When concealed handgun licensees break bad: criminal convictions of concealed handgun licensees in Texas, 2001-2009.
We explored differences in criminal convictions between holders and nonholders of a concealed handgun license (CHL) in Texas. The Texas Department of Public Safety (DPS) provides annual data on criminal convictions of holders and nonholders of CHLs. We used 2001 to 2009 DPS data to investigate the differences in the distribution of convictions for these 2 groups across 9 types of criminal offenses. We calculated z scores for the differences in the types of crimes for which CHL holders and nonholders were convicted. CHL holders were much less likely than nonlicensees to be convicted of crimes. Most nonholder convictions involved higher-prevalence crimes (burglary, robbery, or simple assault). CHL holders' convictions were more likely to involve lower-prevalence crimes, such as sexual offenses, gun offenses, or offenses involving a death. Our results imply that expanding the settings in which concealed carry is permitted may increase the risk of specific types of crimes, some quite serious in those settings. These increased risks may be relatively small. Nonetheless, policymakers should consider these risks when contemplating reducing the scope of gun-free zones.


The formation of the Bicoid morphogen gradient requires protein movement from anteriorly localized mRNA.
The Bicoid morphogen gradient directs the patterning of cell fates along the anterior-posterior axis of the syncytial Drosophila embryo and serves as a paradigm of morphogen-mediated patterning. The simplest models of gradient formation rely on constant protein synthesis and diffusion from anteriorly localized source mRNA, coupled with uniform protein degradation. However, currently such models cannot account for all known gradient characteristics. Recent work has proposed that bicoid mRNA spatial distribution is sufficient to produce the observed protein gradient, minimizing the role of protein transport. Here, we adapt a novel method of fluorescent in situ hybridization to quantify the global spatio-temporal dynamics of bicoid mRNA particles. We determine that >90% of all bicoid mRNA is continuously present within the anterior 20% of the embryo. bicoid mRNA distribution along the body axis remains nearly unchanged despite dynamic mRNA translocation from the embryo core to the cortex. To evaluate the impact of mRNA distribution on protein gradient dynamics, we provide detailed quantitative measurements of nuclear Bicoid levels during the formation of the protein gradient. We find that gradient establishment begins 45 minutes after fertilization and that the gradient requires about 50 minutes to reach peak levels. In numerical simulations of gradient formation, we find that incorporating the actual bicoid mRNA distribution yields a closer prediction of the observed protein dynamics compared to modeling protein production from a point source at the anterior pole. We conclude that the spatial distribution of bicoid mRNA contributes to, but cannot account for, protein gradient formation, and therefore that protein movement, either active or passive, is required for gradient formation.


Residents' perceptions of communication skills in postgraduate medical training programs of Pakistan.
The importance of communication skills in postgraduate medical training is likely to be highlighted given the convergence of research and educational forces. Assessment of these skills in residency training is vital since it can provide basis for policy undertaking among Pakistani medical academia for improving postgraduate training programs. To assess the perceived status of communication skills of residents in different specialties. A cross sectional survey was conducted in four teaching hospitals of Karachi between July 1999 and January 2001. A total of 455 residents in different residency programs were contacted. Residents registered both with College of Physicians and Surgeons of Pakistan and Postgraduate Medical Education office of selected hospitals were included in this study. Responses of residents were obtained on 5-point Likert scale. Indices were formed for three components of communication skills: informative, affective and professional communication. Differences between residents' groups were assessed through analysis of variance. Total informative communication index was lowest for multi-disciplinary (12.05, SD = 4.87) and highest for surgical (15.27, SD = 2.51) residents. Total affective index was lowest for multi-disciplinary (12.58, SD = 5.68) and highest for medical (15.74, SD = 3.59) residents. The group differences for four groups of residency programs were not statistically significant for either professional attributes separately or for the total professional index. The residency programs must establish goals, process and outcomes to incorporate communication skills in postgraduate medical training since this can enhance residents' performance as effective health care providers. Accomplishment of better communication skills can be achieved if the importance of its teaching and training is valued by residency program coordinators.


A model for predicting the risk of de novo stress urinary incontinence in women undergoing pelvic organ prolapse surgery.
To construct and validate a prediction model for estimating the risk of de novo stress urinary incontinence (SUI) after vaginal pelvic organ prolapse (POP) surgery and compare it with predictions using preoperative urinary stress testing and expert surgeons' predictions. Using the data set (n=457) from the Outcomes Following Vaginal Prolapse Repair and Midurethral Sling trial, a model using 12 clinical preoperative predictors of de novo SUI was constructed. De novo SUI was determined by Pelvic Floor Distress Inventory responses through 12 months postoperatively. After fitting the multivariable logistic regression model using the best predictors, the model was internally validated with 1,000 bootstrap samples to obtain bias-corrected accuracy using a concordance index. The model's predictions were also externally validated by comparing findings against actual outcomes using Colpopexy and Urinary Reduction Efforts trial patients (n=316). The final model's performance was compared with experts using a test data set of 32 randomly chosen Outcomes Following Vaginal Prolapse Repair and Midurethral Sling trial patients through comparison of the model's area under the curve against: 1) 22 experts' predictions; and 2) preoperative prolapse reduction stress testing. A model containing seven predictors discriminated between de novo SUI status (concordance index 0.73, 95% confidence interval [CI] 0.65-0.80) in Outcomes Following Vaginal Prolapse Repair and Midurethral Sling participants and outperformed expert clinicians (area under the curve 0.72 compared with 0.62, P<.001) and preoperative urinary stress testing (area under the curve 0.72 compared with 0.54, P<.001). The concordance index for Colpopexy and Urinary Reduction Efforts trial participants was 0.62 (95% CI 0.56-0.69). This individualized prediction model for de novo SUI after vaginal POP surgery is valid and outperforms preoperative stress testing, prediction by experts, and preoperative reduction cough stress testing. An online calculator is provided for clinical use. III.


GRWD1 regulates ribosomal protein L23 levels via the ubiquitin-proteasome system.
Glutamate-rich WD40 repeat-containing 1 (GRWD1) is a Cdt1-binding protein that promotes mini-chromosome maintenance (MCM) loading through its histone chaperone activity. GRWD1 acts as a tumor-promoting factor by downregulating p53 (also known as TP53) via the RPL11-MDM2-p53 axis. Here, we identified GRWD1-interacting proteins using a proteomics approach and showed that GRWD1 interacts with various proteins involved in transcription, translation, DNA replication and repair, chromatin organization, and ubiquitin-mediated proteolysis. We focused on the ribosomal protein ribosomal protein L23 (RPL23), which positively regulates nucleolar stress responses through MDM2 binding and inhibition, thereby functioning as a tumor suppressor. Overexpression of GRWD1 decreased RPL23 protein levels and stability; this effect was restored upon treatment with the proteasome inhibitor MG132. EDD (also known as UBR5), an E3 ubiquitin ligase that interacts with GRWD1, also downregulated RPL23, and the decrease was further enhanced by co-expression of GRWD1. Conversely, siRNA-mediated GRWD1 knockdown upregulated RPL23. Co-expression of GRWD1 and EDD promoted RPL23 ubiquitylation. These data suggest that GRWD1 acts together with EDD to negatively regulate RPL23 via the ubiquitin-proteasome system. GRWD1 expression reversed the RPL23-mediated inhibition of anchorage-independent growth in cancer cells. Our data suggest that GRWD1-induced RPL23 proteolysis plays a role in downregulation of p53 and tumorigenesis.


The probiotic bacterium Lactobacillus casei induces activation of the gut mucosal immune system through innate immunity.
The mechanisms by which probiotic bacteria affect the immune system are unknown yet, but many of them are attributed to an increase in the innate or in the acquired immune response. To study the influence of the probiotic bacterium Lactobacillus casei in the expression of receptors involved in the innate immune response, this bacterium was orally administered to BALB/c mice. After, they were sacrificed; the small intestine and intestinal fluids were collected to measure secretory immunoglobulin A (IgA) specific for L. casei. Mononuclear cells from Peyer's patches were isolated to determine the CD-206 and TLR-2 receptors. In histological slices we determined the number of IgA+, CD4+, CD8+, and CD3+ cells and two cytokines (interleulin-5 [IL-5] and IL-6). CD-206 and TLR-2 increased with respect to the untreated control. We did not observe an increase in the T population or in the IL-5-positive cells. IgA+ cells and IL-6-producing cells increased after 7 days of L. casei administration. We did not find specific antibodies against L. casei. The main immune cells activated after oral L. casei administration were those of the innate immune response, with an increase in the specific markers of these cells (CD-206 and TLR-2), with no modification in the number of T cells.


Tracheal Resection With Primary Anastomosis.
The aim of our study was to present our retrospective experience in the single-stage surgical reconstruction of 21 tracheal stenosis (TS) patients during the last 17 years, considering the characteristics of the treated stenosis, surgical procedures performed, and postoperative outcomes and complications. All demographic and clinical data were collected retrospectively. Chest and neck computed tomography (CT) scans were performed to assess the stenosis, including length, location, and glottic involvement. The stenotic area was evaluated endoscopically according to an adapted Myer and Cotton grading scale. The aetiology of the (TS) was intubation related in 18 patients and idiopathic in three patients. The duration of intubation was 13.00 ± 6.83 days (range, 1 hour to 27 days). According to the Myers-Cotton classification, mean stage of stenosis for the study group was 3.33 ± 0.66 (range, 2-4). Mean length of the stenosis was 2.05 ± 0.80 (range, 1-3.5) cm. The mean number of stenotic segment involved was 3.67 ± 1.24 (range, 2-6). Mean follow-up for the study group, excluding two patients who died in the postoperative period, was 57 (range, 12-326) months. Of the 19 patients who survived, postoperative decannulation was achieved in 16 patients (76.19%), and decannulation was not achieved in 3 patients (14.29%) who are still on a T-tube. Of the 16 patients who are decannulated successfully, additional procedures were applied in 9 patients. Segmental resection with primary anastomosis is an effective method and can be used as the first option in selected patients of (TS).


From genome-based in silico predictions to ex vivo verification of leprosy diagnosis.
The detection of hundreds of thousands of new cases of leprosy every year suggests that transmission of Mycobacterium leprae infection still continues. Unfortunately, tools for identification of asymptomatic disease and/or early-stage M. leprae infection (likely sources of transmission) are lacking. The recent identification of M. leprae-unique genes has allowed the analysis of human T-cell responses to novel M. leprae antigens. Antigens with the most-promising diagnostic potential were tested for their ability to induce cytokine secretion by using peripheral blood mononuclear cells from leprosy patients and controls in five different areas where leprosy is endemic; 246 individuals from Brazil, Nepal, Bangladesh, Pakistan, and Ethiopia were analyzed for gamma interferon responses to five recombinant proteins (ML1989, ML1990, ML2283, ML2346, and ML2567) and 22 synthetic peptides. Of these, the M. leprae-unique protein ML1989 was the most frequently recognized and ML2283 the most specific for M. leprae infection/exposure, as only a limited number of tuberculosis patients responded to this antigen. However, all proteins were recognized by a significant number of controls in areas of endemicity. T-cell responses correlated with in vitro response to M. leprae, suggesting that healthy controls in areas where leprosy is endemic are exposed to M. leprae. Importantly, 50% of the healthy household contacts and 59% of the controls in areas of endemicity had no detectable immunoglobulin M antibodies to M. leprae-specific PGL-I but responded in T-cell assays to >or=1 M. leprae protein. T-cell responses specific for leprosy patients and healthy household contacts were observed for ML2283- and ML0126-derived peptides, indicating that M. leprae peptides hold potential as diagnostic tools. Future work should concentrate on the development of a sensitive and field-friendly assay and identification of additional peptides and proteins that can induce M. leprae-specific T-cell responses.


Incidence and epidemiology of hospitalized influenza cases in rural Thailand during the influenza A (H1N1)pdm09 pandemic, 2009-2010.
Data on the burden of the 2009 influenza pandemic in Asia are limited. Influenza A(H1N1)pdm09 was first reported in Thailand in May 2009. We assessed incidence and epidemiology of influenza-associated hospitalizations during 2009-2010. We conducted active, population-based surveillance for hospitalized cases of acute lower respiratory infection (ALRI) in all 20 hospitals in two rural provinces. ALRI patients were sampled 1∶2 for participation in an etiology study in which nasopharyngeal swabs were collected for influenza virus testing by PCR. Of 7,207 patients tested, 902 (12.5%) were influenza-positive, including 190 (7.8%) of 2,436 children aged <5 years; 86% were influenza A virus (46% A(H1N1)pdm09, 30% H3N2, 6.5% H1N1, 3.5% not subtyped) and 13% were influenza B virus. Cases of influenza A(H1N1)pdm09 first peaked in August 2009 when 17% of tested patients were positive. Subsequent peaks during 2009 and 2010 represented a mix of influenza A(H1N1)pdm09, H3N2, and influenza B viruses. The estimated annual incidence of hospitalized influenza cases was 136 per 100,000, highest in ages <5 years (477 per 100,000) and >75 years (407 per 100,000). The incidence of influenza A(H1N1)pdm09 was 62 per 100,000 (214 per 100,000 in children <5 years). Eleven influenza-infected patients required mechanical ventilation, and four patients died, all adults with influenza A(H1N1)pdm09 (1) or H3N2 (3). Influenza-associated hospitalization rates in Thailand during 2009-10 were substantial and exceeded rates described in western countries. Influenza A(H1N1)pdm09 predominated, but H3N2 also caused notable morbidity. Expanded influenza vaccination coverage could have considerable public health impact, especially in young children.


Attributable risks of hospitalizations for urologic diseases due to heat exposure in Queensland, Australia, 1995-2016.
Heat exposure is a risk factor for urologic diseases. However, there are limited existing studies that have examined the relationship between high temperatures and urologic disease. The aim of this study was to examine the associations between heat exposure and hospitalizations for urologic diseases in Queensland, Australia, during the hot seasons of 1995-2016 and to quantify the attributable risks. We obtained 238 427 hospitalized cases with urologic diseases from Queensland Health between 1 December 1995 and 31 December 2016. Meteorological data were collected from the Scientific Information for Land Owners-a publicly accessible database of Australian climate data that provides daily data sets for a range of climate variables. A time-stratified, case-crossover design fitted with the conditional quasi-Poisson regression model was used to estimate the associations between temperature and hospitalizations for urologic diseases at the postcode level during each hot season (December-March). Attributable rates of hospitalizations for urologic disease due to heat exposure were calculated. Stratified analyses were performed by age, sex, climate zone, socio-economic factors and cause-specific urologic diseases. We found that a 1°C increase in temperature was associated with a 3.3% [95% confidence interval (CI): 2.9%, 3.7%] increase in hospitalization for the selected urologic diseases during the hot season. Hospitalizations for renal failure showed the strongest increase 5.88% (95% CI: 5.25%, 6.51%) among the specific causes of hospital admissions considered. Males and the elderly (≥60 years old) showed stronger associations with heat exposure than females and younger groups. The sex- and age-specific associations with heat exposure were similar across specific causes of urologic diseases. Overall, nearly one-fifth of hospitalizations for urologic diseases were attributable to heat exposure in Queensland. Heat exposure is associated with increased hospitalizations for urologic disease in Queensland during the hot season. This finding reinforces the pressing need for dedicated public health-promotion campaigns that target susceptible populations, especially for those more predisposed to renal failure. Given that short-term climate projections identify an increase in the frequency, duration and intensity of heatwaves, this public health advisory will be of increasing urgency in coming years.


Laparoscopic Hernia Repair with the Extraperitoneal Approach versus Open Hernia Repair in Pediatric Inguinal Hernia: A Systematic Review and Meta-Analysis.
This systematic review and meta-analysis investigated the feasibility and effectiveness of laparoscopic hernia repair with the extraperitoneal approach in pediatric inguinal hernias. Inguinal hernia repair is the most common operation in pediatric surgical practice. Although open hernia repair (OHR) is a well-established procedure with good outcomes, studies have reported acceptable or even better outcomes of laparoscopic hernia repair with the extraperitoneal approach (LHRE). However, a meta-analysis comparing LHRE with OHR is lacking. PubMed, EMBASE, and Cochrane Library databases were searched for randomized controlled trials (RCTs) and comparative studies (prospective or retrospective). Outcomes were metachronous contralateral inguinal hernia (MCIH), hernia recurrence, surgical site infection, operation time, and hospitalization length. A meta-analysis was performed, and risk ratios (RR), weighted mean difference (WMD), and 95% confidence intervals (CI) were calculated using random-effects models. Five RCTs and 21 comparative studies involving 24,479 patients were included. Lower MCIH incidence (RR: 0.11, 95% CI: 0.07 to 0.17; p < 0.00001) and a trend of shorter operation time (WMD: -11.90 min, 95% CI: -16.63 to -7.44; p < 0.00001) were found in the LHRE group. No significant differences in ipsilateral recurrence hernias, surgical site infection, and length of hospitalization were found between the groups. LHRE presented lower MCIH incidence and shorter operation times, with no increase in hernia recurrence, surgical site infection, or length of hospitalization. As more surgeons are increasingly becoming familiar with LHRE, LHRE would be a feasible and effective choice for pediatric inguinal hernia repair.


Effect of nursing home ownership on the quality of post-acute care: an instrumental variables approach.
Given the preferential tax treatment afforded nonprofit firms, policymakers and researchers have been interested in whether the nonprofit sector provides higher nursing home quality relative to its for-profit counterpart. However, differential selection into for-profits and nonprofits can lead to biased estimates of the effect of ownership form. By using "differential distance" to the nearest nonprofit nursing home relative to the nearest for-profit nursing home, we mimic randomization of residents into more or less "exposure" to nonprofit homes when estimating the effects of ownership on quality of care. Using national Minimum Data Set assessments linked with Medicare claims, we use a national cohort of post-acute patients who were newly admitted to nursing homes within an 18-month period spanning January 1, 2004 and June 30, 2005. After instrumenting for ownership status, we found that post-acute patients in nonprofit facilities had fewer 30-day hospitalizations and greater improvement in mobility, pain, and functioning.


Nanopore Analysis of Single-Stranded Binding Protein Interactions with DNA.
We study the binding of E. coli single-stranded binding protein (SSB) to single-stranded DNA (ssDNA) using a solid-state nanopore assay. We find that saturated nucleoprotein complexes can be distinguished easily from free SSB, ssDNA, or double-stranded DNA individually and demonstrate that the high affinity of SSB for ssDNA can be exploited to achieve high-fidelity differentiation from duplex molecules in a mixture. We then study nucleoprotein filament formation by systematically varying the amount of SSB relative to ssDNA. We observe a concomitant shift in the mean amplitude of electrical events that is consistent with weakly cooperative binding. Finally, we compare circular and linearized ssDNA saturated with SSB and use the results to infer structural details of the nucleoprotein complex.


TFH-derived dopamine accelerates productive synapses in germinal centres.
Protective high-affinity antibody responses depend on competitive selection of B cells carrying somatically mutated B-cell receptors by follicular helper T (TFH) cells in germinal centres. The rapid T-B-cell interactions that occur during this process are reminiscent of neural synaptic transmission pathways. Here we show that a proportion of human TFH cells contain dense-core granules marked by chromogranin B, which are normally found in neuronal presynaptic terminals storing catecholamines such as dopamine. TFH cells produce high amounts of dopamine and release it upon cognate interaction with B cells. Dopamine causes rapid translocation of intracellular ICOSL (inducible T-cell co-stimulator ligand, also known as ICOSLG) to the B-cell surface, which enhances accumulation of CD40L and chromogranin B granules at the human TFH cell synapse and increases the synapse area. Mathematical modelling suggests that faster dopamine-induced T-B-cell interactions increase total germinal centre output and accelerate it by days. Delivery of neurotransmitters across the T-B-cell synapse may be advantageous in the face of infection.


Graminicide insensitivity correlates with herbicide-binding co-operativity on acetyl-CoA carboxylase isoforms.
The sensitivity of grass species to important classes of graminicide herbicides inhibiting ACCase (acetyl-CoA carboxylase) is associated with a specific inhibition of the multifunctional ACCase located in the plastids of grasses. In contrast, the multisubunit form of ACCase found in the chloroplasts of dicotyledonous plants is insensitive and the minor cytosolic multifunctional isoforms of the enzyme in both types of plants are also less sensitive to inhibition. We have isolated, separated and characterized the multifunctional ACCase isoforms found in exceptional examples of grasses that are either inherently insensitive to these graminicides, or from biotypes showing acquired resistance to their use. Major and minor multifunctional enzymes were isolated from cell suspension cultures of Festuca rubra and the 'Notts A1'-resistant biotype of Alopecurus myosuroides, and their properties compared with those isolated from cells of wild-type sensitive A. myosuroides or from sensitive maize. Purifications of up to 300-fold were necessary to separate the two isoforms. The molecular masses (200-230 kDa) and K(m) values for all three substrates (ATP, bicarbonate and acetyl-CoA) were similar for the different ACCases, irrespective of their graminicide sensitivity. Moreover, we found no correlation between the ability of isoforms to carboxylate propionyl-CoA and their sensitivity to graminicides. However, insensitive purified forms of ACCase were characterized by herbicide-binding co-operativity, whereas, in contrast, sensitive forms of the enzymes were not. Our studies on isolated individual isoforms of ACCase from grasses support and extend previous indications that herbicide binding co-operativity is the only kinetic property that differentiates naturally or selected insensitive enzymes from the typical sensitive forms usually found in grasses.


Protection and participation: an interactive programme introducing the female condom to migrant sex workers in Cambodia.
The female condom has received much attention for its potential to empower users in negotiating safer sex. Studies demonstrate that the process used to introduce the method can influence subsequent use rates, resulting in calls for comprehensive documentation of introduction activities. This paper details an intervention study introducing the female condom to Vietnamese sex workers in Cambodia. Part of a wider community mobilization approach to reducing HIV/AIDS transmission, the intervention emphasized informed debate, group skills building and collective support. Research methods included both quantitative and qualitative data collection to evaluate the introduction's effect on sex workers' negotiation skills and social support networks. The findings show that approximately 16% of sex workers tried the female condom. Ever-use was significantly associated with participation in intervention workshops, and with indicators of both individual and community empowerment. Sex workers who incorporated the female condom into their work were also more likely to feel a sense of community identity. Introduced through an appropriate process, the female condom can serve as an 'entry point' to building community capacity. It can support sex workers in achieving protected sex and developing cooperative relationships, even in severely restrictive settings.


CD34 and EPCR coordinately enrich functional murine hematopoietic stem cells under normal and inflammatory conditions.
Hematopoiesis is dynamically regulated to maintain blood system function under nonhomeostatic conditions such as inflammation and injury. However, common surface marker and hematopoietic stem cell (HSC) reporter systems used for prospective enrichment of HSCs have been less rigorously tested in these contexts. Here, we use two surface markers, EPCR/CD201 and CD34, to re-analyze dynamic changes in the HSC-enriched phenotypic SLAM compartment in a mouse model of chronic interleukin (IL)-1 exposure. EPCR and CD34 coordinately identify four functionally and molecularly distinct compartments within the SLAM fraction, including an EPCR+/CD34- fraction whose long-term serial repopulating activity is only modestly impacted by chronic IL-1 exposure, relative to unfractionated SLAM cells. Notably, the other three fractions expand in frequency following IL-1 treatment and represent actively proliferating, lineage-primed cell states with limited long-term repopulating potential. Importantly, we find that the Fgd5-ZSGreen HSC reporter mouse enriches for molecularly and functionally intact HSCs regardless of IL-1 exposure. Together, our findings provide further evidence of dynamic heterogeneity within a commonly used HSC-enriched phenotypic compartment under stress conditions. Importantly, they also indicate that stringency of prospective isolation approaches can enhance interpretation of findings related to HSC function when studying models of hematopoietic stress.


The influence of ictal cutaneous allodynia on the response to occipital transcutaneous electrical stimulation in chronic migraine and chronic tension-type headache: a randomized, sham-controlled study.
The objective of this article is to determine whether cutaneous allodynia (CA) influences the response to treatment with occipital transcutaneous electrical stimulation (OTES) in chronic migraine (CM) and chronic tension-type headache (CTTH). One hundred and sixty consecutive patients with CM or CTTH were randomized to be treated with real or sham OTES stimulation three times a day for two consecutive weeks. All patients completed the validated 12-item allodynia symptom checklist for assessing the presence and the severity of CA during headache attack. Primary end-point was change (≥50%) in number of monthly headache-free days. There was a significant difference in the percentage of responders in the real OTES compared with sham OTES group (p <0.001). Importantly, there was not a significant change of monthly headache-free days in the allodynic patients with CM and CTTH treated both with real and sham OTES, while the number of headache-free days per month was significantly reduced in the real (86%) but not in the sham group (7%) of non-allodynic patients with CTTH and CM. Severe CA is associated with decreased response to treatment with OTES in patients with CM and CTTH.


No increased mortality with early aortic aneurysm disease.
In addition to increased risks for aneurysm-related death, previous studies have determined that all-cause mortality in abdominal aortic aneurysm (AAA) patients is excessive and equivalent to that associated with coronary heart disease. These studies largely preceded the current era of coronary heart disease risk factor management, however, and no recent study has examined contemporary mortality associated with early AAA disease (aneurysm diameter between 3 and 5 cm). As part of an ongoing natural history study of AAA, we report the mortality risk associated with presence of early disease. Participants were recruited from three distinct health care systems in Northern California between 2006 and 2011. Aneurysm diameter, demographic information, comorbidities, medication history, and plasma for biomarker analysis were collected at study entry. Survival status was determined at follow-up. Data were analyzed with t-tests or χ(2) tests where appropriate. Freedom from death was calculated via Cox proportional hazards modeling; the relevance of individual predictors on mortality was determined by log-rank test. The study enrolled 634 AAA patients; age 76.4 ± 8.0 years, aortic diameter 3.86 ± 0.7 cm. Participants were mostly male (88.8%), not current smokers (81.6%), and taking statins (76.7%). Mean follow-up was 2.1 ± 1.0 years. Estimated 1- and 3-year survival was 98.2% and 90.9%, respectively. Factors independently associated with mortality included larger aneurysm size (hazard ratio, 2.12; 95% confidence interval, 1.26-3.57 for diameter >4.0 cm) and diabetes (hazard ratio, 2.24; 95% confidence interval, 1.12-4.47). After adjusting for patient-level factors, health care system independently predicted mortality. Contemporary all-cause mortality for patients with early AAA disease is lower than that previously reported. Further research is warranted to determine important factors that contribute to improved survival in early AAA disease.


STED nanoscopy with time-gated detection: theoretical and experimental aspects.
In a stimulated emission depletion (STED) microscope the region in which fluorescence markers can emit spontaneously shrinks with continued STED beam action after a singular excitation event. This fact has been recently used to substantially improve the effective spatial resolution in STED nanoscopy using time-gated detection, pulsed excitation and continuous wave (CW) STED beams. We present a theoretical framework and experimental data that characterize the time evolution of the effective point-spread-function of a STED microscope and illustrate the physical basis, the benefits, and the limitations of time-gated detection both for CW and pulsed STED lasers. While gating hardly improves the effective resolution in the all-pulsed modality, in the CW-STED modality gating strongly suppresses low spatial frequencies in the image. Gated CW-STED nanoscopy is in essence limited (only) by the reduction of the signal that is associated with gating. Time-gated detection also reduces/suppresses the influence of local variations of the fluorescence lifetime on STED microscopy resolution.


The effect of social environment on treatment outcomes in outpatient substance misuse treatment organizations: does race really matter?
This study examines whether the racial mix of clients is related to treatment organization outcome rates after controlling for the social environment in which the organization operates. A nationally representative sample of 326 nonmethadone outpatient substance misuser treatment organizations was surveyed in 1990. Unit analysis is the treatment organization. Outcome measures are the percentages of clients who completed and dropped out of treatment. The percent of Black clients treated at the organization, the socioeconomic status of the organization's area, and other client characteristics, organizational factors, and treatment practices are evaluated through multivariate regression to determine their impact on organizational rates of treatment success and failure among clients. Ordinary least-squares regression analysis indicates that race is not a predictor of treatment success once socioenvironmental factors are included in the analysis. Treatment organizations must be wary of defining a person for treatment only in terms of his or her racial or ethnic group membership. Treatment approaches should place more emphasis on the socioenvironmental influences to which the client is exposed and less emphasis on a client's race.


The effect of predator presence on the behavioral sequence from host selection to reproduction in an invulnerable stage of insect prey.
Predator-prey interactions primarily focus on prey life-stages that are consumed. However, animals in less vulnerable life-stages might also be influenced by the presence of a predator, making our understanding of predation-related impacts across all life-stages of prey essential. It has been previously demonstrated that Podisus maculiventris is a voracious predator of eggs and larvae of Leptinotarsa decemlineata, and that larvae will alter their behavior to avoid predation. However, the adult beetles are not readily consumed by P. maculiventris, raising the question of whether they will respond to predators to protect themselves or their offspring. Here, we examine the effect of predation risk by P. maculiventris, on three adult behaviors of L. decemlineata; colonization, oviposition, and feeding, and the resulting impact on host plant damage. In an open-field test, there was no difference in natural beetle colonization between plots with predation risk and control treatments. However, subsequent host plant damage by adult beetles was 63.9% less in predation risk treatments. Over the lifetime of adult beetles in field mesocosms, per capita feeding was 23% less in the predation risk treatment. Beetle oviposition was 37% less in the presence of predators in a short-term, greenhouse assay, and marginally reduced in longer term field mesocosms. Our results indicate that predation risk can drive relatively invulnerable adult herbivores to adjust behaviors that affect themselves (feeding) and their offspring (oviposition). Thus, the full impact of predator presence must be considered across the prey life cycle.


Validation of whole slide imaging in the primary diagnosis of gynaecological pathology in a University Hospital.
Experience in the use of whole slide imaging (WSI) for primary diagnosis in pathology is very limited. We aimed to determine the accuracy of interpretation of WSI compared with conventional light microscopy (CLM) in the diagnosis of routine gynaecological biopsies. All gynaecological specimens (n=452) received over a 2-month period at the Department of Pathology of the Hospital Clinic of Barcelona were analysed blindly by two gynaecological pathologists, one using CLM and the other WSI. All slides were digitised in a Ventana iScan HT (Roche diagnostics) at 200×. All discrepant diagnoses were reviewed, and a final consensus diagnosis was established. The results were evaluated by weighted κ statistics for two observers. The level of interobserver agreement between WSI and CLM evaluations was almost perfect (κ value: 0.914; 95% CI 0.879 to 0.949) and increased during the study period: κ value 0.890; 95% CI 0.835 to 0.945 in the first period and 0.941; 95%; CI 0.899 to 0.983 in the second period. Major discrepancies (differences in clinical management or prognosis) were observed in 9 cases (2.0%). All discrepancies consisted of small lesions (8 high grade squamous intraepithelial lesions of the uterine cervix, one lymph node micrometastasis of an ovarian carcinoma) underdiagnosed or missed in the WSI or the CLM evaluation. Discrepancies with no or minor clinical relevance were identified in 3.8% of the biopsies. No discrepancy was related to the poor quality of the WSI image. Diagnosis of gynaecological specimens by WSI is accurate and may be introduced into routine diagnosis.


Altered expression of genes associated with telomere maintenance and cell function of human vascular endothelial cell at elevated temperature.
The pathophysiological alterations of vascular endothelial cells induced by heat were studied. Human umbilical venous endothelial cells were cultured for 1 day at three different temperatures (37, 39, and 42 °C). The telomere lengths, the expressions of proteins associated with telomere length maintenance, apoptosis, heat shock, and vascular function were analyzed. The cell growth was not suppressed at 39 °C but suppressed at 42 °C. The mean telomere length did not change, whereas the telomere length distribution altered at 42 °C. Long telomere decreased and middle-sized telomere increased in the telomere length distribution at 42 °C. The telomerase activity did not show any heat-associated alterations. However, of the components of telomerase, telomerase reverse transcriptase was up-regulated along temperature elevation. In contrast, the expression level of RNA component TERC did not altered. Among the analyzed apoptosis-associated proteins, p21 was down-regulated and phosphorylated p53 was up-regulated. Heat shock proteins and NO synthase were up-regulated at 42 °C. These results suggested that induced growth suppression or cell senescence was induced by strong heat stress rather than mild one predominantly in cells bearing long telomeres with p53 activation, and simultaneously activated some telomere-associated factors, heat shock proteins, and NO synthesis probably for heat-resistant cell survival.


Rapid detection of oleander poisoning by Digoxin III, a new Digoxin assay: impact on serum Digoxin measurement.
We studied the potential for detecting oleander with a new immunoassay (Digoxin III, Abbott Laboratories, Abbott Park, IL) by comparing results with those from the fluorescence polarization immunoassay (FPIA) and Digoxin II assay (Abbott). In aliquots of drug-free serum pools supplemented with pure oleandrin or oleander extract, we observed apparent digoxin values using all 3 immunoassays, but values obtained by the Digoxin III were higher than obtained by the other assays. We also observed significant apparent digoxin values in vivo in serum samples of mice 1 and 2 hours after feeding oleander extract. The average half-life of digoxin-like factors was 1.1 hours. In a serum pool (prepared from patients taking digoxin) supplemented with oleander extract, the observed digoxin values were falsely lowered when measured by the Digoxin II but falsely elevated when measured by the Digoxin III and FPIA. Monitoring free digoxin using the Digoxin III cannot eliminate this interference. Digibind neutralized digoxin-like factors of oleander extract; the effect can be monitored by observing a significant reduction in apparent free digoxin levels in the presence of Digibind as measured in protein-free ultrafiltrate using the Digoxin III. The Digoxin III is highly sensitive for measuring oleander.


Red blood cells in sports: effects of exercise and training on oxygen supply by red blood cells.
During exercise the cardiovascular system has to warrant substrate supply to working muscle. The main function of red blood cells in exercise is the transport of O2 from the lungs to the tissues and the delivery of metabolically produced CO2 to the lungs for expiration. Hemoglobin also contributes to the blood's buffering capacity, and ATP and NO release from red blood cells contributes to vasodilation and improved blood flow to working muscle. These functions require adequate amounts of red blood cells in circulation. Trained athletes, particularly in endurance sports, have a decreased hematocrit, which is sometimes called "sports anemia." This is not anemia in a clinical sense, because athletes have in fact an increased total mass of red blood cells and hemoglobin in circulation relative to sedentary individuals. The slight decrease in hematocrit by training is brought about by an increased plasma volume (PV). The mechanisms that increase total red blood cell mass by training are not understood fully. Despite stimulated erythropoiesis, exercise can decrease the red blood cell mass by intravascular hemolysis mainly of senescent red blood cells, which is caused by mechanical rupture when red blood cells pass through capillaries in contracting muscles, and by compression of red cells e.g., in foot soles during running or in hand palms in weightlifters. Together, these adjustments cause a decrease in the average age of the population of circulating red blood cells in trained athletes. These younger red cells are characterized by improved oxygen release and deformability, both of which also improve tissue oxygen supply during exercise.


LuxR solos in Photorhabdus species.
Bacteria communicate via small diffusible molecules to mediate group-coordinated behavior, a process designated as quorum sensing. The basic molecular quorum sensing system of Gram-negative bacteria consists of a LuxI-type autoinducer synthase producing acyl-homoserine lactones (AHLs) as signaling molecules, and a LuxR-type receptor detecting the AHLs to control expression of specific genes. However, many proteobacteria possess one or more unpaired LuxR-type receptors that lack a cognate LuxI-like synthase, referred to as LuxR solos. The enteric and insect pathogenic bacteria of the genus Photorhabdus harbor an extraordinarily high number of LuxR solos, more than any other known bacteria, and all lack a LuxI-like synthase. Here, we focus on the presence and the different types of LuxR solos in the three known Photorhabdus species using bioinformatics analyses. Generally, the N-terminal signal-binding domain (SBD) of LuxR-type receptors sensing AHLs have a motif of six conserved amino acids that is important for binding and specificity of the signaling molecule. However, this motif is altered in the majority of the Photorhabdus-specific LuxR solos, suggesting the use of other signaling molecules than AHLs. Furthermore, all Photorhabdus species contain at least one LuxR solo with an intact AHL-binding motif, which might allow the ability to sense AHLs of other bacteria. Moreover, all three species have high AHL-degrading activity caused by the presence of different AHL-lactonases and AHL-acylases, revealing a high quorum quenching activity against other bacteria. However, the majority of the other LuxR solos in Photorhabdus have a N-terminal so-called PAS4-domain instead of an AHL-binding domain, containing different amino acid motifs than the AHL-sensors, which potentially allows the recognition of a highly variable range of signaling molecules that can be sensed apart from AHLs. These PAS4-LuxR solos are proposed to be involved in host sensing, and therefore in inter-kingdom signaling. Overall, Photorhabdus species are perfect model organisms to study bacterial communication via LuxR solos and their role for a symbiotic and pathogenic life style.


Barriers and Facilitators to Implementing Reduced-Sodium Salts as a Population-Level Intervention: A Qualitative Study.
Widespread use of reduced-sodium salts can potentially lower excessive population-level dietary sodium intake. This study aimed to identify key barriers and facilitators to implementing reduced-sodium salt as a population level intervention. Semi-structured interviews were conducted with key informants from academia, the salt manufacturing industry, and government. We used the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework to inform our interview guides and data analysis. Eighteen key informants from nine countries across five World Health Organization regions participated in the study from January 2020 to July 2020. Participants were concerned about the lack of robust evidence on safety for specific populations such as those with renal impairment. Taste and price compared to regular salt and an understanding of the potential health benefits of reduced-sodium salt were identified as critical factors influencing the adoption of reduced-sodium salts. Higher production costs, low profit return, and reduced market demand for reduced-sodium salts were key barriers for industry in implementation. Participants provided recommendations as potential strategies to enhance the uptake. There are presently substantial barriers to the widespread use of reduced-sodium salt but there are also clear opportunities to take actions that would increase uptake.


A catalyst for system change: a case study of child health network formation, evolution and sustainability in Canada.
The purpose of this study was to examine key processes and supportive and inhibiting factors involved in the development, evolution, and sustainability of a child health network in rural Canada. This study contributes to a relatively new research agenda aimed at understanding inter-organizational and cross-sectoral health networks. These networks encourage collaboration focusing on complex issues impacting health - issues that individual agencies cannot effectively address alone. This paper presents an overview of the study findings. An explanatory qualitative case study approach examined the Network's 13-year lifespan. Data sources were documents and Network members, including regional and 71 provincial senior managers from 11 child and youth service sectors. Data were collected through 34 individual interviews and a review of 127 documents. Interview data were analyzed using framework analysis methods; Prior's approach guided document analysis. Three themes related to network development, evolution and sustainability were identified: (a) Network relationships as system triggers, (b) Network-mediated system responsiveness, and (c) Network practice as political. Study findings have important implications for network organizational development, collaborative practice, interprofessional education, public policy, and public system responsiveness research. Findings suggest it is important to explicitly focus on relationships and multi-level socio-political contexts, such as supportive policy environments, in understanding health networks. The dynamic interplay among the Network members; central supportive and inhibiting factors; and micro-, meso-, and macro-organizational contexts was identified.


Stress management in obesity during a thermal spa residential programme (ObesiStress): protocol for a randomised controlled trial study.
Stress and obesity are two public health issues. The relationship between obesity and stress is biological through the actions of stress on the major hormones that regulate appetite (leptin and ghrelin). Many spa resorts in France specialise in the treatment of obesity, but no thermal spa currently proposes a specific programme to manage stress in obesity. The ObesiStress protocol has been designed to offer a new residential stress management programme. This thermal spa treatment of obesity implements stress management strategies as suggested by international recommendations. 140 overweight or obese participants with a Body Mass Index of >25 kg/m2 and aged over 18 years will be recruited. Participants will be randomised into two groups: a control group of usual practice (restrictive diet, physical activity and thermal spa treatment) and an intervention group with stress management in addition to the usual practice. In the present protocol, parameters will be measured on five occasions (at inclusion, at the beginning of the spa (day 0), at the end of the spa (day 21), and at 6 and 12 months). The study will assess the participants' heart rate variability, cardiac remodelling and function, electrodermal activity, blood markers, anthropometric profile, body composition, psychology and quality of life via the use of questionnaires and bone parameters. The ObesiStress protocol complies with the ethics guidelines for Clinical Research and has been approved by the ethics committee (CPP Sud-Est VI, Clermont-Ferrand - ANSM: 2016-A01774-47). This study aimed to highlight the efficacy of a 21-day thermal spa residential programme of stress management in obesity through objective measurements of well-being and cardiovascular morbidity. Results will be disseminated during several research conferences and articles published in peer-reviewed journals. NCT03578757.


Clinical diagnoses, characteristics of risk behaviour, differences between suicidal and non-suicidal subgroups of Hungarian adolescent outpatients practising self-injury.
Self-injury (SI), self-injurious behaviour (SIB), including suicidal or non-suicidal self-injury (SSI, NSSI) represent an increasing problem among teenagers amounting to a 6-17% prevalence rate in adolescence, yet little data exists on detailed characteristics and associated factors of SI reaching clinical severity. There is also a scarcity of data distinguishing between suicidal and non-suicidal subsamples of self-injuring patients, i.e. showing which predictors contribute to develop self-injurious behaviour with a previous suicidal history (SSI). Clinical diagnoses and characteristics of risk behaviour were examined in a crosssectional design in suicidal and non-suicidal subgroups of Hungarian adolescent outpatients practising self-injurious behaviour. From the total pool of 708 new patients consecutively referred with various psychiatric problems in five regional child psychiatric centres in Western-Hungary over an 18-month period, 105 adolescent outpatients suffering from self-injurious behaviour participated in the study (28 males and 77 females aged from 14 to 18 years, mean age 15.97, SD 1.05). The Ottawa/Queen's self-injury questionnaire (OSI) was used to measure the characteristics of risk behaviour, while the comorbid clinical diagnoses were confirmed by the M.I.N.I. Plus International Neuropsychiatric Interview. Descriptive statistics presented the frequencies of the characteristics of SI, bilateral comparisons were used to reveal relevant items to differentiate between sex, duration of practice and SSI versus NSSI and logistic regression was performed to identify significant predictors of suicidal subtype of self-injuring practice. A total of 60% of the clinical SI population experienced a present or past episode of major depression. The motivation of patients to resist impulses and to discontinue malpractice was low. Cutting and scratching was the most common self-injuring methods. Two-thirds of the sample practised the impulsive type of SI, while 30% practised premeditated SI having an incubation time from 30 min to days and weeks before carrying out SI. Although duration of SI did not distinguish the sample in important aspects, girls and boys differed in several aspects of SI practice. SSI adolescents differed from their NSSI peers in a number of important characteristics including the frequency of actions, injured areas, methods, specific stresses and motivations. SSI adolescents were more likely to favour cutting of the lower leg and drug overdose as modes of SI. SSI adolescents were more likely to report addictive features than their peers with no suicidal motivation. From the aspect of self-injurious practice, logistic regression analysis found only two significant predictors for the combined pathology.


Chordin-induced lineage plasticity of adult SVZ neuroblasts after demyelination.
The mechanisms that regulate the developmental potential of adult neural progenitor populations under physiological and pathological conditions remain poorly defined. Glutamic acid decarboxylase 65 (GAD65)- and Doublecortin (Dcx)-expressing cells constitute major progenitor populations in the adult mouse subventricular zone (SVZ). Under normal physiological conditions, SVZ-derived GAD65-positive and Dcx-positive cells expressed the transcription factor Pax6 and migrated along the rostral migratory stream to the olfactory bulb to generate interneurons. After lysolecithin-induced demyelination of corpus callosum, however, these cells altered their molecular and cellular properties and migratory path. Demyelination upregulated chordin in the SVZ, which redirected GAD65-positive and Dcx-positive progenitors from neuronal to glial fates, generating new oligodendrocytes in the corpus callosum. Our findings suggest that the lineage plasticity of SVZ progenitor cells could be a potential therapeutic strategy for diseased or injured brain.


Electrolyte solvents for high voltage lithium ion batteries: ion correlation and specific anion effects in adiponitrile.
We studied dynamic and structural properties of two lithium conducting salts in the aprotic organic solvent adiponitrile by a combination of atomistic molecular dynamics (MD) simulations, quantum chemical calculations, and experimental findings. The outcomes of our simulations reveal significant differences between both lithium salts, namely lithium tetrafluoroborate (LiBF4) and lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) at various concentrations, which can be mainly attributed to the solvation behavior of the individual anions. The increased tendency of ion complex formation for LiBF4 is reflected by lower values regarding the measured and computed effective ionic conductivities when compared to LiTFSI. All findings highlight the crucial importance of specific anion effects in combination with molecular details of solvation, and advocate the use of adiponitrile as a beneficial solvent in modern lithium ion battery technology with high voltage electrodes.


Cholesterol sulfate is a DOCK2 inhibitor that mediates tissue-specific immune evasion in the eye.
Although immune responses are essential to protect the body from infection, they can also harm tissues. Certain tissues and organs, including the eye, constitute specialized microenvironments that locally inhibit immune reactivity. Dedicator of cytokinesis protein 2 (DOCK2) is a Rac-specific guanine nucleotide exchange factor (GEF) that is predominantly found in hematopoietic cells. DOCK2 plays a key role in immune surveillance because it is essential for the activation and migration of leukocytes. DOCK2 mutations cause severe immunodeficiency in humans. We found that DOCK2-mediated Rac activation and leukocyte migration were effectively inhibited by cholesterol sulfate (CS), but not by cholesterol or other sulfated steroids. CS bound to the catalytic domain of DOCK2 and suppressed its GEF activity. Mass spectrometric quantification revealed that CS was most abundantly produced in the Harderian gland, which provides the lipids that form the oily layer of the tear film. Sulfation of cholesterol is mediated by the sulfotransferases SULT2B1b and, to a lesser extent, SULT2B1a, which are produced from the same gene through alternative splicing. By genetically inactivating Sult2b1, we showed that the lack of CS in mice augmented ultraviolet- and antigen-induced ocular surface inflammation, which was suppressed by administration of eye drops containing CS. Thus, CS is a naturally occurring DOCK2 inhibitor and contributes to the generation of the immunosuppressive microenvironment in the eye.


Blockade of ethanol-induced behavioral sensitization by sodium butyrate: descriptive analysis of gene regulations in the striatum.
Behavioral sensitization induced by repeated ethanol (EtOH) exposure may play a critical role in the development of alcohol dependence. Because recent data demonstrate that histone deacetylase inhibitor (HDACi) may be of interest in the treatment of addiction, we explored the effect of the HDACi sodium butyrate (NaB) on EtOH-induced behavioral sensitization (EIBS) in DBA/2J mice. We also investigated gene regulations in the striatum of sensitized mice using epigenetic- and signal transduction-related PCR arrays. Mice were injected with saline or EtOH (0.5 to 2.5 g/kg) once a day for 10 days. Mice received NaB (200 to 600 mg/kg) 30 minutes before each injection (prevention protocol) or once daily between days 11 and 16 (reversal protocol). At day 17, brains were removed 30 minutes after a saline or EtOH challenge to assess gene and proteins levels. Only the intermediate EtOH doses (1.0 and 2.0 g/kg) were effective in inducing EIBS, and both doses were associated with specific gene regulations in the striatum. The induction of sensitization by 1.0 g/kg (but not 2.0 g/kg) EtOH was dose-dependently prevented or reversed by NaB. Among the 168 studied genes, EIBS blockade was associated with specific gene regulations (bcl-2, bdnf, hdac4, pak1, penk, tacr1, vip…) and changes in brain-derived neurotrophic factor in both striatum and prefrontal cortex. These results indicate that EIBS is associated with specific gene regulations in the striatum depending on the EtOH dose and that NaB can be useful in blocking some long-lasting neuro-adaptations to repeated EtOH administrations.


Cascading extinctions and community collapse in model food webs.
Species loss in ecosystems can lead to secondary extinctions as a result of consumer-resource relationships and other species interactions. We compare levels of secondary extinctions in communities generated by four structural food-web models and a fifth null model in response to sequential primary species removals. We focus on various aspects of food-web structural integrity including robustness, community collapse and threshold periods, and how these features relate to assumptions underlying different models, different species loss sequences and simple measures of diversity and complexity. Hierarchical feeding, a fundamental characteristic of food-web structure, appears to impose a cost in terms of robustness and other aspects of structural integrity. However, exponential-type link distributions, also characteristic of more realistic models, generally confer greater structural robustness than the less skewed link distributions of less realistic models. In most cases for the more realistic models, increased robustness and decreased levels of web collapse are associated with increased diversity, measured as species richness S, and increased complexity, measured as connectance C. These and other results, including a surprising sensitivity of more realistic model food webs to loss of species with few links to other species, are compared with prior work based on empirical food-web data.


The development of a consensus-based nutritional pathway for infants with CHD before surgery using a modified Delphi process.
IntroductionDespite improvements in the medical and surgical management of infants with CHD, growth failure before surgery in many infants continues to be a significant concern. A nutritional pathway was developed, the aim of which was to provide a structured approach to nutritional care for infants with CHD awaiting surgery.Materials and methodsThe modified Delphi process was development of a nutritional pathway; initial stakeholder meeting to finalise draft guidelines and develop questions; round 1 anonymous online survey; round 2 online survey; regional cardiac conference and pathway revision; and final expert meeting and pathway finalisation. Paediatric Dietitians from all 11 of the paediatric cardiology surgical centres in the United Kingdom contributed to the guideline development. In all, 33% of participants had 9 or more years of experience working with infants with CHD. By the end of rounds 1 and 2, 76 and 96% of participants, respectively, were in agreement with the statements. Three statements where consensus was not achieved by the end of round 2 were discussed and agreed at the final expert group meeting. Nutrition guidelines were developed for infants with CHD awaiting surgery, using a modified Delphi process, incorporating the best available evidence and expert opinion with regard to nutritional support in this group.


Donepezil in Parkinson's disease dementia: a randomized, double-blind efficacy and safety study.
Parkinson's disease dementia (PDD) is associated with cholinergic deficits. This report presents an efficacy and safety study of the acetylcholinesterase inhibitor donepezil hydrochloride in PDD. PDD patients (n = 550) were randomized to donepezil (5 or 10 mg) or placebo for 24 weeks. Coprimary end points were the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+; global function). Secondary end points measured executive function, attention, activities of daily living (ADLs), and behavioral symptoms. Safety and tolerability were assessed. ADAS-cog mean changes from baseline to week 24 (end point) were not significant for donepezil in the intent-to-treat population by the predefined statistical model (difference from placebo: -1.45, P = .050, for 5 mg; -1.45, P = .076, for 10 mg). Alternative ADAS-cog analysis, removing the treatment-by-country interaction term from the model, revealed significant, dose-dependent benefit with donepezil (difference from placebo: -2.08, P = .002, for 5 mg; -3.31, P < .001, for 10 mg). The 10-mg group, but not the 5-mg group, had significantly better CIBIC+ scores compared with placebo (3.7 vs 3.9, P = .113, for 5 mg; 3.6 vs 3.9, P = .040, for 10 mg). Secondary end points-Mini-Mental State Exam; Delis-Kaplan Executive Function System; Brief Test of Attention, representing cognitive functions particularly relevant to PDD-showed significant benefit for both donepezil doses (P ≤ .007). There were no significant differences in ADLs or behavior. Adverse events were more common with donepezil but mostly mild/moderate in severity. Although the study did not achieve its predefined primary end points, it presents evidence suggesting that donepezil can improve cognition, executive function, and global status in PDD. Tolerability was consistent with the known safety profile of donepezil. © 2012 Movement Disorder Society.


Breaking a vicious cycle.
Despite prodigious advances in tumor biology research, few tumor-biomarker tests have been adopted as standard clinical practice. This lack of reliable tests stems from a vicious cycle of undervaluation, resulting from inconsistent regulatory standards and reimbursement, as well as insufficient investment in research and development, scrutiny of biomarker publications by journals, and evidence of analytical validity and clinical utility. We offer recommendations designed to serve as a roadmap to break this vicious cycle and call for a national dialogue, as changes in regulation, reimbursement, investment, peer review, and guidelines development require the participation of all stakeholders.


Indirect prediction of total body water content in healthy adult Beagles by single-frequency bioelectrical impedance analysis.
To develop equations for prediction of total body water (TBW) content in unsedated dogs by combining impedance (resistance and reactance) and morphological variables and to compare the results of those equations with TBW content determined by deuterium dilution (TBW(d)). 26 healthy adult Beagles. TBW content was determined directly by deuterium dilution and indirectly with equations developed from measurements obtained by use of a portable bioelectric impedance device and morphological variables including body length, height, weight, and thoracic and abdominal circumferences. Impedance and morphological data from 16 of the 26 dogs were used to determine coefficients for the following 2 equations: TBW(1) = -0.019 (BL(2)/R) + -0.199 (RC + AC) + 0.996 W + 0.081 H + 12.31; and TBW(2) = 0.048 (BL(2)/R) + -0.144 (RC + AC) + 0.777 W + 0.066 H + 0.031 X + 7.47, where AC is abdominal circumference, H is height, BL is body length, R is resistance, RC is rib cage circumference, W is body weight, and × is reactance. Results for TBW(1) (R(2)(1) = 0.843) and TBW(2) (R(2)(2) = 0.816) were highly correlated with the TBW(d). When the equations were validated with data from the remaining 10 dogs, the respective mean differences between TBW(d) and TBW(1) and TBW(2) were 0.17 and 0.11 L, which equated to a nonsignificant underestimation of TBW content by 2.4% and 1.6%, respectively. Results indicated that impedance and morphological data can be used to accurately estimate TBW content in adult Beagles. This method of estimating TBW content is less expensive and easier to perform than is measurement of TBW(d), making it appealing for daily use in veterinary practice.


Making my family proud: The unique contribution of familism pride to the psychological adjustment of Latinx emerging adults.
Familism values serve to provide key cultural scripts in Latinx families, and these values have been associated with positive psychosocial outcomes for Latinx youth (Stein et al., 2014). Yet, how familism values intersect with the experience of positive emotions remains relatively unknown. In particular, familism pride may be an important positive emotion that links familism values to positive psychosocial outcomes. To fill this gap in the literature, the current study developed a measure of familism pride and examined its unique prediction to psychosocial outcomes. Self-report survey data were collected from 2 samples of Latinx emerging adults who were part of a psychology subject pool at a comprehensive university in Los Angeles designated as an Hispanic-serving institution. Sample 1 (n = 352) was 72.2% women with a mean age of 18.9 years, whereas Sample 2 was 68.6% women with a mean age of 19.3 years. Factor analyses supported that familism pride was distinct from familism values (familial support, obligation, reference, respeto). Familism pride was associated with fewer depressive symptoms and greater experience of joy when controlling for familism values in both samples. Our study underscores the importance of examining emotional processes in the study of familism and suggests a new dimension of familism that has not received research attention. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


FimA, a major virulence factor associated with Streptococcus parasanguis endocarditis.
Adherence of microorganisms to damaged heart tissue is a crucial event in the pathogenesis of infective endocarditis. In the present study, we investigated the role of the FimA protein as a potential virulence factor associated with Streptococcus parasanguis endocarditis. FimA is a 36-kDa surface protein that is a recognized adhesin in the oral cavity where it mediates adherence to the salivary pellicle. An insertion mutant and a deletion mutant of S. parasanguis were employed in the rat model of endocarditis to determine the relevance of FimA in endocarditis pathogenesis. Catheterized rats were infected with either the fimA deletion mutant VT929, the fimA insertion mutant VT930, or the isogenic, wild-type S. parasanguis FW213. Rats inoculated with FW213 developed endocarditis more frequently (50.9%) than animals inoculated with either the deletion mutant (2.7%) or the insertion mutant (7.6%) (P < 0.001). A series of in vitro assays were performed to explore the mechanism(s) by which FimA enhanced the infectivity of S. parasanguis. FimA did not inhibit the uptake or the subsequent killing of S. parasanguis by phagocytic granulocytes. Similarly, FimA did not play a role in the adherence to or the aggregation of platelets. Significant differences were noted between FW213 and VT929 (P < 0.05) and FW213 and VT930 (P < 0.001) in their abilities to bind to fibrin monolayers. The mean percent adherence of FW213 to fibrin monolayers (2.1%) was greater than those of VT929 (0.5%) and VT930 (0.12%). Taken together, these results indicate that FimA is a major virulence determinant associated with S. parasanguis endocarditis and further suggest that its role is associated with initial colonization of damaged heart tissue.


Natural history of Niemann-Pick disease type C in a multicentre observational retrospective cohort study.
Niemann-Pick disease type C (NP-C) is a devastating genetic disorder characterised by progressive neurological deterioration. However, data on the progression of neurological manifestations, particularly across different patient age-of-disease onsets, are limited. This is an observational retrospective cohort study designed to assess the progression of neurological disease in patients with NP-C. Physicians were asked to retrospectively complete a web-based questionnaire for each patient, at diagnosis and at up to three follow-up visits. An NP-C-specific disability scale was used to measure disease progression. The scale comprised four key parameters of neurological disease progression; ambulation, manipulation, language and swallowing. Disease progression was evaluated based on the annual rate of change in each parameter and the composite score using a linear mixed model analysis, and by classifying patients according to the number of worsened parameters during the observation period. Data were collected from 57 patients. The rate of deterioration was similar across the four individual parameters of the disability scale. The mean (95% CI) annual disease progression was +0.12 (0.09, 0.15) units. Among patients with a time interval of at least 1 year between diagnosis and last visit (n=49), 42 (86%) patients had progressed disease and 7 (14%) patients had stable disease. Disease progression was consistently more rapid in patients diagnosed in early childhood, compared with those diagnosed in late childhood, or with juvenile or adult presentation. In conclusion, our findings showed a progression in all four parameters of the disability scale, representing a continuous, unbroken progression of neurological manifestations.


Spontaneous murine neuroaxonal dystrophy: a model of infantile neuroaxonal dystrophy.
The neuroaxonal dystrophies (NADs) in human beings are fatal, inherited, neurodegenerative diseases with distinctive pathological features. This report describes a new mouse model of NAD that was identified as a spontaneous mutation in a BALB/c congenic mouse strain. The affected animals developed clinical signs of a sensory axonopathy consisting of hindlimb spasticity and ataxia as early as 3 weeks of age, with progression to paraparesis and severe morbidity by 6 months of age. Hallmark histological lesions consisted of spheroids (swollen axons), in the grey and white matter of the midbrain, brain stem, and all levels of the spinal cord. Ultrastructural analysis of the spheroids revealed accumulations of layered stacks of membranes and tubulovesicular elements, strongly resembling the ultrastructural changes seen in the axons of human patients with endogenous forms of NAD. Mouse NAD would therefore seem a potentially valuable model of human NADs.


Lymph node evaluation is associated with improved survival after surgery for early stage gallbladder cancer.
Guidelines for the current National Comprehensive Cancer Network recommend radical cholecystectomy, including hepatic resection and portal lymph node (LN) dissection, for patients with early stage gallbladder (GB) cancer. We sought to determine the survival benefit conferred by adequate LN evaluation. We used the surveillance, epidemiology and end results (SEER) neoplasm registry to identify patients who had an operation for GB cancer between 1988 and 2004. Patients were classified by stage of disease, operative procedure performed (cholecystectomy alone or radical resection), number of LNs evaluated (0, 1, >1), and receipt of radiation (RT). We included patients with T1B, T2, and T3 neoplasms who were LN positive or negative. Patients with T4 neoplasms and those with metastatic disease were excluded. Multivariate analysis included adjustment for age, race, sex, neoplasm grade, stage, operation performed, receipt of RT, and neoplasm registry. We identified 4,614 patients who underwent operative treatment for stage 1-2B GB (including T1B-T3 and LN positive or negative) cancer between 1988 and 2004. Of 4,614 patients, 9.6% (442) had radical resection, whereas 90.4% (4,172) had cholecystectomy alone. Among patients undergoing radical resection, 56% had LNs evaluated as compared with 28% of patients after cholecystectomy. For patients with T1B and T2 neoplasms who underwent radical resection, pathologic evaluation of at least 1 LN was associated with a significant improvement in median overall survival (OS) compared with those who had no LN evaluated (123 months vs 22 months; P < .0001). Radical resection with no LN evaluation provided similar OS compared with cholecystectomy alone (22 months vs 23 months; P = NS). For patients with T3 neoplasms, radical resection, including pathologic evaluation of at least 1 LN, was also associated with improved OS compared with radical resection with no LN evaluation (12 months vs 7 months; P = .0014). Again, individuals who had radical resection without LN evaluation had similar OS compared with those who had cholecystectomy alone (7 months vs 6 months; P = NS). Individuals who had radical resection with LN evaluation were more likely to receive RT than those who had radical resection without LN evaluation (33.1% vs 19.1%; P = .002). In multivariate analysis (including adjustment for RT), however, LN evaluation was still associated with a decrease in mortality compared with no LN evaluated (HR = 0.611; 95% CI = 0.484, 0.770). The pathologic evaluation of additional LN (>1) did not provide any additional benefit compared with the evaluation of a single node (HR = 0.795; 95% CI = 0.571, 1.107). Radical resection alone (without LN evaluation) did not provide any benefit over cholecystectomy alone (HR = 1.098; 95% CI = 0.971, 1.241). LN evaluation is a critical component of radical resection for GB cancer. In the absence of LN evaluation, radical resection provides no benefit over cholecystectomy alone.


Compound palmar ganglion with carpal tunnel syndrome.
Compound palmer ganglion is an uncommon condition characterized by a swelling in the distal part of volar aspect of wrist and communicating with another swelling over palm across the flexor retinaculum. It commonly results from tuberculous tenosynovitis. It may lead to carpal tunnel syndrome and need surgical excision with division of flexor retinaculum.


Comparative tests of parasite species richness in primates.
Some hosts harbor diverse parasite communities, whereas others are relatively parasite free. Many factors have been proposed to account for patterns of parasite species richness, but few studies have investigated competing hypotheses among multiple parasite communities in the same host clade. We used a comparative data set of 941 host-parasite combinations, representing 101 anthropoid primate species and 231 parasite taxa, to test the relative importance of four sets of variables that have been proposed as determinants of parasite community diversity in primates: host body mass and life history, social contact and population density, diet, and habitat diversity. We defined parasites broadly to include not only parasitic helminths and arthropods but also viruses, bacteria, fungi, and protozoa, and we controlled for effects of uneven sampling effort on per-host measures of parasite diversity. In nonphylogenetic tests, body mass was correlated with total parasite diversity and the diversity of helminths and viruses. When phylogeny was taken into account, however, body mass became nonsignificant. Host population density, a key determinant of parasite spread in many epidemiological models, was associated consistently with total parasite species richness and the diversity of helminths, protozoa, and viruses tested separately. Geographic range size and day range length explained significant variation in the diversity of viruses.


Rival male chemical cues evoke changes in male pre- and post-copulatory investment in a flour beetle.
Males can gather information on the risk and intensity of sperm competition from their social environment. Recent studies have implicated chemosensory cues, for instance cuticular hydrocarbons (CHCs) in insects, as a key source of this information. Here, using the broad-horned flour beetle (Gnatocerus cornutus), we investigated the importance of contact-derived rival male CHCs in informing male perception of sperm competition risk and intensity. We experimentally perfumed virgin females with male CHCs via direct intersexual contact and measured male pre- and post-copulatory investment in response to this manipulation. Using chemical analysis, we verified that this treatment engendered changes to perfumed female CHC profiles, but did not make perfumed females "smell" mated. Despite this, males responded to these chemical changes. Males increased courtship effort under low levels of perceived competition (from 1-3 rivals), but significantly decreased courtship effort as perceived competition rose (from 3-5 rivals). Furthermore, our measurement of ejaculate investment showed that males allocated significantly more sperm to perfumed females than to control females. Together, these results suggest that changes in female chemical profile elicited by contact with rival males do not provide males with information on female mating status, but rather inform males of the presence of rivals within the population and thus provide a means for males to indirectly assess the risk of sperm competition.


Do stressful life events during pregnancy modify associations between phthalates and anogenital distance in newborns?
Anogenital distance (AGD) has been used as a marker of fetal androgen action to identify endocrine disrupting chemicals. A US study (TIDES) has reported that the association between some phthalates and reduced AGD in males was only apparent in sons of mothers reporting no stressful life events (SLEs) during pregnancy. The objective of the current study was to examine the potential modifying effect of SLEs and their subjective impact on associations between prenatal phthalates and AGD. First trimester urines from the MIREC Study were analysed for phthalate metabolites and AGD was measured in neonates. Post-delivery, the women answered questions on SLEs during the pregnancy. Women reporting 1 or more SLEs during pregnancy were considered a "higher stressor" group, whereas women reporting no SLEs or who reported a SLE that was perceived as not at all stressful were considered a "lower stressor" group. Multivariable linear regression models were fit stratified by stressor group. Maternal stressor, AGD and phthalates results were available for 153 females and 147 males. A summary measure of androgen-disrupting phthalates (Σ AD) was associated with significantly longer AGDs in females from the higher stressor group. These effect sizes were increased when the perceived impact was restricted to moderately or very much stressful. In males, all phthalates were associated with longer anopenile distance (APD), regardless of stressor group; however, higher Σ AD was associated with significantly longer APD in the lower stressor group. In contrast to the TIDES study, we did not observe shorter AGDs in male infants prenatally exposed to di-(2-ethylhexyl) phthalates, regardless of maternal stressor level. In conclusion, we were unable to replicate the findings of the TIDES study, but did find some evidence that prenatal SLEs may modify associations between phthalates and female AGD. Further research with other populations and measures of prenatal stress may shed more light on whether prenatal stress is an important effect modifier of associations between phthalates (or other chemicals) and anogenital distance.


Distinct roles for the anterior temporal lobe and angular gyrus in the spatiotemporal cortical semantic network.
Semantic knowledge is supported by numerous brain regions, but the spatiotemporal configuration of the network that links these areas remains an open question. The hub-and-spokes model posits that a central semantic hub coordinates this network. In this study, we explored distinct aspects that define a semantic hub, as reflected in the spatiotemporal modulation of neural activity and connectivity by semantic variables, from the earliest stages of semantic processing. We used source-reconstructed electro/magnetoencephalography, and investigated the concreteness contrast across three tasks. In a whole-cortex analysis, the left anterior temporal lobe (ATL) was the only area that showed modulation of evoked brain activity from 100 ms post-stimulus. Furthermore, using Dynamic Causal Modeling of the evoked responses, we investigated effective connectivity amongst the candidate semantic hub regions, that is, left ATL, supramarginal/angular gyrus (SMG/AG), middle temporal gyrus, and inferior frontal gyrus. We found that models with a single semantic hub showed the highest Bayesian evidence, and the hub region was found to change from ATL (within 250 ms) to SMG/AG (within 450 ms) over time. Our results support a single semantic hub view, with ATL showing sustained modulation of neural activity by semantics, and both ATL and AG underlying connectivity depending on the stage of semantic processing.


Deregulated profiles of urinary microRNAs may explain podocyte injury and proximal tubule dysfunction in normoalbuminuric patients with type 2 diabetes mellitus.
MicroRNAs (miRNAs) are short non-coding RNA species that are important post-transcriptional regulators of gene expression. The aim of the study was to establish a potential explanation of podocyte damage and proximal tubule (PT) dysfunction induced by deregulated miRNAs expression in the course of type 2 diabetes mellitus (DM). A total of 68 patients with type 2 DM and 11 healthy subjects were enrolled in a cross-sectional study and assessed concerning urinary albumin:creatinine ratio (UACR), urinary N-acetyl-β-D-glucosamininidase (NAG), urinary kidney injury molecule-1, urinary nephrin, podocalyxin, synaptopodin, estimated glomerular filtration rate (eGFR), urinary miRNA21, miRNA124, and miRNA192. In univariable regression analysis, miRNA21, miRNA124, and miRNA192 correlated with urinary nephrin, synaptopodin, podocalyxin, NAG, KIM-1, UACR, and eGFR. Multivariable regression analysis yielded models in which miRNA192 correlated with synaptopodin, uNAG, and eGFR (R2=0.902; P<0.0001), miRNA124 correlated with synaptopodin, uNAG, UACR, and eGFR (R2=0.881; P<0.0001), whereas miRNA21 correlated with podocalyxin, uNAG, UACR, and eGFR (R2=0.882; P<0.0001). Urinary miRNA192 expression was downregulated, while urinary miRNA21 and miRNA124 expressions were upregulated. In patients with type 2 DM, there is an association between podocyte injury and PT dysfunction, and miRNA excretion, even in the normoalbuminuria stage. This observation documents a potential role of the urinary profiles of miRNA21, miRNA124, and miRNA192 in early DN. Despite their variability across the segments of the nephron, urinary miRNAs may be considered as a reliable tool for the identification of novel biomarkers in order to characterize the genetic pattern of podocyte damage and PT dysfunction in early DN of type 2 DM.


A review of psychosocial pre-treatment predictors of weight control.
Prompted by the large heterogeneity of individual results in obesity treatment, many studies have attempted to predict weight outcomes from information collected from participants before they start the programme. Identifying significant predictors of weight loss outcomes is central to improving treatments for obesity, as it could help professionals focus efforts on those most likely to benefit, suggest supplementary or alternative treatments for those less likely to succeed, and help in matching individuals to different treatments. To date, however, research efforts have resulted in weak predictive models with limited practical usefulness. The two primary goals of this article are to review the best individual-level psychosocial pre-treatment predictors of short- and long-term (1 year or more) weight loss and to identify research needs and propose directions for further work in this area. Results from original studies published since 1995 show that few previous weight loss attempts and an autonomous, self-motivated cognitive style are the best prospective predictors of successful weight management. In the more obese samples, higher initial body mass index (BMI) may also be correlated with larger absolute weight losses. Several variables, including binge eating, eating disinhibition and restraint, and depression/mood clearly do not predict treatment outcomes, when assessed before treatment. Importantly, for a considerable number of psychosocial constructs (e.g. eating self-efficacy, body image, self-esteem, outcome expectancies, weight-specific quality of life and several variables related to exercise), evidence is suggestive but inconsistent or too scant for an informed conclusion to be drawn. Results are discussed in the context of past and present conceptual and methodological limitations, and several future research directions are described.


Brain tissue volume changes following weight gain in adults with anorexia nervosa.
To measure brain volume deficits among underweight patients with anorexia nervosa (AN) compared to control participants and evaluate the reversibility of these deficits with short-term weight restoration. Brain volume changes in gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) were examined in 32 adult women with AN and compared to 21, age and body mass index-range matched control women. Patients with AN had a significant increase in GM (p = .006, η(2) = 0.14) and WM volume (p = .001, η(2) = 0.19) following weight restoration. Patients on average had lower levels of GM at low weight (647.63 ± 62.07 ml) compared to controls (679.93 ± 53.31 ml), which increased with weight restoration (662.64 ± 69.71 ml), but did not fully normalize. This study suggests that underweight adult patients with AN have reduced GM and WM volumes that increase with short-term weight restoration.


Metamorphopsia and letter recognition.
Acuity is the most commonly used measure of visual function, and reductions in acuity are associated with most eye diseases. Metamorphopsia--a perceived distortion of visual space--is another common symptom of visual impairment and is currently assessed qualitatively using Amsler (1953) charts. In order to quantify the impact of metamorphopsia on acuity, we measured the effect of physical spatial distortion on letter recognition. Following earlier work showing that letter recognition is tuned to specific spatial frequency (SF) channels, we hypothesized that the effect of distortion might depend on the spatial scale of visual distortion just as it depends on the spatial scale of masking noise. Six normally sighted observers completed a 26 alternate forced choice (AFC) Sloan letter identification task at five different viewing distances, and the letters underwent different levels of spatial distortion. Distortion was controlled using spatially band-pass filtered noise that spatially remapped pixel locations. Noise was varied over five spatial frequencies and five magnitudes. Performance was modeled with logistic regression and worsened linearly with increasing distortion magnitude and decreasing letter size. We found that retinal SF affects distortion at midrange frequencies and can be explained with the tuning of a basic contrast sensitivity function, while object-centered distortion SF follows a similar pattern of letter object recognition sensitivity and is tuned to approximately three cycles per letter (CPL). The interaction between letter size and distortion makes acuity an unreliable outcome for metamorphopsia assessment.


Is the Addition of a Polyol to Hyaluronic Acid a Significant Advance in the Treatment of Osteoarthritis?
Viscosupplementation with intra-articular injections of hyaluronic acid is recommended as a second line treatment for knee OA, after failure of non-pharmacological modalities and usual pain killers. Nevertheless there are still controversies regarding clinical relevance of its effects. Research is looking for the best way to improve the performance of viscosupplementation in order to obtain a faster, longer-lasting and more pronounced effect. Antioxidants have been assessed in combination with hyaluronic acid because the injected hyaluronate is rapidly degraded by the reactive oxygen species, present in large amounts in the OA synovial fluid, limiting its residence time into the joint. Sorbitol and mannitol which have intrinsic free radical scavenger properties have been the most studied antioxidants. Sodium hyaluronate and polyols develop together a complex based on a dense network of hydrogen bonds which do not modify the visco-elsatic properties of hyaluronic acid. The oxygen free radicals neutralization by mannitol has been proven to delay the degradation of both linear and cross-linked HA in several in vitro models of oxidative stress. The antioxidant effect of these polyols may also play a role in accelerating onset of analgesia, as demonstrated in a double blind controlled trial comparing a mannitol-modified viscosupplement to regular hyaluronic acid. The addition of mannitol and sorbitol to hyaluronic acid does not alter the safety and local tolerability. In summary, adding a polyol to hyaluronic acid may improve the effects of viscosupplementation by reducing the rate of degradation of HA leading to a faster effect on pain relief without increasing the risk of adverse effect.


Molecular Sequence of Events and Signaling Pathways in Cerebral Metastases.
Brain metastases are the leading cause of morbidity and mortality among cancer patients, and are reported to occur in about 40% of cancer patients with metastatic disease in the United States of America. Primary tumor cells appear to detach from the parent tumor site, migrate, survive and pass through the blood brain barrier in order to establish cerebral metastases. This complex process involves distinct molecular and genetic mechanisms that mediate metastasis from these primary organs to the brain. Furthermore, an interaction between the invading cells and cerebral milieu is shown to promote this process as well. Here, we review the mechanisms by which primary cancer cells metastasize to the brain via a mechanism called epithelial-to-mesenchymal transition, as well as the involvement of certain microRNA and genetic aberrations implicated in cerebral metastases from the lung, breast, skin, kidney and colon. While the mechanisms governing the development of brain metastases remain a major hindrance in treatment, understanding and identification of the aforementioned molecular pathways may allow for improved management and discovery of novel therapeutic targets.


VEGFR2 and Src kinase inhibitors suppress Andes virus-induced endothelial cell permeability.
Hantaviruses predominantly infect human endothelial cells and, in the absence of cell lysis, cause two diseases resulting from increased vascular permeability. Andes virus (ANDV) causes a highly lethal acute pulmonary edema termed hantavirus pulmonary syndrome (HPS). ANDV infection enhances the permeability of endothelial cells in response to vascular endothelial growth factor (VEGF) by increasing signaling responses directed by the VEGFR2-Src-VE-cadherin pathway, which directs adherens junction (AJ) disassembly. Here we demonstrate that inhibiting pathway-specific VEGFR2 and Src family kinases (SFKs) blocks ANDV-induced endothelial cell permeability. Small interfering RNA (siRNA) knockdown of Src within ANDV-infected endothelial cells resulted in an ∼70% decrease in endothelial cell permeability compared to that for siRNA controls. This finding suggested that existing FDA-approved small-molecule kinase inhibitors might similarly block ANDV-induced permeability. The VEGFR2 kinase inhibitor pazopanib as well as SFK inhibitors dasatinib, PP1, bosutinib, and Src inhibitor 1 dramatically inhibited ANDV-induced endothelial cell permeability. Consistent with their kinase-inhibitory concentrations, dasatinib, PP1, and pazopanib inhibited ANDV-induced permeability at 1, 10, and 100 nanomolar 50% inhibitory concentrations (IC(50)s), respectively. We further demonstrated that dasatinib and pazopanib blocked VE-cadherin dissociation from the AJs of ANDV-infected endothelial cells by >90%. These findings indicate that VEGFR2 and Src kinases are potential targets for therapeutically reducing ANDV-induced endothelial cell permeability and, as a result, capillary permeability during HPS. Since the functions of VEGFR2 and SFK inhibitors are already well defined and FDA approved for clinical use, these findings rationalize their therapeutic evaluation for efficacy in reducing HPS disease. Endothelial cell barrier functions are disrupted by a number of viruses that cause hemorrhagic, edematous, or neurologic disease, and as a result, our findings suggest that VEGFR2 and SFK inhibitors should be considered for regulating endothelial cell barrier functions altered by additional viral pathogens.


Vaccination with Flt3L-induced CD8α+ dendritic cells prevents CD4+ T helper cell-mediated experimental autoimmune myocarditis.
Experimental autoimmune myocarditis (EAM) represents a CD4(+) T helper (Th) cell-mediated mouse model of inflammatory heart disease. Interferon (IFN)-γ, typically produced by Th1 cells, reduces EAM severity in myosin heavy-chain-(MyHC)-α peptide/Complete Freund adjuvant-immunized mice. Thus, developing a vaccination strategy that promotes differentiation of Th1 cells may be beneficial in EAM. FMS-like tyrosine kinase 3 ligand (Flt3L)-induced splenic CD8α(+) dendritic cells (DC), which produce interleukin (IL)-12p35, were identified to selectively induce biased differentiation towards Th1. Mice vaccinated with MyHC-α-loaded Flt3L-induced splenic CD8α(+) DC were protected from EAM. In contrast, when Flt3L-induced splenic CD8α(+) DC were pre-stimulated and over-activated with LPS and αCD40 antibodies or loaded with unspecific OVA(323-339) peptide instead of MyHC-α peptide, mice developed similar disease scores as non-vaccinated controls. Vaccination efficacy depended on IFN-γ, since CD8α(+)-vaccinated IFN-γR(-/-) mice were not protected. Importantly, splenic CD8α(+) vaccination was independent of regulatory T cells. Taken together, Flt3L-induced dendritic cell-based antigen-specific vaccination limits expansion of auto-reactive Th cells and protects mice from autoimmune heart inflammation.


Venlafaxine in children, adolescents, and young adults with autism spectrum disorders: an open retrospective clinical report.
Autism is characterized by social deficits, communication and language impairments, narrow restricted interests, repetitive behaviors, inattention, and hyperactivity. While selective serotonin reuptake inhibitors have demonstrated efficacy in treating core symptoms of autism, norepinephrine reuptake inhibitors have demonstrated efficacy in symptoms of attention-deficit hyperactivity disorder (ADHD). An open, retrospective clinical study with venlafaxine evaluated its effect on core symptoms of autism as well as associated features of ADHD. Ten consecutive subjects meeting Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), criteria for an autism spectrum disorder were treated with venlafaxine, initiated at 12.5 mg per day and adjusted on a flexible basis. Six of 10 completers were judged to be sustained treatment responders, by scoring 1 (very much improved) or 2 (much improved) on the Clinical Global Impressions improvement scale. Venlafaxine was effective in low dosages (mean, 24.37 mg/day; range, 6.25 to 50 mg/day) and was well tolerated. Improvement was noted in repetitive behaviors and restricted interests, social deficits, communication and language function, inattention, and hyperactivity. Controlled treatment trials with venlafaxine are warranted in autism spectrum disorders.


Duration and intensity of the radiation pulse from a flash tube.
The peak current, power, and half-peak duration of the current through a flash tube are determined. The flash tube may be considered as an element in an R-L-C circuit whose electrical behavior is dependent on a single parameter. The variation of tube current with voltage is examined and the plasma impedance determined. The intensity, rise time, decay time, and half-peak duration of the radiation pulse are determined for a range of tube geometries and gas pressures. The duration of the radiation pulse depends on that of the current, but the intensity is dependent on both gas pressure and power density.