An international multicentre prospective audit of elective rectal cancer surgery; operative approach versus outcome, including transanal total mesorectal excision (TaTME).
Transanal total mesorectal excision (TaTME) has rapidly emerged as a novel approach for rectal cancer surgery. Safety profiles are still emerging and more comparative data is urgently needed. This study aimed to compare indications and short-term outcomes of TaTME, open, laparoscopic, and robotic TME internationally. A pre-planned analysis of the European Society of Coloproctology (ESCP) 2017 audit was performed. Patients undergoing elective total mesorectal excision (TME) for malignancy between 1 January 2017 and 15 March 2017 by any operative approach were included. The primary outcome measure was anastomotic leak. Of 2579 included patients, 76.2% (1966/2579) underwent TME with restorative anastomosis of which 19.9% (312/1966) had a minimally invasive approach (laparoscopic or robotic) which included a transanal component (TaTME). Overall, 9.0% (175/1951, 15 missing outcome data) of patients suffered an anastomotic leak. On univariate analysis both laparoscopic TaTME (OR 1.61, 1.02-2.48, P = 0.04) and robotic TaTME (OR 3.05, 1.10-7.34, P = 0.02) were associated with a higher risk of anastomotic leak than non-transanal laparoscopic TME. However this association was lost in the mixed-effects model controlling for patient and disease factors (OR 1.23, 0.77-1.97, P = 0.39 and OR 2.11, 0.79-5.62, P = 0.14 respectively), whilst low rectal anastomosis (OR 2.72, 1.55-4.77, P < 0.001) and male gender (OR 2.29, 1.52-3.44, P < 0.001) remained strongly associated. The overall positive circumferential margin resection rate was 4.0%, which varied between operative approaches: laparoscopic 3.2%, transanal 3.8%, open 4.7%, robotic 1%. This contemporaneous international snapshot shows that uptake of the TaTME approach is widespread and is associated with surgically and pathologically acceptable results.


Expression of CD133, E-cadherin and WWOX in colorectal cancer and related analysis.
To detect the expression of CD133, E-cadherin and WWOX in colorectal cancer, analyze the correlations and pathological significance of the biomarkers. Two hundred and ten patients with colorectal cancer treated surgically between January 2007 and December 2015 were analyzed retrospectively. All patients had pathologic specimens and integrated clinical data. Pathologic specimens were retrieved for immunohistochemical examination of the expressions of CD133, WWOX and E-cadherin. The clinical data of these patients including gender, age, tumor location, tumor size, tumor differentiation, invasion depth, hepatic metastases, lymphatic metastasis, UICC stage and recurrence of tumor were retrieved to investigate their demographics and clinical characteristics. In 210 specimens of colorectal cancer, the positive expression rate of CD133, E-cadherin and WWOX was 61.9%, 40.5% and 41.9%, respectively. The expression of CD133, E-cadherin and WWOX was significantly correlated with lymphatic metastasis, hepatic metastases and UICC stage (p<0.05). The expression of CD133 was negatively correlated with WWOX and E-cadherin (p<0.05), and the expression of WWOX was positively correlated with E-cadherin in specimens (p<0.05). A detection of CD133, E-cadherin and WWOX can facilitate physicians in predicting the progression and prognosis of colorectal cancer.


Change in Albuminuria and Risk of Renal and Cardiovascular Outcomes: Natural Variation Should Be Taken into Account.
Changes in urinary albumin-to-creatinine ratio (UACR) may affect the risk of advanced chronic kidney disease (CKD). How much the association changes after taking account for natural variation in UACR and the length of time taken to observe changes in UACR is unknown. English Clinical Practice Research Datalink records (2000-2015) with linkage to secondary care and death certification were used to identify prospective cohorts with at least 2 measures of UACR within 1, 2, and 3 years. Adjusted Cox regression assessed the separate relevance of the baseline UACR and the UACR change to the risk of developing stages 4 to 5 CKD and end-stage renal disease (ESRD). Associations were compared before and after accounting for the effects of the natural variation in UACR (i.e., regression to the mean). A total of 212,810 individuals had baseline UACR measurements; 22% had a UACR ≥3.4 mg/mmol, and 3% had UACR ≥33.9 mg/mmol. During a median 4-year follow-up, 5976 developed stage 4 to 5 CKD, and 1076 developed ESRD. There were strong associations between baseline UACR and stage 4 to 5 CKD or ESRD risk, which doubled in strength after accounting for regression to the mean. Over 3 years, the hazard ratios (95% confidence intervals) for stage 4 to 5 CKD, relative to stable UACR, were 0.62 (0.50-0.77) for at least a halving of UACR and 2.68 (2.29-3.14) for at least a doubling of UACR. Associations were weaker for shorter exposure windows (and for cardiovascular disease or death), but strengthened after allowing for regression to the mean. Baseline values and subsequent medium-term increases in albuminuria are both associated with substantially increased risk of developing advanced CKD. Standard analyses, not allowing for natural variation in UACR, may underestimate these associations.


Engagement with genetic discrimination: concerns and experiences in the context of Huntington disease.
It has been over 20 years since the inception of predictive testing for Huntington disease (HD), yet the social implications of knowing one's genetic risk for HD have not been fully explored. Genetic discrimination (GD) is a potential risk associated with predictive testing. Although anecdotal reports of GD have been documented, there is a paucity of research on the nature and experiences of GD in the context of HD. The purpose of this study was to describe the concerns and experiences of GD in the HD community. Semistructured interviews were conducted with 45 genetically tested and 10 untested individuals and analyzed using grounded theory methods. Our findings demonstrate that a majority of individuals were concerned about (37/55) and experienced GD (32/55) across a variety of contexts that extend beyond the traditionally examined contexts of insurance and employment to include family, social, government, and health-care domains. We describe a process of engagement with GD in which individuals formed meaningful interpretations of GD and personalized its risk and consequences in their lives. Our findings provide an insight into some of the specific processes and factors influencing engagement with GD. These results help identify areas where more education and support is needed and provide direction to genetic professionals supporting their clients as they confront issues of GD and genetic testing.


Self-organization of meaning and the reflexive communication of information.
Following a suggestion from Warren Weaver, we extend the Shannon model of communication piecemeal into a complex systems model in which communication is differentiated both vertically and horizontally. This model enables us to bridge the divide between Niklas Luhmann's theory of the self-organization of meaning in communications and empirical research using information theory. First, we distinguish between communication relations and correlations among patterns of relations. The correlations span a vector space in which relations are positioned and can be provided with meaning. Second, positions provide reflexive perspectives. Whereas the different meanings are integrated locally, each instantiation opens global perspectives - 'horizons of meaning' - along eigenvectors of the communication matrix. These next-order codifications of meaning can be expected to generate redundancies when interacting in instantiations. Increases in redundancy indicate new options and can be measured as local reduction of prevailing uncertainty (in bits). The systemic generation of new options can be considered as a hallmark of the knowledge-based economy.


High-dose intramuscular triamcinolone in severe, chronic, life-threatening asthma.
Despite oral corticosteroid therapy, some patients with asthma have frequent exacerbations requiring emergency room visits, hospitalization, and occasionally, mechanical ventilation. We compared the effects of high-dose intramuscular triamcinolone with oral prednisone in patients with severe chronic asthma. In a double-blind, placebo-controlled, cross-over study that spanned all seasons, we treated 12 patients with high-dose intramuscular triamcinolone (360 mg over the first three days of the treatment period) or low-dose oral prednisone (median dose, 12.5 mg per day throughout the period; range 0 to 30). The two three-month treatment periods were separated by a three-month washout period. During all periods the patients were allowed to take additional doses of prednisone for acute exacerbations of asthma. After receiving triamcinolone, the patients had significantly better peak expiratory flow rates than while receiving prednisone (the average [+/- SEM] weekly percent of the predicted value during the triamcinolone period was 91.5 +/- 6.9, as compared with 75.0 +/- 5.9 for the prednisone period; P less than 0.05). During the prednisone period there were 21 emergency room visits and 10 hospitalizations, but there were none during the triamcinolone period (P less than 0.05). There were two episodes of ventilatory failure during the prednisone period. Total steroid doses were significantly smaller during the triamcinolone period than during the prednisone period (P less than 0.04). Steroidal side effects were more pronounced after treatment with triamcinolone than after treatment with prednisone (P less than 0.1). We conclude that high-dose intramuscular triamcinolone is more effective than low-dose prednisone in patients with severe, chronic, life-threatening asthma, but steroidal side effects are somewhat worse.


Using 3 TLR ligands as a combination adjuvant induces qualitative changes in T cell responses needed for antiviral protection in mice.
TLR ligands are promising candidates for the development of novel vaccine adjuvants that can elicit protective immunity against emerging infectious diseases. Adjuvants have been used most frequently to increase the quantity of an immune response. However, the quality of a T cell response can be more important than its quantity. Stimulating certain pairs of TLRs induces a synergistic response in terms of activating dendritic cells and eliciting/enhancing T cell responses through clonal expansion, which increases the number of responding T cells. Here, we have found that utilizing ligands for 3 TLRs (TLR2/6, TLR3, and TLR9) greatly increased the protective efficacy of vaccination with an HIV envelope peptide in mice when compared with using ligands for only any 2 of these TLRs; surprisingly, increased protection was induced without a marked increase in the number of peptide-specific T cells. Rather, the combination of these 3 TLR ligands augmented the quality of the T cell responses primarily by amplifying their functional avidity for the antigen, which was necessary for clearance of virus. The triple combination increased production of DC IL-15 along with its receptor, IL-15Ralpha, which contributed to high avidity, and decreased expression of programmed death-ligand 1 and induction of Tregs. Therefore, selective TLR ligand combinations can increase protective efficacy by increasing the quality rather than the quantity of T cell responses.


The Toe Walking Tool: a novel method for assessing idiopathic toe walking children.
The diagnosis of idiopathic toe walking (ITW) is achieved by the exclusion of all medical causes associated with toe walking. In order to identify children with this gait type, an online Toe Walking Tool questionnaire was developed that utilized questions to identify healthy idiopathic toe walkers and excluded those who toe walk as a result of a medical condition. A Delphi panel process was conducted to establish the relevance and validity of the questions. A group of 10 allied health professionals assessed 12 children utilizing the Toe Walking Tool. A kappa was calculated to determine reliability. Clinicians agreed the questionnaire was an appropriate and effective assessment tool. The tool proved valid in that no child tested who toe walked as a result of a medical condition was able to progress through the testing process. Testing group of practitioners had a Fleiss Kappa agreement of 0.928. The Toe Walking Tool is a valid and reliable method of assessing children who present to the general allied health clinician with toe walking. This tool can assist with the decision of when to refer a child for further specialist investigation of their toe walking.


TRAF1: lord without a RING.
Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) constitute a family of adaptor proteins that associate with the cytosolic tail of particular TNF-family receptors (TNFR) and regulate cytokine signaling by linking TNFRs with downstream protein kinases, ubiquitin ligases, and other effector proteins. A total of six members of this family (TRAF1-6) have been identified in mammals. TRAF1 is unique among TRAFs because it lacks a RING finger domain present in TRAF2-6 that has been shown to be required for TRAF2- and TRAF6-mediated activities. TRAF1 also has the most restricted expression among TRAFs, and is found almost exclusively in activated lymphocytes, dendritic cells, and certain epithelia. Recent evidence obtained from TRAF1(-/-) mice shows that TRAF1-deficient T cells are hyper-responsive to TNF-alpha, having increased T cell receptor (TCR)-dependent T cell proliferation rates in vitro. Also, these TRAF1(-/-) mice had increased sensitivity to TNF-alpha-induced skin necrosis in vivo. These results support a role for TRAF1 as a negative regulator of signaling by certain TNF-family receptors. This review summarizes current knowledge about TRAF1, focusing on the new information provided by these TRAF1-deficient mice. Also, the pros and cons of TRAFs as potential targets for drug discovery are discussed.


Genetic and Molecular Approaches to Study Neuronal Migration in the Developing Cerebral Cortex.
The migration of neuronal cells in the developing cerebral cortex is essential for proper development of the brain and brain networks. Disturbances in this process, due to genetic abnormalities or exogenous factors, leads to aberrant brain formation, brain network formation, and brain function. In the last decade, there has been extensive research in the field of neuronal migration. In this review, we describe different methods and approaches to assess and study neuronal migration in the developing cerebral cortex. First, we discuss several genetic methods, techniques and genetic models that have been used to study neuronal migration in the developing cortex. Second, we describe several molecular approaches to study aberrant neuronal migration in the cortex which can be used to elucidate the underlying mechanisms of neuronal migration. Finally, we describe model systems to investigate and assess the potential toxicity effect of prenatal exposure to environmental chemicals on proper brain formation and neuronal migration.


What matters is when you play: Investigating the relationship between online video games addiction and time spent playing over specific day phases.
Online video gaming is now widely considered an activity possibly related to addictive behaviors, so that the diagnosis of Internet Gaming Disorder (IGD) is now included both in DSM-5 and ICD-11; however, there is still debate about some specific features of such disorder. One debated aspect is time spent playing: IGD gamers certainly play a high amount of time, but, on the other hand, also highly-engaged individuals or people working with video games (e.g.: eSports professional players) may play a lot without developing IGD. The literature agrees on the importance of deepening the role of time spent playing video games in IGD, to understand if it can be considered a symptom useful for the diagnosis, or not: one possibility is that time spent playing is not important in an absolute sense, but relatively to specific day phases. The present research involved 133 participants to test the relationship between average time spent playing over day phases (morning, afternoon, night; week, weekend days), age, game preferences and IGD. IGD score positively predicted time spent playing during weekend mornings, which are a day phase usually dedicated to other activities. Instead, time spent playing during afternoon was negatively predicted by age, according to this day phase being more related to youngsters' spare time, while night playing was related to preference for game genres which need dedicated time to organize multi-playing. Discussion deals with the utility of these preliminary results for future, more systematic research on IGD and its distinctive symptoms.


Hepatic glycogen supercompensation activates AMP-activated protein kinase, impairs insulin signaling, and reduces glycogen deposition in the liver.
The objective of this study was to determine how increasing the hepatic glycogen content would affect the liver's ability to take up and metabolize glucose. During the first 4 h of the study, liver glycogen deposition was stimulated by intraportal fructose infusion in the presence of hyperglycemic-normoinsulinemia. This was followed by a 2-h hyperglycemic-normoinsulinemic control period, during which the fructose infusion was stopped, and a 2-h experimental period in which net hepatic glucose uptake (NHGU) and disposition (glycogen, lactate, and CO(2)) were measured in the absence of fructose but in the presence of a hyperglycemic-hyperinsulinemic challenge including portal vein glucose infusion. Fructose infusion increased net hepatic glycogen synthesis (0.7 ± 0.5 vs. 6.4 ± 0.4 mg/kg/min; P < 0.001), causing a large difference in hepatic glycogen content (62 ± 9 vs. 100 ± 3 mg/g; P < 0.001). Hepatic glycogen supercompensation (fructose infusion group) did not alter NHGU, but it reduced the percent of NHGU directed to glycogen (79 ± 4 vs. 55 ± 6; P < 0.01) and increased the percent directed to lactate (12 ± 3 vs. 29 ± 5; P = 0.01) and oxidation (9 ± 3 vs. 16 ± 3; P = NS). This change was associated with increased AMP-activated protein kinase phosphorylation, diminished insulin signaling, and a shift in glycogenic enzyme activity toward a state discouraging glycogen accumulation. These data indicate that increases in hepatic glycogen can generate a state of hepatic insulin resistance, which is characterized by impaired glycogen synthesis despite preserved NHGU.


Epidemiology of human herpesvirus type 8 and parvovirus B19 infections and their association with HIV-1 among men who have sex with men and injection drug users in Taiwan.
Human herpesvirus 8 (HHV-8), the causal agent of Kaposi's sarcoma (KS), is transmitted sexually among men who have sex with men (MSM), but little is known of its transmission among injection drug users (IDUs). By contrast, human parvovirus B19 (B19), a causative agent for anemia, is most frequently detected in IDUs. The aim of this study was to investigate the associations between HHV-8 infection and human immunodeficiency virus type 1 (HIV-1), and between B-19 and HIV-1 among MSM and IDUs patients. Serum samples from 553 IDUs and 231 MSM were analyzed for anti-HHV-8 lytic and anti-B19 viral structural capsid protein 2 (VP-2) antibodies using enzyme immunoassay, indirect immunofluorescence, and immunoblot assays. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the associations between different viral infections. HIV-1-seropositive MSM had significantly higher rates of HHV-8 infection than seronegative MSM (32.3% and 15.4%, respectively; OR = 2.62, 95% CI = 1.37-5.02). Among HIV-1/AIDS patient groups, MSM had significantly higher HHV-8 seropositive rates (32.3% vs. 6.6%, p < 0.0001) and lower B19 infection rates (35.4% vs. 78.8%, p < 0.001) than IDUs. In addition, HIV-1-infected MSM were 5.95 times (95% CI = 3.38-10.46) more likely to be infected with HHV-8 than male HIV-1-infected IDUs. By contrast, male IDUs were 6.74 times odds (95% CI = 4.28-10.61) more likely to contract B19 infection than MSM. In Taiwan, MSM have a significantly higher prevalence for HHV-8 than IDUs. The contrasting risks of HHV-8 and B19 infections between different HIV-1/AIDS groups suggest that the efficiency of viral infection is affected by their distinct transmission routes.


Role of central nervous system glucagon-like Peptide-1 receptors in enteric glucose sensing.
Ingested glucose is detected by specialized sensors in the enteric/hepatoportal vein, which send neural signals to the brain, which in turn regulates key peripheral tissues. Hence, impairment in the control of enteric-neural glucose sensing could contribute to disordered glucose homeostasis. The aim of this study was to determine the cells in the brain targeted by the activation of the enteric glucose-sensing system. We selectively activated the axis in mice using a low-rate intragastric glucose infusion in wild-type and glucagon-like peptide-1 (GLP-1) receptor knockout mice, neuropeptide Y-and proopiomelanocortin-green fluorescent protein-expressing mice, and high-fat diet diabetic mice. We quantified the whole-body glucose utilization rate and the pattern of c-Fos positive in the brain. Enteric glucose increased muscle glycogen synthesis by 30% and regulates c-Fos expression in the brainstem and the hypothalamus. Moreover, the synthesis of muscle glycogen was diminished after central infusion of the GLP-1 receptor (GLP-1Rc) antagonist Exendin 9-39 and abolished in GLP-1Rc knockout mice. Gut-glucose-sensitive c-Fos-positive cells of the arcuate nucleus colocalized with neuropeptide Y-positive neurons but not with proopiomelanocortin-positive neurons. Furthermore, high-fat feeding prevented the enteric activation of c-Fos expression. We conclude that the gut-glucose sensor modulates peripheral glucose metabolism through a nutrient-sensitive mechanism, which requires brain GLP-1Rc signaling and is impaired during diabetes.


Linear equations method for modal decomposition using intensity information.
The linear equations method is proposed to calculate the complete modal content of the partially coherent laser beam using only the intensity information. This method could give not only the incoherent expansion coefficients of the modal decomposition but also the cross-correlation expansion coefficients using the intensity profiles in several planes of finite distance along the propagation direction. A simulation is also presented to verify the validity of this theory. In our algorithm, the minimum and maximum mode orders should be known a priori, so we provide an estimation method for the two parameters.


Depression and physical health multimorbidity: primary data and country-wide meta-analysis of population data from 190 593 people across 43 low- and middle-income countries.
Despite the known heightened risk and burden of various somatic diseases in people with depression, very little is known about physical health multimorbidity (i.e. two or more physical health co-morbidities) in individuals with depression. This study explored physical health multimorbidity in people with clinical depression, subsyndromal depression and brief depressive episode across 43 low- and middle-income countries (LMICs). Cross-sectional, community-based data on 190 593 individuals from 43 LMICs recruited via the World Health Survey were analysed. Multivariable logistic regression analysis was done to assess the association between depression and physical multimorbidity. Overall, two, three and four or more physical health conditions were present in 7.4, 2.4 and 0.9% of non-depressive individuals compared with 17.7, 9.1 and 4.9% among people with any depressive episode, respectively. Compared with those with no depression, subsyndromal depression, brief depressive episode and depressive episode were significantly associated with 2.62, 2.14 and 3.44 times higher odds for multimorbidity, respectively. A significant positive association between multimorbidity and any depression was observed across 42 of the 43 countries, with particularly high odds ratios (ORs) in China (OR 8.84), Laos (OR 5.08), Ethiopia (OR 4.99), the Philippines (OR 4.81) and Malaysia (OR 4.58). The pooled OR for multimorbidity and depression estimated by meta-analysis across 43 countries was 3.26 (95% confident interval 2.98-3.57). Our large multinational study demonstrates that physical health multimorbidity is increased across the depression spectrum. Public health interventions are required to address this global health problem.


Perceptions and plans for prevention of Ebola: results from a national survey.
Literature suggests that Americans may have higher levels of perceived threat to Ebola than are warranted. We surveyed 1018 U.S. adults from a nationally representative Internet panel about their knowledge, perceived threat, and behavioral intentions during the 2014 Ebola outbreak. Eighty-six percent of respondents knew that Ebola could be transmitted through blood and bodily fluids. However, a large percentage had some inaccurate knowledge and 19 % believed Ebola would spread to the U.S. Respondents favored mandatory quarantine (63 %) and travel bans (55 %). Confidence in the ability of the media and government to accurately report on or prevent a U.S. epidemic was low. Fifty-two percent intended to engage in behaviors such as avoiding public transportation. Despite low perceived susceptibility, half intended to engage in behaviors to prevent transmission and large numbers favored policies not currently recommended by health officials. The extreme nature of Ebola virus likely motivated people to engage in behaviors and favor policies that were not necessary given the low risk of transmission in the U.S. Health officials should ensure the public has accurate information about Ebola and bolster confidence in the government's ability to control infectious diseases in case of a future outbreak in the U.S.


Indicators of differences in immunization rates of Mexican American and white non-Hispanic infants in a Medicaid managed care system.
Immunization levels of Mexican American and white non-Hispanic infants enrolled in Arizona's Medicaid managed care demonstration project, a prototype of the model proposed for a reformed health care system, were compared and the influence of sociodemographic characteristics, acculturation levels, health beliefs of the mothers, and infant health status on immunization levels were assessed. The study used data collected from office records, birth certificates, and household interviews. The random sample included 292 white non-Hispanic and 274 Mexican American infants. White non-Hispanic infants received more immunizations by age 1 than the Mexican American infants. However, after controlling for a full set of explanatory variables in a multiple regression analysis, ethnicity was no longer a significant predictor of immunization levels. Significant predictors of a higher number of immunizations included fewer siblings, older maternal age, and higher maternal education. Health insurance and enrollment in a managed care plan were not sufficient to ensure adequate immunization of these Medicaid enrolled infants. Results are discussed in terms of previous research and the essential functions of public health as outlined in the Institute of Medicine's Report on the Future of Public Health.


The role of Bcl-xL in mouse RPE cell survival.
PURPOSE. Retinal pigment epithelial (RPE) cell survival plays a critical role in normal physiology and in retinal diseases, such as age-related macular degeneration (AMD) and proliferative vitreoretinopathy (PVR). We have previously demonstrated that Bcl-x(L) is an important cell survival protein in human RPE (hRPE) cells. Herein, we determined the role of Bcl-x(L) as a survival protein in mouse RPE (mRPE) cells. METHODS. Survival factor gene expression and Bcl-x(L) protein distribution were determined using qRT-PCR and immunohistochemistry, respectively. Cultured mRPE cells were transfected with two modified 2'-O-methoxyethoxy antisense oligonucleotides (ASOs): Bcl-x(L)-mismatched control and Bcl-x(L)-specific. Bcl-x(L) protein levels were analyzed using Western blot. To determine the effects of survival factor regulation in mRPE cells, cultured cells were treated for 24 hours with mouse TNF-α, human IL-1β, and human TNF-α. RESULTS. Bcl-x(L) was the most highly expressed survival factor in both mouse eyecup and cultured mRPE cells, whereas Bax was the most highly expressed antisurvival factor. Bcl-x(L) was expressed in the RPE layer, and the distribution among the retinal layers was similar to that observed in human eyecups. IL-1β and TNF-α had minimal effect on Bcl-x(L) and Bax expression and strongly upregulated Traf-1. Transfection with Bcl-x(L)-specific ASO resulted in markedly diminished Bcl-x(L) gene expression, Bcl-x(L) protein levels, and cell number. CONCLUSIONS. Bcl-x(L) is the most highly expressed survival gene in mRPE cells and is essential for mRPE cell survival. Our data suggest that mouse tissue is an appropriate model for investigations of RPE survival factor genes.


Association of the HL-A7 cross-reacting group with a specific reaginic antibody response in allergic man.
A relatively small proportion (17 percent) of individuals highly allergic to ragweed were found to develop marked reaginic (immunoglobulin E-mediated) skin sensitivity to a minor ragweed pollen allergen Ra5 (molecular weight 5200). Sensitivity to Ra5 was significantly associated with the possession of a major histocompatibility antigen of the HL-A7 cross-reacting group. This appears to be the first evidence of a strong association between a specific immune response and a specific group of closely related HL-A antigens in man.


Things we still haven't learned (so far).
Null hypothesis significance testing (NHST) is like an immortal horse that some researchers have been trying to beat to death for over 50 years but without any success. In this article we discuss the flaws in NHST, the historical background in relation to both Fisher's and Neyman and Pearson's statistical ideas, the common misunderstandings of what p < .05 actually means, and the 2010 APA publication manual's clear, but most often ignored, instructions to report effect sizes and to interpret what they all mean in the real world. In addition, we discuss how Bayesian statistics can be used to overcome some of the problems with NHST. We then analyze quantitative articles published over the past three years (2012-2014) in two top-rated sport and exercise psychology journals to determine whether we have learned what we should have learned decades ago about our use and meaningful interpretations of statistics.


Purification and analysis of checkpoint protein complexes from Saccharomyces cerevisiae.
The DNA damage-dependent checkpoint of Saccharomyces cerevisiae is a paradigm for eukaryotic checkpoint pathways that regulate cell cycle progression in the presence of insults to the genetic material. In order to better understand this pathway, we undertook a biochemical study of the proteins implicated in its functioning. Analysis of the hydrodynamic properties of a protein in a crude mixture can give insights into possible tertiary organization such as participation in high-molecular-mass protein complexes. We here describe the determination of Stokes radius and sedimentation coefficients for the Rad24 protein, which enabled us to predict that this protein was a component of a protein complex in crude yeast extracts. This led us to develop a protocol to purify this complex to homogeneity in order to determine the component proteins. The methods described here should be applicable to the hydrodynamic analysis and subsequent purification of any soluble protein from organisms amenable to genetic manipulation, such as yeast, as long as the function of that protein is not perturbed by the addition of an epitope tag.


Adrenergic responses to sustained handgrip in patients with juvenile-onset-type diabetes mellitus.
1. The response of plasma noradrenaline, arterial blood pressure and heart rate to sustained handgrip at 30% of maximal voluntary contraction was studied in patients with long-term juvenile-onset-type diabetes millitus and healthy subjects of comparable age. 2. There was no significant difference between the intensity and duration of handgrip in diabetic patients and healthy subjects. 3. Sustained handgrip produced an increase in plasma concentration of noradrenaline both in diabetic and healthy subjects but the response in the diabetic subjects was significantly less. 4. The increase in systolic blood pressure during handgrip was significantly greater in diabetic subjects than in normal subjects. The increases in diastolic and mean blood pressure did not differ significantky. 5. The increase in heart rate during handgrip was greater in healthy subjects than in diabetic subjects. The response was smaller in diabetic patients with retinopathy than in the patients without retinopathy. 6. The sustained handgrip test may be useful for the diagnosis of abnormal sympathetic nervous system and haemodnynamic responsiveness in diabetic patients.


Chromosome 17 loss-of-heterozygosity studies in benign and malignant tumors in neurofibromatosis type 1.
Neurofibromatosis type 1 (NF1) is a common autosomal dominant condition characterized by benign tumor (neurofibroma) growth and increased risk of malignancy. Dermal neurofibromas, arising from superficial nerves, are primarily of cosmetic significance, whereas plexiform neurofibromas, typically larger and associated with deeply placed nerves, extend into contiguous tissues and may cause serious functional impairment. Malignant peripheral nerve sheath tumors (MPNSTs) seem to arise from plexiform neurofibromas. The NF1 gene, on chromosome segment 17q11.2, encodes a protein that has tumor suppressor function. Loss of heterozygosity (LOH) for NF1 has been reported in some neurofibromas and NF1 malignancies, but plexiform tumors have been poorly represented. Also, the studies did not always employ the same markers, preventing simple comparison of the frequency and extent of LOH among different tumor types. Our chromosome 17 LOH analysis in a cohort of three tumor types was positive for NF1 allele loss in 2/15 (13%) dermal neurofibromas, 4/10 (40%) plexiform neurofibromas, and 3/5 (60%) MPNSTs. Although the region of loss varied, the p arm (including TP53) was lost only in malignant tumors. The losses in the plexiform tumors all included sequences distal to NF1. No subtle TP53 mutations were found in any tumors. This study also reports the identification of both NF1 "hits" in plexiform tumors, further supporting the tumor suppressor role of the NF1 gene in this tumor type.


Oral administration of active hexose correlated compound enhances host resistance to West Nile encephalitis in mice.
West Nile virus (WNV) poses a serious threat to public health, especially to the elderly and the immuno-compromised. Neither vaccines nor treatments are available for humans. Active hexose correlated compound (AHCC) is an extract of Lentinula edodes of the Basidiomycete family of fungi rich in alpha-glucans. In this study, we evaluated the effect of AHCC on host susceptibility in the murine model of WNV infection. Mice orally administered with AHCC (600 mg/kg) every other day for 1 wk before and at d 1 and 3 postinfection were assessed using viremia levels, survival rate, and protective immunity. AHCC administration in young (6- to 8-wk-old) mice attenuated viremia and mortality following lethal WNV infection. WNV-specific IgM and IgG production and gammadelta T cell expansion were also enhanced in these mice. Aged (21- to 22-mo-old) mice were more susceptible to WNV infection than young mice, partially due to the dysfunction of gammadelta T cell subsets. AHCC administration in aged mice enhanced the protective Vgamma1(+) T cell response as well as WNV-specific IgG but not IgM antibodies production. AHCC administration in aged mice attenuated viremia levels but led to no difference in mortality rate. Overall, our data suggests that AHCC enhances protective host immune responses against WNV infection in young and aged mice. Dietary supplementation with AHCC may be potentially immunotherapeutic for WNV-susceptible populations.


Longitudinal clinical findings and outcome among patients with Cryptococcus gattii infection in British Columbia.
Cryptococcus gattii (Cg) infection emerged in British Columbia in 1999. A longitudinal, clinical description of patients has not been reported. Medical records were reviewed for Cg patients identified through surveillance (1999-2007). Risk factors for Cg mortality were explored using multivariate Cox regression; longitudinal patterns in serum cryptococcal antigen (SCrAg) titers and the probability of chest cryptococcomas over time were estimated using cubic B-splines in mixed-effects regression models. Among 152 patients, 111 (73.0%) were culture confirmed. Isolated lung infection was present in 105 (69.1%) patients; 47 (30.9%) had central nervous system infection, with or without lung involvement. Malignancy was the provisional diagnosis in 64 (42.1%) patients. Underlying diseases were present in 91 (59.9%) patients; 23 (15.1%) were immunocompromised, and 23 (15.1%) had asymptomatic disease. There were only 2 (1.8%) culture positive relapses, both within 12 months of follow-up. The estimated median time to resolution of lung cryptococcomas and decline in SCrAg titer to <1:8 was 2.8 and 2.9 years, respectively. Cg-related and all-cause mortality among culture-confirmed cases at 12 months' follow-up was 23.3% and 27.2%, respectively. Cg-related mortality was associated with age >50 years (hazard ratio [HR], 15.6; 95% confidence interval [CI], 1.9-130.5) and immunocompromise (HR, 5.8; CI, 1.5-21.6). All Cg-related mortality occurred among culture-positive cases within 1 year of diagnosis. Cryptococcomas and serum antigenemia were slow to resolve. However, late onset of failed therapy or relapse was uncommon, suggesting that delayed resolution of these findings does not require prolongation of treatment beyond that recommended by guidelines.


Histopathological changes and nitric oxide synthase activity in corpus cavernosum from rats with neurogenic erectile dysfunction.
To investigate changes in histology and nitric oxide synthase (NOS) activity in cavernosal tissues from rats with neurogenic erectile dysfunction induced experimentally. Twenty-four adult male Sprague-Dawley rats were divided equally into three groups and underwent a sham operation (control, group 1), unilateral (group 2) or bilateral (group 3) cavernosal nerve resection. Three months later they were killed and the cavernosal tissues analysed histologically by light and transmission electron microscopy, with NOS activity detected using an NADPH-diaphorase staining technique. On light and electron microscopy, while penile nerves and cavernosal smooth muscle cells had a normal morphological appearance in the eight control rats, there were degenerative changes of the myelinated penile nerves and axonal fibrosis in groups 2 and 3. However, these changes were not significant. Using NADPH-diaphorase staining, NOS activity was detected in all three groups in endothelial cells and cavernosal structures. However, the staining was more intense in endothelial cells and cavernosal muscles of rats in group 2 than in the other groups. NOS activity was increased in the cavernosal tissue after cavernosal denervation, but the pharmacological action of nitric oxide may be impaired.


A prospective study of lycopene and tomato product intake and risk of prostate cancer.
Dietary lycopene and tomato products may reduce risk of prostate cancer; however, uncertainty remains about this possible association. We evaluated the association between intake of lycopene and specific tomato products and prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, a multicenter study designed to investigate cancer early detection methods and etiologic determinants. Participants completed both a general risk factor and a 137-item food frequency questionnaire at baseline. A total of 1,338 cases of prostate cancer were identified among 29,361 men during an average of 4.2 years of follow-up. Lycopene intake was not associated with prostate cancer risk. Reduced risks were also not found for total tomato servings or for most tomato-based foods. Statistically nonsignificant inverse associations were noted for pizza [all prostate cancer: relative risk (RR), 0.83; 95% confidence interval (95% CI), 0.67-1.03 for >or=1 serving/wk versus < 0.5 serving/mo; P(trend)=0.06 and advanced prostate cancer: RR, 0.79; 95% CI, 0.56-1.10; P(trend)=0.12] and spaghetti/tomato sauce consumption (advanced prostate cancer: RR=0.81, 95% CI, 0.57-1.16 for >or=2 servings/wk versus<1 serving/mo; P(trend)=0.31). Among men with a family history of prostate cancer, risks were decreased in relation to increased consumption of lycopene (P(trend)=0.04) and specific tomato-based foods commonly eaten with fat (spaghetti, P(trend)=0.12; pizza, P(trend)=0.15; lasagna, P(trend)=0.02). This large study does not support the hypothesis that greater lycopene/tomato product consumption protects from prostate cancer. Evidence for protective associations in subjects with a family history of prostate cancer requires further corroboration.


Self-hardening and thermoresponsive alpha tricalcium phosphate/pluronic pastes.
Although calcium phosphate cements (CPCs) are used for bone regeneration in a wide range of clinical applications, various physicochemical phenomena are known to hinder their potential use in minimally invasive surgery or in highly vascularized surgical sites, mainly because of their lack of injectability or their low washout resistance. The present work shows that the combination of CPCs with an inverse-thermoresponsive hydrogel is a good strategy for finely tuning the cohesive and rheological properties of CPCs to achieve clinical acceptable injectability to prevent phase separation during implantation and cohesion to avoid washout of the paste. The thermoresponsive CPC developed combines alpha-tricalcium phosphate with an aqueous solution of pluronic F127, which exhibits an inverse thermoresponsive behaviour, with a gelling transformation at around body temperature. These novel CPCs exhibited temperature-dependent properties. Addition of the polymer enhanced the injectability of the paste, even at a low liquid-to-powder ratio, and allowed the rheological properties of the cement to be tuned, with the injection force decreasing with the temperature of the paste. Moreover, the cohesion of the paste was also temperature-dependent and increased as the temperature of the host medium increased due to gelling induced in the paste. The thermoresponsive cement exhibited excellent cohesion and clinically acceptable setting times at 37°C, irrespective of the initial temperature of the paste. The addition of pluronic F127 slightly delayed the setting reaction in the early stages but did not hinder the full transformation to calcium-deficient hydroxyapatite. Moreover, the frozen storage of premixed thermoresponsive cement pastes was explored, the main physicochemical properties of the cements being maintained upon thawing, even after 18months of frozen storage. This avoids the need to mix the cement in the operating theatre and allows its use off-the-shelf. The reverse thermoresponsive cements studied herein open up new perspectives in the surgical field, where the sequential gelling/hardening of these novel cements could allow for a better and safer clinical application. Calcium phosphate cements are attractive bone substitutes due to their similarity to the bone mineral phase. Although they can be injectable, cohesion and stability of the paste are crucial in terms of performance and safety. A common strategy is the combination with hydrogels. However, this often results in a decrease of viscosity with increasing temperature, which can lead to extravasation and particle leakage from the bone defect. The preferred evolution would be the opposite: a low viscosity would enhance mixing and injection, and an instantaneous increase of viscosity after injection would ensure washout resistance to the blood flow. Here we develop for the first time a calcium phosphate cement exhibiting reverse thermoresponsive properties using a poloxamer featuring inverse thermal gelling.


Increased aggression during human group contests when competitive ability is more similar.
Theoretical analyses and empirical studies have revealed that conflict escalation is more likely when individuals are more similar in resource-holding potential (RHP). Conflicts can also occur between groups, but it is unknown whether conflicts also escalate more when groups are more similar in RHP. We tested this hypothesis in humans, using data from two professional sports competitions: football (the Bundesliga, the German first division of football) and basketball (the NBA, the North American National Basketball Association). We defined RHP based on the league ranks of the teams involved in the competition (i.e. their competitive ability) and measured conflict escalation by the number of fouls committed. We found that in both sports the number of fouls committed increased when the difference in RHP was smaller. Thus, we provide what is to our best knowledge the first evidence that, as in conflicts between individuals, conflicts escalate more when groups are more similar in RHP.


The Underrepresentation of Females in Studies Assessing the Impact of High-Dose Exercise on Cardiovascular Outcomes: a Scoping Review.
High-dose exercise-induced cardiac outcomes may vary between sexes. However, many studies investigating the cardiovascular effects of high-dose exercise have excluded or under-recruited females. This scoping review aimed to describe the recruitment of females in studies assessing the impact of high-dose exercise on cardiovascular outcomes and describe how this has changed over time. This scoping review followed the protocol outlined by Arksey and O'Malley and is reported as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) guidelines. The OVID and EMBASE databases were searched for studies that assessed the effects of high-dose exercise on cardiovascular outcomes. Both professional and nonprofessional groups were included. The review found 2973 studies, and 250 met the inclusion criteria including cumulatively 17,548,843 subjects. Over half the studies (n = 127) excluded females entirely, and only 8 (3.2%) studies recruited all-female participants. The overall mean percentage of females recruited was 18.2%. The mean percentage was 14.5% in studies conducted before 2011 and 21.8% in studies conducted after 2011. Females are an underrepresented group in studies assessing the cardiovascular outcomes related to high-dose exercise. As cardiovascular outcomes vary between sexes, translating findings from a largely male-based evidence may not be appropriate. Future investigators should aim to establish and overcome barriers to female recruitment.


[Glass ceiling and slippery stairs? Gender inequalities and strategies for change in the Spanish Society of Public Health and Health Services Administration].
In scientific societies, as in other social fields, women's participation in decision making is lower than that of men. We describe the situation in SESPAS (Spanish Society of Public Health and Health Services Administration) where, despite representing a 40% of its members, very few women have been in positions in which decisions are taken or in those of professional recognition. The process of change implemented during recent years and some of the effects of the actions taken are presented. Making the existing inequalities known has generated debate and interest in the intervention. A gender and public health working group was set up. In the last two years more women have been promoted to more senior positions in SESPAS.


Performance and time to become negative after treatment of three malaria rapid diagnostic tests in low and high malaria transmission settings.
The performance of different malaria rapid diagnostic tests (RDT) may be influenced by transmission intensity and by the length of time each test requires to become negative after treatment and patient's recovery. Results of three RDTs (two HRP2 and one pLDH antigen-based tests) were compared to blood smear microscopy (the gold standard method) in children under 5 years of age living in a high versus low malaria intensity setting in southwestern Uganda. In each setting, 212 children, who tested positive by at least one RDT and by microscopy, were treated with artemether-lumefantrine. RDTs and microscopy were then repeated at fixed intervals to estimate each test's time to negativity after treatment and patient recovery. In the two settings, sensitivities ranged from 98.4 to 99.2 % for the HRP2 tests and 94.7 to 96.1 % for the pLDH test. Specificities were 98.9 and 98.8 % for the HRP2 tests and 99.7 % for the pLDH test in the low-transmission setting and 79.7, 80.7 and 93.9 %, respectively, in the high-transmission setting. Median time to become negative was 35-42 or more days for the HRP2 tests and 2 days for the pLDH test. High transmission contexts and a long time to become negative resulted in considerably reduced specificities for the HRP2 tests. Choice of RDT for low- versus high-transmission settings should balance risks and benefits of over-treatment versus missing malaria cases. Registry number at ClinicalTrial.gov: NCT01325974.


Combined percutaneous and transarterial devascularisation of juvenile nasopharyngeal angiofibroma with protection of internal carotid artery: A modification of the technique.
Juvenile nasal angiofibroma (JNA) is a hypervascularised, benign, but locally aggressive tumour that grows in the posterior, upper part of the nasal cavity and invades surrounding anatomical structures. The treatment of choice is surgical removal, but complete resection of the tumour can be hampered because of profuse perioperative bleeding. Preoperative embolisation of the tumour has been proposed as an effective method for prevention of perioperative bleeding, thereby shortening of the time of the operation. In this report of five cases, we describe successful preoperative devascularisation of the tumour by applying a modified method of direct intratumoural injection of the liquid embolic agent Onyx combined with protection of the internal carotid artery. The control of bleeding during the embolisation and occlusion of the maxillary or sphenopalatine artery was achieved by using a bi-luminal balloon catheter. Such use of the dual-lumen catheter in treatment of JNA has not been reported so far in the medical literature.


Focus issue: teaching tools and learning opportunities.
Science Signaling provides authoring experience for students and resources for educators. Students experience the writing and revision process involved in authoring short commentary articles that are published in the Journal Club section. By publishing peer-reviewed teaching materials, Science Signaling provides instructors with feedback that improves their materials and an outlet to share their tips and techniques and digital resources with other teachers.


Temporally irregular mnemonic persistent activity in prefrontal neurons of monkeys during a delayed response task.
An important question in neuroscience is whether and how temporal patterns and fluctuations in neuronal spike trains contribute to information processing in the cortex. We have addressed this issue in the memory-related circuits of the prefrontal cortex by analyzing spike trains from a database of 229 neurons recorded in the dorsolateral prefrontal cortex of 4 macaque monkeys during the performance of an oculomotor delayed-response task. For each task epoch, we have estimated their power spectrum together with interspike interval histograms and autocorrelograms. We find that 1). the properties of most (about 60%) neurons approximated the characteristics of a Poisson process. For about 25% of cells, with characteristics typical of interneurons, the power spectrum showed a trough at low frequencies (<20 Hz) and the autocorrelogram a dip near zero time lag. About 15% of neurons had a peak at <20 Hz in the power spectrum, associated with the burstiness of the spike train; 2). a small but significant task dependency of spike-train temporal structure: delay responses to preferred locations were characterized not only by elevated firing, but also by suppressed power at low (<20 Hz) frequencies; and 3). the variability of interspike intervals is typically higher during the mnemonic delay period than during the fixation period, regardless of the remembered cue. The high irregularity of neural persistent activity during the delay period is likely to be a characteristic signature of recurrent prefrontal network dynamics underlying working memory.


Predicting single-neuron activity in locally connected networks.
The characterization of coordinated activity in neuronal populations has received renewed interest in the light of advancing experimental techniques that allow recordings from multiple units simultaneously. Across both in vitro and in vivo preparations, nearby neurons show coordinated responses when spontaneously active and when subject to external stimuli. Recent work (Truccolo, Hochberg, & Donoghue, 2010 ) has connected these coordinated responses to behavior, showing that small ensembles of neurons in arm-related areas of sensorimotor cortex can reliably predict single-neuron spikes in behaving monkeys and humans. We investigate this phenomenon using an analogous point process model, showing that in the case of a computational model of cortex responding to random background inputs, one is similarly able to predict the future state of a single neuron by considering its own spiking history, together with the spiking histories of randomly sampled ensembles of nearby neurons. This model exhibits realistic cortical architecture and displays bursting episodes in the two distinct connectivity schemes studied. We conjecture that the baseline predictability we find in these instances is characteristic of locally connected networks more broadly considered.


Enzyme stability of microencapsulated Bifidobacterium animalis ssp. lactis Bb12 after freeze drying and during storage in low water activity at room temperature.
Stability of enzymes such as β-galactosidase (β-gal), β-glucosidase (β-glu), lactate dehydrogenase (LDH), pyruvate kinase (PK), hexokinase (HK), and ATPase of microencapsulated Bifidobacterium animalis ssp. lactis Bb12 after freeze-drying and after 10 wk of storage at low water activity (a(w)) at room temperature was studied. Bacteria were microencapsulated using alginate formulation with or without mannitol fortification (sodium alginate and mannitol [SAM] and sodium alginate [SA], respectively) by creating gel beads followed by freeze drying. Two types of dried gel beads were then stored at low a(w), such as 0.07, 0.1, and 0.2; storage in an aluminum foil was used as control. All storage was carried out at room temperature of 25 °C for 10 wk. Measurement of β-gal, β-glu, LDH, PK, HK, and ATPase (with or without exposure to pH 2.0 for 2 h) activities was carried out before freeze drying, after freeze drying, and after 10 wk of storage. There was a significant decrease in almost all enzyme activities, except that of PK. SAM and SA showed no different effect on maintaining enzyme activities during freeze drying. Storage for 10 wk at room temperature at various low a(w) using SAM and SA system had a significant effect on retention of most enzymes studied, except that of PK and LDH. Storage at a(w) of 0.07 and 0.1 was more effective in maintaining enzyme activities than storage at a(w) of 0.2 and in an aluminum foil. However, mannitol fortification into alginate system did not significantly improve retention of enzymes during 10 wk of storage.


Right mini-parasternotomy may be a good minimally invasive alternative to full sternotomy for cardiac valve operations-a propensity-adjusted analysis.
Limited realworld data existed for miniparasternotomy approach with good sample size in Asian cohorts and most previous studies were eclipsed by case heterogeneity. The goal of this study was to compare safety and quality outcomes of cardiac noncoronary valve operations by miniparasternotomy and full sternotomy approaches on riskadjusted basis. From our hospital database, we retrieved the cases of non-coronary valve operations from 1 January 2005 to 31 December 2012, including re-do, emergent, and combined procedures. Estimated EuroScore-II and propensity score for choosing mini-parasternotomy were adjusted for in the regression models on hospital mortality, complications (pneumonia, stroke, sepsis, etc.), and quality parameters (length of stay, ICU time, ventilator time, etc.). Non-complicated cases, defined as survival to discharge, ventilator use not over one week, and intensive care unit stay not over two weeks, were used for quality parameters. There were 283 miniparasternotomy and 177 full sternotomy cases. EuroScore-II differed significantly (medians 2.1 vs. 4.7, p<0.001). Propensity scores for choosing miniparasternotomy were higher with lower EuroScore-II (OR=0.91 per 1%, p<0.001), aortic regurgitation (OR=2.3, p=0.005), and aortic non-mitral valve disease (OR=3.9, p<0.001). Adjusted for propensity score and EuroScore-II, mini-parasternotomy group had less pneumonia (OR=0.32, p=0.043), less sepsis (OR=0.31, p=0.045), and shorter non-complicated length of stay (coefficient=7.2 (day), p<0.001) than full sternotomy group, whereas Kaplan-Meier survival, non-complicated ICU time, non-complicated ventilator time, and 30-day mortality did not differ significantly. The propensity-adjusted analysis demonstrated encouraging safety and quality outcomes for mini-parasternotomy valve operation in carefully selected patients.


Vital pulp therapy with new materials: new directions and treatment perspectives--permanent teeth.
Pulp necrosis in immature teeth subsequent to caries has a major impact on long-term tooth retention. The aim of vital pulp therapy is to maintain pulp viability by eliminating bacteria from the dentin-pulp complex and to establish an environment in which apexogenesis can occur. A complicating factor in treating immature teeth is the difficulty predicting the degree of pulpal damage. The ability of the clinician to manage the health of the remaining pulpal tissue during the procedure is paramount. Currently, the best method appears to be the ability to control pulpal hemorrhage by using sodium hypochlorite. Mineral trioxide aggregate (MTA) currently is the optimum material for use in vital pulp therapy. Compared with the traditional material of calcium hydroxide, it has superior long-term sealing ability and stimulates a higher quality and greater amount of reparative dentin. In the medium-term clinical assessment, it has demonstrated a high success rate. Thus, MTA is a good substitute for calcium hydroxide in vital pulp procedures.


Methodological Problems on the Way to Integrative Human Neuroscience.
Neuroscience is a multidisciplinary effort to understand the structures and functions of the brain and brain-mind relations. This effort results in an increasing amount of data, generated by sophisticated technologies. However, these data enhance our descriptive knowledge, rather than improve our understanding of brain functions. This is caused by methodological gaps both within and between subdisciplines constituting neuroscience, and the atomistic approach that limits the study of macro- and mesoscopic issues. Whole-brain measurement technologies do not resolve these issues, but rather aggravate them by the complexity problem. The present article is devoted to methodological and epistemic problems that obstruct the development of human neuroscience. We neither discuss ontological questions (e.g., the nature of the mind) nor review data, except when it is necessary to demonstrate a methodological issue. As regards intradisciplinary methodological problems, we concentrate on those within neurobiology (e.g., the gap between electrical and chemical approaches to neurophysiological processes) and psychology (missing theoretical concepts). As regards interdisciplinary problems, we suggest that core disciplines of neuroscience can be integrated using systemic concepts that also entail human-environment relations. We emphasize the necessity of a meta-discussion that should entail a closer cooperation with philosophy as a discipline of systematic reflection. The atomistic reduction should be complemented by the explicit consideration of the embodiedness of the brain and the embeddedness of humans. The discussion is aimed at the development of an explicit methodology of integrative human neuroscience, which will not only link different fields and levels, but also help in understanding clinical phenomena.


Increasing Referrals to a YMCA-Based Diabetes Prevention Program: Effects of Electronic Referral System Modification and Provider Education in Federally Qualified Health Centers.
The Diabetes Prevention Program has been translated to community settings with varying success. Although primary care referrals are used for identifying and enrolling eligible patients in the Diabetes Prevention Program, little is known about the effects of strategies to facilitate and sustain eligible patient referrals using electronic health record systems. To facilitate and sustain patient referrals, a modification to the electronic health record system was made and combined with provider education in 6 federally qualified health centers in the Bronx, New York. Referral data from April 2012 through November 2014 were analyzed using segmented regression analysis. Patient referrals increased significantly after the modification of the electronic health record system and implementation of the provider education intervention. Before the electronic system modification, 0 to 2 patients were referred per month. During the following year (September 2013 through August 2014), which included the provider education intervention, referrals increased to 1 to 9 per month and continued to increase to 5 to 11 per month from September through November 2014. Modification of an electronic health record system coupled with a provider education intervention shows promise as a strategy to identify and refer eligible patients to community-based Diabetes Prevention Programs. Further refinement of the electronic system for facilitating referrals and follow-up of eligible patients should be explored.


Meeting the physical activity guidelines and survival after breast cancer: findings from the after breast cancer pooling project.
The 2008 Physical Activity (PA) Guidelines recommend engaging in at least 2.5 h (10 MET-hours/week) of moderate intensity PA per week (defined as 4 METs) to reduce risk of morbidity and mortality. This analysis was conducted to investigate whether this recommendation can be extended to breast cancer survivors. Data from four studies of breast cancer survivors measuring recreational PA from semi-quantitative questionnaires a median of 23 months post-diagnosis (interquartile range 18-32 months) were pooled in the After Breast Cancer Pooling Project (n = 13,302). Delayed entry Cox proportional hazards models were applied in data analysis with adjustment for age, post-diagnosis body mass index, race/ethnicity, menopausal status, TNM stage, cancer treatment, and smoking history. Engaging in at least 10 MET-hours/week of PA was associated with a 27% reduction in all-cause mortality (n = 1,468 events, Hazard Ratio (HR) = 0.73, 95% CI, 0.66-0.82) and a 25% reduction in breast cancer mortality (n = 971 events, HR = 0.75, 95% CI 0.65-0.85) compared with women who did not meet the PA Guidelines (<10 MET-hours/week). Risk of breast cancer recurrence (n = 1,421 events) was not associated with meeting the PA Guidelines (HR = 0.96, 95% CI, 0.86-1.06). These data suggest that adhering to the PA guidelines may be an important intervention target for reducing mortality among breast cancer survivors.


Biphasic nature of gastric emptying.
The existence of a lag phase during the gastric emptying of solid foods is controversial. It has been hypothesised that among other early events, the stomach requires a period of time to process solid food to particles small enough to be handled as a liquid. At present no standardised curve fitting techniques exist for the characterisation and quantification of the lag phase or the emptying rate of solids and liquids. We have evaluated the ability of a modified power exponential function to define the emptying parameters of two different solid meals. Dual labelled meals were administered to 24 normal volunteers. The subjects received meals consisting of either Tc-99m in vivo labelled chicken liver or Tc-99m-egg, which have different densities, and In-111-DTPA in water. The emptying curves were biphasic in nature. For solids, this represented an initial delay in emptying or lag phase followed by an equilibrium emptying phase characterised by a constant rate of emptying. The curves were analysed using a modified power exponential function of the form y(t) = 1-(1-e-kt)beta, where y(t) is the fractional meal retention at time t, k is the gastric emptying rate in min-1, and beta is the extrapolated y-intercept from the terminal portion of the curve. The length of the lag phase and half-emptying time increased with solid food density (31 +/- 8 min and 77.6 +/- 11.2 min for egg and 62 +/- 16 min and 94.1 +/- 14.2 min for chicken liver, respectively). After the lag phase, both solids had similar emptying rates, and these rates were identical to those of the liquids. In vitro experiments indicated that the egg meal disintegrated much more rapidly than the chicken liver under mechanical agitation in gastric juice, lending further support to the hypothesis that the initial lag in emptying of solid food is due to the processing of food into particles small enough to pass the pylorus. We conclude that the modified power exponential model permits characterisation of the biphasic nature of gastric emptying allowing for quantification of the lag phase and the rate of emptying for both solids and liquids.


Culture change and ethnic-minority health behavior: an operant theory of acculturation.
Data on acculturation and ethnic-minority health indicate that acculturation has opposite effects on the same health behavior among different ethnic groups; opposite effects on different health behaviors within an ethnic group; opposite effects on the same health behavior for the women vs. the men of most ethnic groups; and no effect whatsoever on some health behaviors for some ethnic groups. This evidence is so incoherent that it is unintelligible, and hence it continues to be largely useless to health psychology and behavioral medicine. This paper presents a new theory of acculturation that renders these confusing data coherent by predicting such changes in minority health behavior a priori. By so doing, the operant model of acculturation has the potential to improve health promotion and disease prevention and thereby reduce ethnic health disparities.


Open pre-schools at integrated health services-A program theory.
Family centres in Sweden are integrated services that reach all prospective parents and parents with children up to their sixth year, because of the co-location of the health service with the social service and the open pre-school. The personnel on the multi-professional site work together to meet the needs of the target group. The article explores a program theory focused on the open pre-schools at family centres. A multi-case design is used and the sample consists of open pre-schools at six family centres. The hypothesis is based on previous research and evaluation data. It guides the data collection which is collected and analysed stepwise. Both parents and personnel are interviewed individually and in groups at each centre. The hypothesis was expanded to a program theory. The compliance of the professionals was the most significant element that explained why the open access service facilitated positive parenting. The professionals act in a compliant manner to meet the needs of the children and parents as well as in creating good conditions for social networking and learning amongst the parents. The compliance of the professionals in this program theory of open pre-schools at family centres can be a standard in integrated and open access services, whereas the organisation form can vary. The best way of increasing the number of integrative services is to support and encourage professionals that prefer to work in a compliant manner.


The role of BRCA1-associated protein 1 in the diagnosis of malignant mesothelioma in effusion and fine-needle aspiration cytology.
Malignant mesothelioma (MM) is a diagnostically challenging entity in cytology specimens due to the lack of architectural context and a cytomorphologic overlap between malignant and reactive mesothelial cells (RMCs). A diagnostic marker with excellent specificity is not currently available in clinical practice. The newly appreciated BRCA1-associated protein 1 (BAP1) antibody may help distinguish MM from RMC based on its immunohistochemical (IHC) staining pattern but its role in cytopathology is controversial. Immunohistochemistry with BAP1 antibody was performed on cell blocks from 39 cytology specimens including 13 cases of RMC and 26 cases of effusion and fine-needle aspiration specimens (FNAC) with tissue-specimen-proven MM. Cases were dichotomised into positive and negative cohorts. Positivity was defined as >50% loss of nuclear BAP1 IHC staining. Of the 26 MM cases, a slight majority (14/26, 54%) showed loss of BAP1 nuclear IHC staining, while all 13 RMC controls showed strong nuclear BAP1 IHC staining. MM was more likely to show loss of BAP1 than RMC (P < .001); and peritoneal MM was more likely to demonstrate loss of BAP1 than pleural MM (P = .04). There was perfect specificity at 1.0 and positive predictive value of 1.0 for loss of nuclear BAP1 IHC staining. However, only modest sensitivity at 0.52 and negative predictive value of 0.50 was seen. These data confirm that absence of BAP1 nuclear staining identifies malignant mesothelial cells. On the other hand, positive BAP1 nuclear staining can occur in both benign and malignant pleural effusions.


Computed tomography-assisted management of a mandibular dentigerous cyst in a dog with a nasal carcinoma.
A 6-year-old neutered male Boston Terrier was examined to determine the cause of sneezing, bilateral nasal discharge, nasal congestion, lethargy, and coughing of 2 months' duration. An undifferentiated nasal carcinoma was diagnosed. During computed tomography (CT) evaluation of response to tomotherapy radiation treatment, a mandibular dentigerous cyst, associated with an unerupted left mandibular first premolar, was monitored for expansion. The dog had a profound response to radiation treatment, and the nasal carcinoma totally resolved. It was determined on the basis of CT that the rate of expansion of the dentigerous cyst was placing the dog at risk for mandibular fracture and loss of vitality to the surrounding teeth. The unerupted left mandibular first premolar and associated dentigerous cyst were surgically removed and submitted for histologic evaluation. Images obtained during sequential CT evaluations performed after radiation treatment of nasal carcinoma should be examined for evidence of the primary neoplasm as well as to detect unrelated lesions of the orofacial region that can compromise the quality of life. Findings of CT evaluations can be used to determine when and how to initiate treatment for dentigerous cysts in regard to the patient's response to radiation treatment.


Optical properties of scandium films in the far and the extreme ultraviolet.
The optical properties of thin Sc films deposited in ultrahigh-vacuum conditions have been investigated in the 6.7-174.4-nm spectral range. We measured transmittance and multiangle reflectance in situ in the 53.6-174.4 nm spectral range and used these measurements to obtain the complex refractive index of a Sc film at every individual wavelength investigated. Transmittance measurements were made of Sc samples that were deposited over grids coated with a support C film. The transmittance and the extinction coefficient of Sc films at wavelengths shorter than 30 nm were measured ex situ. The ex situ samples were protected with an additional top C film before their removal from vacuum. To our knowledge, these are the first optical measurements of Sc films reported in the spectral ranges cited.


Fidelity mechanisms of DNA polymerase beta.
DNA polymerase 3 (Pol beta) is one of the best characterized eukaryotic DNA polymerases. Pol beta is a member of the X family of DNA polymerases. The Pol beta protein has two catalytic activities: DNA polymerase activity and dRP lyase activity. Pol beta has no known proofreading activity, so its accuracy in vitro results exclusively from the nucleotide selectivity of this enzyme. Presteady-state kinetic analysis has shown that Pol beta functions in nucleotide selectivity predominantly during phosphodiester bond formation, although this enzyme also possesses some ability to discriminate the correct from the incorrect deoxynucleoside triphosphate (dNTP) substrate during ground state binding. Recent results strongly suggest that Pol beta does not employ an induced fit mechanism of nucleotide discrimination. The fidelity of Pol beta appears to be determined through steric exclusion against the incorrect substrate and by the precise positioning of the catalytic residues, DNA, and substrate within the active site of the enzyme. Imprecise positioning of active site residues or DNA can result in the incorporation of the incorrect substrate into DNA. Amino acid residues both distant and near to the active site of Pol beta influence its geometry, suggesting that the movements and positioning of subdomains of Pol beta have a significant impact upon its fidelity.


Reactions to framing of cessation messages: insights from dual-smoker couples.
Couples in which both members smoke (dual-smoker couples) have not been the explicit target of cessation interventions. Quit rates are lower and relapse rates are higher among individuals in dual-smoker couples. A potentially effective strategy to motivate dual-smoker couples to quit is to convey messages that highlight how the positive outcomes of quitting (gain frame) or the negative outcomes of continued smoking (loss frame) affect the couple rather than the individual smoker. We explored whether dual-smoker couples' smoking behaviors (e.g., amount smoked) and desire to quit would differ as a function of message frame (gain vs. loss) or outcome focus (individual vs. couple). Dual-smoker couples (N = 40) completed a baseline survey and were then randomized to review gain- or loss-framed messages that varied whether the outcomes influenced the individual or the couple. Main outcomes were desire to quit after reading messages and smoking behaviors at a 1-month follow-up. Couple-focused messages produced the strongest desire to quit and decreased amount of cigarettes smoked at follow-up. The latter effect was mediated by desire to quit. Loss-framed messages produced inconsistent effects on desire to quit. There were no significant interactions between outcome focus and message framing. Findings suggest that messages emphasizing how smoking affects both partners can motivate cessation among dual-smoker couples. Contrary to findings showing that gain-framed messages motivate cessation targeting individual smokers, results suggest that loss-framed messages may be more persuasive than gain-framed messages when the target of the outcome involves significant others.


Development of pH-Responsive Biopolymeric Nanocapsule for Antibacterial Essential Oils.
It is generally believed that antibacterial essential oils have the potential to become one of the alternatives in preventing diarrheal diseases of monogastric animals. The disadvantage is their low efficiency per oral due to easy degradation during digestion in the stomach. This study compares the efficacy of chitosan, alginate-chitosan, guar gum-chitosan, xanthan gum-chitosan and pectin-chitosan nanocapsules to the synthesis of pH-responsive biopolymeric nanocapsule for Thymus vulgaris, Rosmarinus officinalis and Syzygium aromaticum essential oils. Using spectrophotometric approach and gas chromatography, release kinetics were determined in pH 3, 5.6 and 7.4. The growth rates of S. aureus and E. coli, as well as minimal inhibition concentration of essential oils were studied. The average encapsulation efficiency was 60%, and the loading efficiency was 70%. The size of the nanocapsules ranged from 100 nm to 500 nm. Results showed that chitosan-guar gum and chitosan-pectin nanocapsules released 30% of essential oils (EOs) at pH 3 and 80% at pH 7.4 during 3 h. Similar release kinetics were confirmed for thymol, eugenol and α-pinene. Minimal inhibition concentrations of Thymus vulgaris and Syzygium aromaticum essential oils ranged from 0.025 to 0.5%. Findings of this study suggest that the suitable pH-responsive nanocapsule for release, low toxicity and antibacterial activity is based on chitosan-guar gum structure.


Attenuation of Intestinal Epithelial Cell Migration During Cryptosporidium parvum Infection Involves Parasite Cdg7_FLc_1030 RNA-Mediated Induction and Release of Dickkopf-1.
Intestinal infection by Cryptosporidium is known to cause epithelial cell migration disorder but the underlying mechanisms are unclear. Previous studies demonstrated that a panel of parasite RNA transcripts of low protein-coding potential are delivered into infected epithelial cells. Using multiple models of intestinal cryptosporidiosis, we report here that C. parvum infection induces expression and release of the dickkopf protein 1 (Dkk1) from intestinal epithelial cells. Delivery of parasite Cdg7_FLc_1030 RNA to intestinal epithelial cells triggers transactivation of host Dkk1 gene during C. parvum infection. Release of Dkk1 is involved in C. parvum-induced inhibition of cell migration of epithelial cells, including noninfected bystander cells. Moreover, Dkk1-mediated suppression of host cell migration during C. parvum infection involves inhibition of Cdc42/Par6 signaling. Our data support the hypothesis that attenuation of intestinal epithelial cell migration during Cryptosporidium infection involves parasite Cdg7_FLc_1030 RNA-mediated induction and release of Dkk1 from infected cells.


Using elemental analyses and multivariate statistics to identify the off-site dispersion from informal e-waste processing.
Electronic waste (e-waste) is informally processed and recycled in Agbogbloshie in Accra (Ghana), which may be the largest such site in West Africa. This industry can lead to significant environmental contamination. In this study, surface dust samples were collected at a range of sites within Accra to establish the offsite consequences of such activities. Fifty-one samples were collected and analysed for 69 elements by ICP-mass spectrometry after nitric acid digestion. The data indicated a significant enrichment in metals associated with solder and copper wire at the site itself and a downwind dispersion of this source material to a distance of approximately 2.0 km. Chlorine and bromine were also elevated at this site as residues from polyvinyl chloride combustion and flame retardants respectively. The elemental composition indicated that only low technology electrical equipment was being treated this way. Multivariate statistical analyses by principal components analysis and polytopic vector analysis identified three sources contributing to the system; (i) burn site residue dispersing within 2 km from the source site, (ii) marine matter on the beaches alone and (iii) the baseline soil conditions of the city of Accra. Risk ratios and hazard quotients developed from the measured concentrations indicated that copper was providing the greatest risk to inhabitants in most cases although nickel, vanadium, chromium and zinc also contributed.


Efficient chromosome biorientation and the tension checkpoint in Saccharomyces cerevisiae both require Bir1.
Accurate chromosome segregation requires the capture of sister kinetochores by microtubules from opposite spindle poles prior to the initiation of anaphase, a state termed chromosome biorientation. In the budding yeast Saccharomyces cerevisiae, the conserved protein kinase Ipl1 (Aurora B in metazoans) is critical for ensuring correct chromosomal alignment. Ipl1 associates with its activators Sli15 (INCENP), Nbl1 (Borealin), and Bir1 (Survivin), but while Sli15 clearly functions with Ipl1 to promote chromosome biorientation, the role of Bir1 has been uncertain. Using a temperature-sensitive bir1 mutant (bir1-17), we show that Bir1 is needed to permit efficient chromosome biorientation. However, once established, chromosome biorientation is maintained in bir1-17 cells at the restrictive temperature. Ipl1 is partially delocalized in bir1-17 cells, and its protein kinase activity is markedly reduced under nonpermissive conditions. bir1-17 cells arrest normally in response to microtubule depolymerization but fail to delay anaphase when sister kinetochore tension is reduced. Thus, Bir1 is required for the tension checkpoint. Despite their robust mitotic arrest in response to nocodazole, bir1-17 cells are hypersensitive to microtubule-depolymerizing drugs and show a more severe biorientation defect on recovery from nocodazole treatment. The role of Bir1 therefore may become more critical when spindle formation is delayed.


Changing characteristics of typhoid fever in Taiwan.
Typhoid fever, a systemic disease caused by Salmonella typhi, is classically characterized by fever and abdominal symptoms. Although now considered uncommon, it seems to have re-emerged in Taiwan in recent years. We conducted a retrospective study of the clinical characteristics and microbiologic findings in 24 confirmed cases of typhoid fever treated over a 7-year period at a medical center in northern Taiwan. There were 11 males and 13 females, including 15 adults (over 18 years in age) and 9 children. Their mean age was 24.7 years (range, 9 months to 58 years). Twelve patients had recently returned from abroad, mostly from Southeast Asia. The most common complaints were fever (24/24), diarrhea (18/24), abdominal pain (10/24), and cough (10/24). The average duration of fever before diagnosis was 14.1 days, with a maximum of 30 days. Relative bradycardia was noted in 6 patients. Leukopenia was noted in 2 patients. S. typhi was isolated from blood culture in 20 cases, from stool culture in 3 cases, and from bone marrow culture in 1 case. Widal test was only positive initially in 7/18 cases. Fever of unknown origin was the most common initial diagnosis. Typhoid or enteric fever was impressed initially in only 2 cases. Almost all isolates of S. typhi were susceptible to antibiotics currently used for typhoid fever, with only 1 isolate resistant to chloramphenicol. All patients survived after antibiotic treatment. Only 1 patient developed recurrence after a 10-day course of ceftriaxone. In conclusion, the diagnosis of typhoid fever is often challenging due to non-specific symptoms and lack of an immediate confirmatory test. It is important to include this disease in the differential diagnosis of febrile patients with abdominal symptoms.


Noise characterization of broadband fiber Cherenkov radiation as a visible-wavelength source for optical coherence tomography and two-photon fluorescence microscopy.
Optical sources in the visible region immediately adjacent to the near-infrared biological optical window are preferred in imaging techniques such as spectroscopic optical coherence tomography of endogenous absorptive molecules and two-photon fluorescence microscopy of intrinsic fluorophores. However, existing sources based on fiber supercontinuum generation are known to have high relative intensity noise and low spectral coherence, which may degrade imaging performance. Here we compare the optical noise and pulse compressibility of three high-power fiber Cherenkov radiation sources developed recently, and evaluate their potential to replace the existing supercontinuum sources in these imaging techniques.


Wogonin increases doxorubicin sensitivity by down-regulation of IGF-1R/AKT signaling pathway in human breast cancer.
Currently drug resistance has remained a major challenge in successful breast cancer therapy. Wogonin, one of the active components of scutellaria baicalensis, has shown anticarcinogenic, chemopreventive, and immunoregulatory functions. The present study aimed to explore whether wogonin exerted synergistic cytotoxicity with doxorubicin in breast cancer. Our data indicated that wogonin inhibited the proliferation of breast cancer cells in a dose- and time-dependent manner. Combined treatment with wogonin increased the doxorubicin sensitivity in breast cancer cells. Moreover, administration with wogonin alone or in combination with doxorubicin suppressed the expression of insulin like growth factor 1 receptor (IGF-1R) in Bcap-37 and MCF-7 cells. Incubation with insulin like growth factor (IGF) I or IGF-II promoted cell growth, which was reversed by wogonin co-administration. Mechanically, we found that down-regulation of IGF-1R diminished the chemosensitization role of wogonin in breast cancer. In addition, wogonin suppressed the phosphorylation levels of AKT and addition of AKT inhibitor abolished the synergistic cytotoxicity of wogonin and doxorubicin. Taken together, combined treatment with wogonin increased the doxorubicin sensitivity in breast cancer cells through regulation of IGF-1R/AKT signaling pathway. Therefore, these findings demonstrated that combination therapy with wogonin led to better therapeutic effects via regulating IGF-1R/AKT signaling pathway in doxorubicin-based chemotherapy for breast cancer.


Right ventricular segmentation in cardiac MRI with moving mesh correspondences.
This study investigates automatic propagation of the right ventricle (RV) endocardial and epicardial boundaries in 4D (3D+time) magnetic resonance imaging (MRI) sequences. Based on a moving mesh (or grid generation) framework, the proposed algorithm detects the endocardium and epicardium within each cardiac phase via point-to-point correspondences. The proposed method has the following advantages over prior RV segmentation works: (1) it removes the need for a time-consuming, manually built training set; (2) it does not make prior assumptions as to the intensity distributions or shape; (3) it provides a sequence of corresponding points over time, a comprehensive input that can be very useful in cardiac applications other than segmentation, e.g., regional wall motion analysis; and (4) it is more flexible for congenital heart disease where the RV undergoes high variations in shape. Furthermore, the proposed method allows comprehensive RV volumetric analysis over the complete cardiac cycle as well as automatic detections of end-systolic and end-diastolic phases because it provides a segmentation for each time step. Evaluated quantitatively over the 48-subject data set of the MICCAI 2012 RV segmentation challenge, the proposed method yielded an average Dice score of 0.84±0.11 for the epicardium and 0.79±0.17 for the endocardium. Further, quantitative evaluations of the proposed approach in comparisons to manual contours over 23 infant hypoplastic left heart syndrome patients yielded a Dice score of 0.82±0.14, which demonstrates the robustness of the algorithm.


A multimodal cell census and atlas of the mammalian primary motor cortex.
Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1-5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.


Regional differences in cervical cancer incidence among American Indians and Alaska Natives, 1999-2004.
Reports from limited geographic regions indicate higher rates of cervical cancer incidence in American Indian and Alaska Native (AI/AN) women than in women of other races. However, accurate determinations of cervical cancer incidence in AI/AN women have been hampered by racial misclassification in central cancer registries. The authors linked data from cancer registries participating in the National Program of Cancer Registries (NPCR) and the Surveillance, Epidemiology, and End Results (SEER) Program with Indian Health Service (IHS) enrollment records to improve identification of AI/AN race. NPCR and SEER data were combined to estimate annualized age-adjusted rates (expressed per 100,000 persons) for the diagnosis years 1999 to 2004. Analyses focused on counties known to have less racial misclassification, and results were stratified by IHS Region. Approximately 56% of AI/ANs in the US reside in these counties. The authors examined overall and age-specific incidence rates and stage at diagnosis for AI/AN women compared with non-Hispanic white (NHW) women. Invasive cervical cancer incidence rates among AI/AN women varied nearly 2-fold across IHS regions, with the highest rates reported in the Southern Plains (14.1) and Northern Plains (12.5); the lowest rates were in the Eastern region and the Pacific Coast. Overall, AI/AN women had higher rates of cervical cancer than NHW women and were more likely to be diagnosed with later stage disease. The wide regional variation of invasive cervical cancer incidence indicates an important need for health services research regarding cervical cancer screening and prevention education as well as policy development regarding human papillomavirus vaccine use, particularly in the regions with high incidence rates. Cancer 2008;113(5 suppl):1234-43. Published 2008 by the American Cancer Society.


High species diversity in fleshy-fruited tropical understory plants.
Key innovations may increase the number of taxa in a clade that possesses the proposed innovation in comparison to its sister group that lacks the trait through either increased speciation or reduced extinction rates. Comparing sister clades across several independent lineages provides statistical support that the trait has increased species diversity. Previous studies have indicated that there may not be a relationship between biotic dispersal and higher species diversity, but only a few of these studies specified habit, habitat, or type of disperser. No previous study has specified all of the above parameters and used a phylogenetic approach. This article examines species diversity in numerous lineages of tropical understory plants with small, fleshy, bird-dispersed fruits for which a reliable estimate of phylogenetic relationships is available. Clades with fleshy fruits are significantly more diverse than sister clades with dry fruits.


Do the rich get richer? An empirical analysis of the Bitcoin transaction network.
The possibility to analyze everyday monetary transactions is limited by the scarcity of available data, as this kind of information is usually considered highly sensitive. Present econophysics models are usually employed on presumed random networks of interacting agents, and only some macroscopic properties (e.g. the resulting wealth distribution) are compared to real-world data. In this paper, we analyze Bitcoin, which is a novel digital currency system, where the complete list of transactions is publicly available. Using this dataset, we reconstruct the network of transactions and extract the time and amount of each payment. We analyze the structure of the transaction network by measuring network characteristics over time, such as the degree distribution, degree correlations and clustering. We find that linear preferential attachment drives the growth of the network. We also study the dynamics taking place on the transaction network, i.e. the flow of money. We measure temporal patterns and the wealth accumulation. Investigating the microscopic statistics of money movement, we find that sublinear preferential attachment governs the evolution of the wealth distribution. We report a scaling law between the degree and wealth associated to individual nodes.


Impact of Comorbidity, Race, and Marital Status in Men Referred for Prostate Biopsy with PSA >20 ng/mL: A Pilot Study in High-Risk Patients.
Objective. To assess the impact of comorbidity, race, and marital status on overall survival (OS) among men presenting for prostate biopsy with PSA >20 ng/mL. Methods. Data were reviewed from 2000 to 2012 and 78 patients were included in the cohort. We analyzed predictors of OS using a Cox proportional hazards model and the association between Charlson Comorbidity Index (CCI) score and PCa diagnosis or high-grade cancer using logistic regression and multinomial regression models, respectively. Results. The median age of patients was 62.5 (IQR 57-73) years. Median CCI was 3 (IQR 2-4), 69% of patients were African American men, 56% of patients were married, and 85% of patients had a positive biopsy. CCI (HR 1.52, 95% CI 1.19, 1.94), PSA (HR 1.62, 95% CI 1.09, 2.42), and Gleason sum (HR 2.04, 95% CI 1.17, 3.56) were associated with OS. CCI was associated with Gleason sum 7 (OR 4.06, 95% CI 1.04, 15.89) and Gleason sum 8-10 (OR 4.52, 95% CI 1.16, 17.54) PCa. Conclusions. CCI is an independent predictor of high-grade disease and worse OS among men with PCa. Race and marital status were not significantly associated with survival in this cohort. Patient comorbidity is an important component of determining the optimal approach to management of prostate cancer.


Theory of mind and emotional awareness deficits in patients with somatoform disorders.
To explore whether deficits are present in the mental representation of emotion signals and whether these are related to more general deficits in Theory of Mind (ToM) functioning test. To test this hypothesis in patients suffering from somatoform disorders, we used the Frith-Happé-Animations Task (AT)-an established ToM measure. We previously demonstrated that somatization in psychiatric patients is associated with decreased emotional awareness as measured by the Levels of Emotional Awareness Scale (LEAS). These findings suggest that individuals with decreased emotional awareness often fail to experience affective arousal as feelings and instead experience emotional distress somatically. We administered the AT and the LEAS to 30 hospitalized patients with somatoform disorders and 30 healthy controls matched for sex, age, and educational level. Emotional awareness on the LEAS, the emotional content of AT narratives, and ToM content on the AT were assessed. Patients with somatoform disorders scored significantly lower on the LEAS than healthy controls. Patients also demonstrated both reduced emotional content and reduced ToM functioning on the AT compared with control subjects. Deficits in ToM functioning in patients overlapped with but were not fully explained by deficits in the emotional content of animation narratives. The combination of ToM functioning and LEAS scores permitted a correct classification of 80% of patients and 73% of controls. Patients with somatoform disorders requiring inpatient treatment manifest deficits in both emotional awareness and ToM functioning. These deficits may underlie the phenomenon of somatization.


Collective motion of rod-shaped self-propelled particles through collision.
Self-propelled rods, which propel by themselves in the direction from the tail to the head and align nematically through collision, have been well-investigated theoretically. Various phenomena including true long-range ordered phase with the Giant number fluctuations, and the collective motion composed of many vorices were predicted using the minimal mathematical models of self-propelled rods. Using filamentous bacteria and running microtubules, we found that the predicted phenomena by the minimal models occur in the real world. This strongly indicates that there exists the unified description of self-propelled rods independent of the details of the systems. The theoretically predicted phenomena and the experimental results concerning the phenomena are reviewed.