical markers of purine metabolism (ie, hypoxanthine, xanthine oxidase), free radical formation (malondialdehyde), muscle tissue disruption (myoglobin, creatine kinase), and muscle soreness after physical exertion. However, markers of physical performance (ie, strength, power, get up and go) were not affected by supplementation. These findings support our previous findings of l-carnitine in younger people that such supplementation can reduce chemical damage to tissues after exercise and optimize the processes of muscle tissue repair and remodeling.


The effect of ill health and socioeconomic status on labor force exit and re-employment: a prospective study with ten years follow-up in the Netherlands.
The aim of this study was to investigate the effect of ill health and socioeconomic status on labor force exit due to unemployment, early retirement, disability pension, or becoming economically inactive. A secondary objective was to investigate the effect of ill health and socioeconomic status on return to work. A representative sample of the Dutch working population (N=15 152) was selected for a prospective study with ten years follow-up (93 917 person-years). Perceived health and individual and household characteristics were measured at baseline with the Permanent Quality of Life Survey (POLS) during 1999-2002. Statistics Netherlands ascertained employment status monthly from January 1999 to December 2008. Cox proportional hazards analyses were used to determine the factors that predicted labor force exit and return to work. Ill health increased the likelihood of labor force exit into unemployment [hazard ratio (HR) 1.89], disability pension (HR 6.39), and early retirement (HR 1.20), but was not a determinant of becoming economically inactive (HR 1.07). Workers with low socioeconomic status were, even after adjusting for ill health, more likely to leave the labor force due to unemployment, disability pension, and economic inactivity. Workers with ill health at baseline were less likely to return to work after unemployment (HR 0.75) or disability pension (HR 0.62). Socioeconomic status did not influence re-employment. Ill health is an important determinant for entering and maintaining paid employment. Workers with lower education were at increased risk for health-based selection out of paid employment. Policies to improve labor force participation, especially among low socioeconomic level workers, should protect workers with health problems against exclusion from the labor force.


Stage and survival in breast cancer patients in screened and non-screened Danish and Swedish populations.
Comparisons between the Danish and Swedish Cancer Registry revealed a 9% difference in 5-year survival for breast cancer patients diagnosed between 1983 and 1989. The purpose of this study was to determine whether previous differences in survival and stage still exist or whether the Danish figures approach those of the Swedish registry. Complete population-based cohorts of patients with breast cancer in the years 1996-1997 from well-defined areas in Denmark and Sweden were compared. The study regions were a Danish (Funen) and a Swedish (Malmö) county with mammography screening and two Danish counties without screening. No difference in extent of disease or survival was observed between screening areas regardless of country. However, there were significant differences in stage distribution and survival between screening populations and Danish non-screening populations, to the benefit of populations provided with a screening programme. Five-year survival was 5-6%, higher in screening populations than in Danish non-screening counties. Corresponding disease-specific survival enhanced the difference. In a multivariate analysis increasing age, tumour size and stage decreased survival. Adjusting for these factors eliminated differences in survival according to country/county. Survival difference could be attributed to early diagnosis and favourable stage in populations offered mammography screening and was not related to nation. Denmark may, through early detection, approach the beneficial stage distribution and survival observed in Sweden.


Deletion mutants in the gene encoding the herpes simplex virus type 1 immediate-early protein ICP0 exhibit impaired growth in cell culture.
We report the construction and characterization of deletion mutants in the herpes simplex virus type 1 gene encoding the immediate-early protein ICP0. In the event that ICP0 proved to play an essential role in virus replication, ICP0-transformed Vero cells were generated to serve as permissive hosts for such mutants. Two mutants, dlX0.7 and dlX3.1, were isolated in these cells by a marker rescue-transfer procedure involving the rescue of an ICP4 deletion mutant and the simultaneous insertion of a linked deletion in the ICP0 gene. Mutant dlX0.7 contained a 700-base-pair deletion in both copies of ICP0. The deletion lay entirely within the transcript specified by the gene. dlX0.7 induced the synthesis of an ICP0-specific mRNA that was approximately 0.7 kilobases smaller than the corresponding mRNA specified by wild-type virus. The 3.1-kilobase deletion in both copies of the ICP0 gene in mutant dlX3.1 removed the majority of the transcriptional-regulatory signals and coding sequences, retaining only sequences at the 3' end of the gene. As expected, no ICP0-specific mRNA was detected in dlX3.1-infected Nero cells (G418-resistant Vero cells). Both mutants grew in all cells tested, although their burst sizes were 10- to 100-fold lower than that of wild-type virus. Although the plaque sizes of dlX0.7 and dlX3.1 were equally small on Nero and ICP0-transformed cells, the plating efficiency of the mutants was 15- to 50-fold greater on ICP0-transformed cells than on Nero cells. The mutants exhibited modest interference with the growth of wild-type virus in mixed infections, an effect that was abolished by UV irradiation of the mutants, implying that interference required viral gene expression. Polypeptide profiles generated by the mutants in Nero cells were qualitatively similar to that of wild-type virus. Quantitatively, only slight reductions in the levels of certain late viral polypeptides were observed, a phenomenon also borne out by analysis of viral glycoproteins. Both mutants induced the synthesis of significant, although reduced, levels of viral DNA relative to wild-type virus. Taken together, the results demonstrate that ICP0 is not essential for productive infection in cell culture but that this protein plays a significant role in viral growth, as indicated by the impaired abilities of the mutants to replicate.


Involvement of the cell cycle-regulated nuclear factor HiNF-D in cell growth control of a human H4 histone gene during hepatic development in transgenic mice.
Regulation of the cell cycle-controlled histone gene promoter factor HiNF-D was examined in vivo. Proliferative activity was measured by DNA replication-dependent histone mRNA levels, and HiNF-D binding activity was found to correlate with cell proliferation in most tissues. Furthermore, HiNF-D is down-regulated during hepatic development, reflecting the onset of differentiation and quiescence. The contribution of transcription to histone gene expression was directly addressed in transgenic mice by using a set of fusion constructs containing a human H4 histone gene promoter linked to three different genes. Transgene expression in both fetal and adult mice paralleled endogenous mouse histone mRNA levels in most tissues, consistent with this promoter conferring developmental, cell growth-related transcriptional regulation. Our results suggest that HiNF-D is stringently regulated in vivo in relation to cell growth and support a primary role for HiNF-D in the proliferation-specific expression of H4 histone genes in the intact animal. Further, the data presented here provide an example in which apparent tissue specificity of gene expression reflects the proliferative state of various tissues and demonstrate that multiple levels of histone gene regulation are operative in vivo.


QuickBrain MRI for the detection of acute pediatric traumatic brain injury.
OBJECTIVE The current gold-standard imaging modality for pediatric traumatic brain injury (TBI) is CT, but it confers risks associated with ionizing radiation. QuickBrain MRI (qbMRI) is a rapid brain MRI protocol that has been studied in the setting of hydrocephalus, but its ability to detect traumatic injuries is unknown. METHODS The authors performed a retrospective cohort study of pediatric patients with TBI who were undergoing evaluation at a single Level I trauma center between February 2010 and December 2013. Patients who underwent CT imaging of the head and qbMRI during their acute hospitalization were included. Images were reviewed independently by 2 neuroradiology fellows blinded to patient identifiers. Image review consisted of identifying traumatic mass lesions and their intracranial compartment and the presence or absence of midline shift. CT imaging was used as the reference against which qbMRI was measured. RESULTS A total of 54 patients met the inclusion criteria; the median patient age was 3.24 years, 65% were male, and 74% were noted to have a Glasgow Coma Scale score of 14 or greater. The sensitivity and specificity of qbMRI to detect any lesion were 85% (95% CI 73%-93%) and 100% (95% CI 61%-100%), respectively; the sensitivity increased to 100% (95% CI 89%-100%) for clinically important TBIs as previously defined. The mean interval between CT and qbMRI was 27.5 hours, and approximately half of the images were obtained within 12 hours. CONCLUSIONS In this retrospective pilot study, qbMRI demonstrated reasonable sensitivity and specificity for detecting a lesion or injury seen with neuroimaging (radiographic TBI) and clinically important acute pediatric TBI.


Tumor- and organ-dependent infiltration by myeloid-derived suppressor cells.
Myeloid-derived suppressor cells (MDSCs) increase during tumor growth and following cytoreductive therapy resulting in immune dysfunction and tumor escape from host control. We report organ- and tumor-specific expansion of MDSCs, differences in their molecular and membrane phenotypes and T-cell suppressive activity. A significant increase in MDSCs was observed within the spleen, peripheral blood (PB), bone marrow (BM), lungs, and livers of mice bearing orthotopic 4T1, but not CI66 mammary tumors. The PB of 4T1 TB mice had the highest frequency of MDSCs (78.6±2.1%). Similarly, the non-parenchymal cells (NPCs) in the tumor tissue, livers and lungs of 4T1 tumor-bearing (TB) mice had an increased MDSCs frequency. Studies into Gr-1 and Ly-6C staining of MDSCs revealed significant increases in CD11b+Gr-1(dull)Ly-6C(high) and CD11b+Gr-1(bright)Ly-6C(low) subsets. The frequency of MDSCs inversely correlated with the CD3+ T-cell frequency in the spleen, and blood of 4T1 TB mice and was associated with a significant decrease in splenic and NPCs IFN-γ and IL-12 transcript levels, as well as significantly increased levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), stem cell factor (SCF), granulocyte colony-stimulating factor (G-CSF), interleukin-10 (IL-10), interleukin-13 (IL-13), arginase-1 (ARG-1), nitric oxide synthase (NOS-2), vascular endothelial growth factor-A (VEGF-A) transcripts. In summary, MDSCs are significantly increased not only in lymphoid organs, but also in parenchymal organs including lungs and livers of TB mice, where they may facilitate metastasis to these organ sites.


Effect of adenovirus-mediated RNA interference on endogenous microRNAs in a mouse model of multidrug resistance protein 2 gene silencing.
RNA interference with viral vectors that express short hairpin RNAs (shRNAs) has emerged as a powerful tool for functional genomics and therapeutic purposes. However, little is known about shRNA in vivo processing, accumulation, functional kinetics, and side effects related to shRNA saturation of the cellular gene silencing machinery. Therefore, we constructed first-generation recombinant adenoviruses encoding different shRNAs against murine ATP-binding cassette multidrug resistance protein 2 (Abcc2), which is involved in liver transport of bilirubin to bile, and analyzed Abcc2 silencing kinetics. C57/BL6 mice injected with these viruses showed significant impairment of Abcc2 function for up to 3 weeks, as reflected by increased serum bilirubin levels. The lack of Abcc2 function correlated with a specific reduction of Abcc2 mRNA and with high levels of processed shRNAs targeting Abcc2. Inhibition was lost at longer times postinfection, correlating with a decrease in the accumulation of processed shRNAs. This finding suggests that a minimal amount of processed shRNAs is required for efficient silencing in vivo. This system was also used to evaluate the effect of shRNA expression on the saturation of silencing factors. Saturation of the cellular silencing processing machinery alters the accumulation and functionality of endogenous microRNAs (miRNAs) and pre-miRNAs. However, expression of functional exogenous shRNAs did not change the levels of endogenous miRNAs or their precursors. In summary, this work shows that adenoviral vectors can deliver sufficient shRNAs to mediate inhibition of gene expression without saturating the silencing machinery.


Paravertebral blocks in patients undergoing mastectomy with or without immediate reconstruction provides improved pain control and decreased postoperative nausea and vomiting.
Mastectomy is associated with postoperative nausea and pain. We evaluated whether paravertebral block (PVB) use altered opioid use, antiemetic use, and length of stay in patients undergoing mastectomy. We performed a retrospective cohort analysis of all patients who underwent mastectomy with or without PVB from 2008 to 2010. Patient demographics, operative procedure, intraoperative medications, postoperative opioid and antiemetic use, and length of stay were reviewed. Statistical analysis included univariable and multivariable analysis. A total of 605 patients were identified, of whom 526 patients were evaluable. A total of 294 patients underwent mastectomy without PVB (132 bilateral), and 232 patients underwent mastectomy with PVB (148 bilateral). Immediate reconstruction was performed in 203 (39 %) patients. Need for any postoperative antiemetic was less frequent in the PVB group (39 vs. 57 %, p < 0.0001). Day of surgery opioid use was lower in the PVB group than the non-PVB group (mean ± SD 40.1 ± 15.2 vs. 47.6 ± 17.7 morphine equivalents, p < 0.0001). Decreased opioid use was seen in unilateral mastectomy without reconstruction and bilateral mastectomy with and without immediate reconstruction. The proportion of patients discharged within 36 h of surgery was significantly higher in the PVB group (55 vs. 42 %, p = 0.0031). On multivariable analysis controlling for year of surgery, patient age and surgeon, PVB use affected antiemetic use and opioid use but not hospital length of stay. PVB results in decreased opioid use and decreased need for postoperative antiemetic medication in patients undergoing mastectomy. The greatest benefit is seen in patients undergoing bilateral mastectomy with immediate breast reconstruction.


Identification and Characterization of 33 Bacillus cereus sensu lato Isolates from Agricultural Fields from Eleven Widely Distributed Countries by Whole Genome Sequencing.
The phylogeny, identification, and characterization of 33 B. cereus sensu lato isolates originating from 17 agricultural soils from 11 countries were analyzed on the basis of whole genome sequencing. Phylogenetic analyses revealed all isolates are divided into six groups, which follows the generally accepted phylogenetic division of B. cereus sensu lato isolates. Four different identification methods resulted in a variation in the identity of the isolates, as none of the isolates were identified as the same species by all four methods-only the recent identification method proposed directly reflected the phylogeny of the isolates. This points to the importance of describing the basis and method used for the identification. The presence and percent identity of the protein product of 19 genes potentially involved in pathogenicity divided the 33 isolates into groups corresponding to phylogenetic division of the isolates. This suggests that different pathotypes exist and that it is possible to differentiate between them by comparing the percent identity of proteins potentially involved in pathogenicity. This also reveals that a basic link between phylogeny and pathogenicity is likely to exist. The geographical distribution of the isolates is not random: they are distributed in relation to their division into the six phylogenetic groups, which again relates to different ecotypes with different temperature growth ranges. This means that we find it easier to analyze and understand the results obtained from the 33 B. cereus sensu lato isolates in a phylogenetic, patho-type and ecotype-oriented context, than in a context based on uncertain identification at the species level.


The social norms of alcohol-related negative consequences.
Social norms for alcohol use are important influences on individual college student drinking. The present study extends social norms research by examining alcohol-related consequences and, in particular, whether similar misperceptions exist regarding the frequency and evaluation of these consequences over time. College student drinkers (N = 624) participating in a longitudinal study completed Web-based surveys assessing alcohol use and related consequences, as well as their beliefs about frequency and evaluation of consequences for the typical college student. Findings suggest that students overestimated how often typical college students experience negative consequences and underestimated how negatively other students evaluated those consequences. Finally, results support a bidirectional model for alcohol-related consequences, possibly indicating a reciprocal, mutually influential feed-forward loop of norms and consequences that promotes maintenance of college student drinking and consequences.