Identifying spinal sensory pathways activated by noxious esophageal acid.
The transient receptor potential vanilloid 1 (TRPV1) channel is critical for spinal afferent signaling of burning pain throughout the body. Such pain frequently originates from the esophagus, following acid reflux. The contribution of TRPV1 to spinal nociceptor signaling from the esophagus remains unclear. We aimed to identify the spinal afferent pathways that convey nociceptive signaling from the esophagus, specifically those sensitive to acid, and the extent to which TRPV1 contributes. Acid/pepsin (150 mM HCl/1 mg mL(-1) pepsin) or saline/pepsin was perfused into the esophageal lumen of anesthetized wild-type and TRPV1 null mice over 20 min, followed by atraumatic perfuse fixation and removal of the cervical and thoracic spinal cord and dorsal root ganglia (DRG). To identify neurons responsive to esophageal perfusate, immunolabeling for neuronal activation marker phosphorylated extracellular receptor-regulated kinase (pERK) was used. Labeling for calcitonin gene-related peptide (CGRP) and isolectin B4 (IB4) was then used to characterize responsive neurons. Esophageal acid/pepsin perfusion significantly increased the number of pERK-immunoreactive (IR) neurons in the DRG and the cervical and thoracic spinal cord dorsal horn (DH) relative to saline/pepsin (DRG P < 0.01; cervical DH P < 0.05 and thoracic DH P < 0.005). The number of pERK-IR neurons following acid perfusion was significantly attenuated in TRPV1 -/- mice (DH P < 0.05 and DRG P < 0.05). This study has identified populations of spinal afferent DRG neurons and DH neurons involved in signaling of noxious acid from the esophagus. There is a major contribution of TRPV1 to signaling within these pathways.


Coincidental changes in behavior and plasma cortisol in unrestrained pigs after intracerebroventricular injection of tumor necrosis factor-alpha.
The coincidental behavioral and physiological responses to inflammatory stimuli administered either peripherally or centrally were evaluated. In the first study, twenty castrated male pigs were injected ip with 0, 0.5, 5, or 50 microg/kg BW lipopolysaccharide (LPS). Body temperature was monitored telemetrically, and serial blood samples were collected via an indwelling jugular catheter for determination of plasma cortisol and tumor necrosis factor-alpha (TNF-alpha) concentrations. Sickness behaviors were measured during 10-min tests at 0, 2, 4, 8, 12, and 24 h post injection. The 5 and 50 microg/kg doses of LPS increased plasma concentrations of cortisol and TNF-alpha, while inducing anorexia, hypersomnia, and fever. In contrast, although 0.5 microg/kg LPS induced acute anorexia, hypersomnia, and fever, it did not increase plasma TNF-alpha; and the cortisol response was small and transient, suggesting the behavioral system in pigs is more responsive to LPS than the hypothalamic-pituitary-adrenal (HPA) axis. Because LPS-induced behavior and activation of the HPA axis involve proinflammatory cytokines in the brain, in a second study, unrestrained pigs with jugular catheters were injected intracerebroventricularly (I.C.V.) with recombinant porcine TNF-alpha. Vehicle or TNF-alpha (0, 5, or 50 ng/kg) was injected I.C.V., and plasma cortisol and behavior were determined as before. Pigs injected I.C.V. with 50 ng/kg TNF-alpha showed anorexia, hypersomnia, and an abrupt increase in plasma cortisol concentration. Whereas 5 ng/kg TNF-alpha I.C.V. also induced marked sickness behavior, it failed to stimulate the HPA axis, as indicated by plasma cortisol levels. That there was a distinct difference in the magnitude of behavioral and endocrine responses to LPS and TNF-alpha suggests that different systems that are responsive to inflammatory stimuli exhibit different sensitivities.


Beta-carotene affects oxidative stress-related DNA damage in lung epithelial cells and in ferret lung.
Beta-carotene (BC) was found to enhance lung cancer risk in smokers. This adverse effect was unexpected because BC was thought to act as an anti-oxidant against cigarette smoke-derived radicals. These radicals can directly or indirectly damage DNA, leading to the formation of pro-mutagenic DNA lesions such as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and 3-(2-deoxy-beta-D-erythro-pentafuranosyl)pyrimido[1,2-alpha]purin-10(3H)-one deoxyguanosine (M(1)dG). Later, it was suggested that high concentrations of BC could also result in pro-oxidant effects. Therefore, we investigated whether high but physiologically feasible concentrations of BC were able to alter (i) the formation of radicals in vitro assessed by electron spin resonance spectroscopy, (ii) the levels of 8-oxo-dG and M(1)dG in vitro in lung epithelial cells after incubation with hydrogen peroxide (H(2)O(2)) and the smoke-derived carcinogen benzo[a]pyrene (B[a]P) and (iii) the levels of 8-oxo-dG and M(1)dG in vivo in ferrets' lung after chronic exposure to B[a]P. BC increased in vitro hydroxyl radical formation in the Fenton reaction but inhibited the formation of carbon-centered radicals. Similarly, BC was able to enhance 8-oxo-dG in vitro in lung epithelial cells. On the other hand, BC significantly inhibited M(1)dG formation in lung epithelial cells, especially after induction of M(1)dG by H(2)O(2) or B[a]P. Finally, BC supplementation of ferrets also resulted in a significant decrease in M(1)dG, but in contrast to the in vitro experiments, no effect was observed on 8-oxo-dG levels, probably because of increased base excision repair capacities as assessed by a modified comet assay. These data indicate that the fate of BC being a pro- or anti-oxidant strongly depends on the type of radical involved.


Incorporating climate change and exotic species into forecasts of riparian forest distribution.
We examined the impact climate change (CC) will have on the availability of climatically suitable habitat for three native and one exotic riparian species. Due to its increasing prevalence in arid regions throughout the western US, we predicted that an exotic species, Tamarix, would have the greatest increase in suitable habitat relative to native counterparts under CC. We used an ecological niche model to predict range shifts of Populus fremontii, Salix gooddingii, Salix exigua and Tamarix, from present day to 2080s, under five general circulation models and one climate change scenario (A1B). Four major findings emerged. 1) Contrary to our original hypothesis, P. fremontii is projected to have the greatest increase in suitable habitat under CC, followed closely by Tamarix. 2) Of the native species, S. gooddingii and S. exigua showed the greatest loss in predicted suitable habitat due to CC. 3) Nearly 80 percent of future P. fremontii and Salix habitat is predicted to be affected by either CC or Tamarix by the 2080s. 4) By the 2080s, 20 percent of S. gooddingii habitat is projected to be affected by both Tamarix and CC concurrently, followed by S. exigua (19 percent) and P. fremontii (13 percent). In summary, while climate change alone will negatively impact both native willow species, Tamarix is likely to affect a larger portion of all three native species' distributions. We discuss these and other results in the context of prioritizing restoration and conservation efforts to optimize future productivity and biodiversity. As we are accounting for only direct effects of CC and Tamarix on native habitat, we present a possible hierarchy of effects- from the direct to the indirect- and discuss the potential for the indirect to outweigh the direct effects. Our results highlight the need to account for simultaneous challenges in the face of CC.


Using Hybrid Telepractice for Supporting Parents of Children with ASD during the COVID-19 Lockdown: A Feasibility Study in Iran.
During the three-month closure of clinics and day centers in Iran due to the coronavirus disease 2019 (COVID-19) lockdown, parents of children with Autism Spectrum Disorder (ASD) became solely responsible for their care and education. Although centers maintained telephone contact, it quickly became evident that parents needed more detailed advice and guidance. Staff from 30 daycare centers volunteered to take part in a two-month online support and training course for 336 caregivers of children with ASD of different ages. In addition to the provision of visual and written information, synchronous video sessions were used to coach parents on the learning goals devised for the children. Both qualitative and quantitative data were collected to understand the acceptability of using telepractice and the outcomes achieved. A low dropout rate and positive feedback from parents indicated that they perceived telepractice sessions to be useful. The factors contributing to parents' satisfaction were identified. Although the use of telepractice would be a good alternative for caregivers in any future lockdowns, it could also be used in conjunction with daycare center services to encourage greater parental participation, or with families living in areas with no day centers. Further studies are needed to compare telepractice to usual daycare face-to-face interventions, and to document its impact and cost-effectiveness for parents and children.


Evolution and expression of the transplantation antigen gene family.
We have cloned 26 different class I genes that are located in the major histocompatibility complex of the C57BL/10 mouse. Two of the three class I genes found in the H-2 complex encode the H-2Kb and H-2Db antigens; the other 23 class I genes map to the adjacent Tla complex. We have grouped the cosmids containing these genes into three clusters: one cluster links the H-2K and I-A regions, one cluster links the H-2D and Qa-2 regions, and the final cluster maps to the TL region. The class I gene organizations in the Qa-2 and TL regions of the C57BL/10 and BALB/c mice are generally similar, but there are several polymorphic segments. The Qa-2 region of both mice seems to have evolved by the duplication of gene pairs; furthermore, the H-2K region may have been generated by the translocation of a gene pair from the Qa-2 region. We have evidence that several of the genes in the Qa-2 region are expressed.


Randomized, Double-Blind, Phase II Study of Temozolomide in Combination With Either Veliparib or Placebo in Patients With Relapsed-Sensitive or Refractory Small-Cell Lung Cancer.
Purpose Both temozolomide (TMZ) and poly (ADP-ribose) polymerase (PARP) inhibitors are active in small-cell lung cancer (SCLC). This phase II, randomized, double-blind study evaluated whether addition of the PARP inhibitor veliparib to TMZ improves 4-month progression-free survival (PFS). Patients and Methods A total of 104 patients with recurrent SCLC were randomly assigned 1:1 to oral veliparib or placebo 40 mg twice daily, days 1 to 7, and oral TMZ 150 to 200 mg/m2/day, days 1 to 5, of a 28-day cycle until disease progression, unacceptable toxicity, or withdrawal of consent. Response was determined by imaging at weeks 4 and 8, and every 8 weeks thereafter. Improvement in PFS at 4 months was the primary end point. Secondary objectives included overall response rate (ORR), overall survival (OS), and safety and tolerability of veliparib with TMZ. Exploratory objectives included PARP-1 and SLFN11 immunohistochemical expression, MGMT promoter methylation, and circulating tumor cell quantification. Results No significant difference in 4-month PFS was noted between TMZ/veliparib (36%) and TMZ/placebo (27%; P = .19); median OS was also not improved significantly with TMZ/veliparib (8.2 months; 95% CI, 6.4 to 12.2 months; v 7.0 months; 95% CI, 5.3 to 9.5 months; P = .50). However, ORR was significantly higher in patients receiving TMZ/veliparib compared with TMZ/placebo (39% v 14%; P = .016). Grade 3/4 thrombocytopenia and neutropenia more commonly occurred with TMZ/veliparib: 50% versus 9% and 31% versus 7%, respectively. Significantly prolonged PFS (5.7 v 3.6 months; P = .009) and OS (12.2 v 7.5 months; P = .014) were observed in patients with SLFN11-positive tumors treated with TMZ/veliparib. Conclusion Four-month PFS and median OS did not differ between the two arms, whereas a significant improvement in ORR was observed with TMZ/veliparib. SLFN11 expression was associated with improved PFS and OS in patients receiving TMZ/veliparib, suggesting a promising biomarker of PARP-inhibitor sensitivity in SCLC.


Biophysical controls on cluster dynamics and architectural differentiation of microbial biofilms in contrasting flow environments.
Ecology, with a traditional focus on plants and animals, seeks to understand the mechanisms underlying structure and dynamics of communities. In microbial ecology, the focus is changing from planktonic communities to attached biofilms that dominate microbial life in numerous systems. Therefore, interest in the structure and function of biofilms is on the rise. Biofilms can form reproducible physical structures (i.e. architecture) at the millimetre-scale, which are central to their functioning. However, the spatial dynamics of the clusters conferring physical structure to biofilms remains often elusive. By experimenting with complex microbial communities forming biofilms in contrasting hydrodynamic microenvironments in stream mesocosms, we show that morphogenesis results in 'ripple-like' and 'star-like' architectures--as they have also been reported from monospecies bacterial biofilms, for instance. To explore the potential contribution of demographic processes to these architectures, we propose a size-structured population model to simulate the dynamics of biofilm growth and cluster size distribution. Our findings establish that basic physical and demographic processes are key forces that shape apparently universal biofilm architectures as they occur in diverse microbial but also in single-species bacterial biofilms.


Pressure gradient related to energy conversion in the aorta.
In this study, we analyzed a common form of experimental investigation of blood vessels, in which measurements are obtained with branches ligated. Utilizing representative pressure and flow pulses and the full expression for the equation of motion, we calculated the axial pressure gradient, in the time domain at a plane in the descending aorta. The time function representing the ratio between axial pressure gradient and axial flow for the resulting tapering geometry was subjected to Fourier analysis. The harmonics were utilized to obtain the real and imaginary components of the longitudinal impedance as if it were a linear system. In a linear system, the real and imaginary components represent the viscous and inertial properties of the fluid, respectively. For the system studied, however, the real part contained both viscous and substantial in-phase components arising from the inertial terms of the equation of motion. The real part, therefore, cannot be interpreted as indicative solely of dissipated energy. When measurements are obtained from an adulterated system, caution must be exercised if the interpretation is to be considered that of the real system. The analysis clarifies an anomalous issue concerning resistive features of the aorta.


The moderating influence of demographic characteristics, social support, and religious coping on the effectiveness of a multicomponent psychosocial caregiver intervention in three racial ethnic groups.
This article extends the findings from the Resources for Enhancing Alzheimer's Caregiver Health (REACH II) program, a multisite randomized clinical trial of a multicomponent psychosocial intervention, to improve the well-being of informal caregivers (CGs) of persons with dementia. We used residual change scores and stepwise hierarchical regression analyses to explore separately in 3 racial ethnic groups (Hispanic or Latino, Black or African American, and White or Caucasian) how the effects of the intervention were moderated by CG characteristics (sex, age, education, and relationship), CG resources (social support), and religious coping. The results indicated that CG's age and religious coping moderated the effects of the intervention for Hispanics and Blacks. The older Hispanic and Black CGs who received the intervention reported a decrease in CG burden from baseline to follow-up. Black CGs with less religious coping who received the intervention also reported a decrease in depressive symptoms from baseline to follow-up.


Has the rate of extensive surgery to treat idiopathic clubfoot declined in the United States?
In the late 1990s, renewed interest emerged in less invasive treatment options, most notably the Ponseti method, to correct idiopathic clubfoot deformity. Recently, reports from several centers have demonstrated that such minimally invasive techniques may be used reliably to correct this complex deformity. The present study sought to determine whether the rate of extensive surgical releases to treat idiopathic clubfoot in the United States has decreased. We used data from the Centers for Disease Control and Prevention and the Nationwide Inpatient Sample to determine the number of live births, the number of patients diagnosed with clubfoot, and the number of extensive surgical releases that were performed each year from 1996 to 2006. The trends over time were evaluated with use of regression analysis, and changes in frequency were analyzed with use of time series analysis. The percentage of clubfeet that were treated with surgery in each year was calculated by dividing the number of surgical release procedures by the number of clubfoot diagnoses. Between 1996 and 2006, the estimated number of patients under six months of age diagnosed with clubfoot remained fairly constant, averaging 2140 infants per year. The linear equation estimated a slight decrease of approximately thirty-one infants with clubfoot per year (R(2) = 0.51, p < 0.05). In contrast, in the same decade, the estimated number of surgical releases performed in patients less than twelve months of age decreased substantially, from 1641 releases in 1996 to 230 releases in 2006. The linear equation estimated a decrease of approximately 157 surgical releases per year (R(2) = 0.83, p < 0.05). The trend analysis indicated that the percentage of clubfeet treated with surgical release generally decreased over time at a rate of 6.7% per year, decreasing from just over 70% in 1996 to just over 10% in 2006 (R(2) = 0.81, p < 0.05). In the United States between 1996 and 2006, the rate of extensive surgery to treat idiopathic clubfoot in patients less than twelve months old decreased substantially. This trend is likely due to an increased use of less invasive techniques, such as the Ponseti method, which a growing body of evidence has shown to be a viable treatment option for clubfoot.


Targeting hypoxic cells through the DNA damage response.
Exposure to hypoxia-induced replication arrest initiates a DNA damage response that includes both ATR- and ATM-mediated signaling. DNA fiber analysis was used to show that these conditions lead to a replication arrest during both the initiation and elongation phases, and that this correlated with decreased levels of nucleotides. The DNA damage response induced by hypoxia is distinct from the classical pathways induced by damaging agents, primarily due to the lack of detectable DNA damage, but also due to the coincident repression of DNA repair in hypoxic conditions. The principle aims of the hypoxia-induced DNA damage response seem to be the induction of p53-dependent apoptosis or the preservation of replication fork integrity. The latter is of particular importance should reoxygenation occur. Tumor reoxygenation occurs as a result of spontaneous changes in blood flow and also therapy. Cells experiencing hypoxia and/or reoxygenation are, therefore, sensitive to loss or inhibition of components of the DNA damage response, including Chk1, ATM, ATR, and poly(ADP-ribose) polymerase (PARP). In addition, restoration of hypoxia-induced p53-mediated signaling may well be effective in the targeting of hypoxic cells. The DNA damage response is also induced in endothelial cells at moderate levels of hypoxia, which do not induce replication arrest. In this situation, phosphorylation of H2AX has been shown to be required for proliferation and angiogenesis and is, therefore, an attractive potential therapeutic target.


Sister chromatid exchanges in lymphocyte cultures of patients previously treated with dibromodulcitol.
Acute non-lymphatic leukaemia and myelodysplasia occur in a larger percentage of patients treated with dibromodulcitol (DBD) than in patients treated with other cytostatics. Sister chromatid exchanges (SCE) in the lymphocytes in peripheral blood as well as other haematological parameters were measured in women with breast cancer to investigate whether women who had previously been treated with DBD as a part of their treatment regime had an increased frequency of SCE or another haematological abnormality attributable to DBD. SCE levels were elevated in women treated with DBD as well as in those treated with other cytostatics compared to the untreated control group. All other haematological parameters were normal. There was no significant difference in the number of SCEs between the patients who received DBD and those treated with other cytostatics. The increased frequencies of SCE in the treated patients are attributable to various cytostatic agents, and there is no significant permanent increase in the frequency of SCE after exposure to DBD.


An examination of the impact of clinically significant levels of posttraumatic stress disorder symptomatology on the classification of pain as mild, moderate, or severe in a sample of veterans with chronic pain.
Chronic pain affects approximately 50% of veterans, half of whom also suffer from posttraumatic stress disorder (PTSD). Researchers have previously identified a method for translating 0-10 pain scales to categories of pain (mild, moderate, or severe pain) to make pain ratings more meaningful in the context of category-based treatment guidelines. Although one such study focused on veterans with pain, none have considered whether empirically derived cutoffs differ based on the presence of clinically significant levels of PTSD symptomatology. Therefore, the purpose of the study presented here was to replicate previous findings on pain categorization in veterans and to assess whether the cutoffs differ based on the presence or absence of clinically significant levels of PTSD symptomatology. On the basis of the responses of 198 veterans, our results supported the previous finding that scores of 1-4 are classified as mild pain, 5-7 as moderate, and 8-10 as severe. In addition, veterans with comorbid pain and clinically significant levels of PTSD symptomatology were found to have a lower cutoff between mild and moderate pain, but they did not have a different cutoff between moderate and severe pain. These results, which support that lower levels of pain severity are associated with higher levels of pain-related interference for veterans with comorbid pain and clinically significant levels of PTSD symptomatology relative to veterans with pain without clinically significant levels of PTSD symptomatology, highlight the importance of considering contextual factors (e.g., psychosocial factors) when assessing a veteran's pain severity.


Racial and Ethnic Variations in Lung Cancer Incidence and Mortality: Results From the Women's Health Initiative.
This study aimed to evaluate racial/ethnic differences in lung cancer incidence and mortality in the Women's Health Initiative Study, a longitudinal prospective cohort evaluation of postmenopausal women recruited from 40 clinical centers. Lung cancer diagnoses were centrally adjudicated by pathology review. Baseline survey questionnaires collected sociodemographic and health information. Logistic regression models estimated incidence and mortality odds by race/ethnicity adjusted for age, education, calcium/vitamin D, body mass index, smoking (status, age at start, duration, and pack-years), alcohol, family history, oral contraceptive, hormones, physical activity, and diet. The cohort included 129,951 women--108,487 (83%) non-Hispanic white (NHW); 10,892 (8%) non-Hispanic black (NHB); 4,882 (4%) Hispanic; 3,696 (3%) Asian/Pacific Islander (API); 534 (< 1%) American Indian/Alaskan Native; and 1,994 (1%) other. In unadjusted models, Hispanics had 66% lower odds of lung cancer compared with NHW (odds ratio [OR], 0.34; 95% CI, 0.2 to 0.5), followed by API (OR, 0.45; 95% CI, 0.27 to 0.75) and NHB (OR, 0.75; 95% CI, 0.59 to 0.95). In fully adjusted multivariable models, the decreased lung cancer risk for Hispanic compared with NHW women attenuated to the null (OR, 0.59; 95% CI, 0.35 to 0.99). In unadjusted models Hispanic and API women had decreased risk of death compared with NHW women (OR, 0.30 [95% CI, 0.15 to 0.62] and 0.34 [95% CI, 0.16 to 0.75, respectively); however, no racial/ethnic differences were found in risk of lung cancer death in fully adjusted models. Differences in lung cancer incidence and mortality are associated with sociodemographic, clinical, and behavioral factors. These findings suggest modifiable exposures and behaviors may contribute to differences in incidence of and mortality by race/ethnicity for postmenopausal women. Interventions focused on these factors may reduce racial/ethnic differences in lung cancer incidence and mortality.


Acidianus Tailed Spindle Virus: a New Archaeal Large Tailed Spindle Virus Discovered by Culture-Independent Methods.
The field of viral metagenomics has expanded our understanding of viral diversity from all three domains of life (Archaea, Bacteria, and Eukarya). Traditionally, viral metagenomic studies provide information about viral gene content but rarely provide knowledge about virion morphology and/or cellular host identity. Here we describe a new virus, Acidianus tailed spindle virus (ATSV), initially identified by bioinformatic analysis of viral metagenomic data sets from a high-temperature (80°C) acidic (pH 2) hot spring located in Yellowstone National Park, followed by more detailed characterization using only environmental samples without dependency on culturing. Characterization included the identification of the large tailed spindle virion morphology, determination of the complete 70.8-kb circular double-stranded DNA (dsDNA) viral genome content, and identification of its cellular host. Annotation of the ATSV genome revealed a potential three-domain gene product containing an N-terminal leucine-rich repeat domain, followed by a likely posttranslation regulatory region consisting of high serine and threonine content, and a C-terminal ESCRT-III domain, suggesting interplay with the host ESCRT system. The host of ATSV, which is most closely related to Acidianus hospitalis, was determined by a combination of analysis of cellular clustered regularly interspaced short palindromic repeat (CRISPR)/Cas loci and dual viral and cellular fluorescence in situ hybridization (viral FISH) analysis of environmental samples and confirmed by culture-based infection studies. This work provides an expanded pathway for the discovery, isolation, and characterization of new viruses using culture-independent approaches and provides a platform for predicting and confirming virus hosts. Virus discovery and characterization have been traditionally accomplished by using culture-based methods. While a valuable approach, it is limited by the availability of culturable hosts. In this research, we report a virus-centered approach to virus discovery and characterization, linking viral metagenomic sequences to a virus particle, its sequenced genome, and its host directly in environmental samples, without using culture-dependent methods. This approach provides a pathway for the discovery, isolation, and characterization of new viruses. While this study used an acidic hot spring environment to characterize a new archaeal virus, Acidianus tailed spindle virus (ATSV), the approach can be generally applied to any environment to expand knowledge of virus diversity in all three domains of life.


Catheter ablation treatment of supraventricular tachycardia-induced cardiomyopathy.
To investigate the efficacy of radiofrequency catheter ablation (RFCA) as an alternative nonpharmacological therapy for tachycardia-induced cardiomyopathy. A retrospective study of 8 pediatric patients (age range, 10 months to 21 years) who underwent RFCA for an incessant supraventricular tachycardia-induced cardiomyopathy. A patient's tachycardia was considered incessant if the tachycardia was present more than 75% of the time. The left ventricular shortening fraction, as measured by echocardiography, before and after ablation, was used as the index of cardiac function. Cardiomyopathy was defined as a left ventricular shortening fraction of 28% or less. Following RFCA, 7 patients had total resolution of their tachycardia and were discharged from the hospital with no antiarrhythmic medications. The remaining patient's tachycardia was modified by the catheter ablation and was subsequently controlled with flecainide acetate. With follow-up ranging from 9 months to 3 years, all patients have normal cardiac function as documented by echocardiography. No significant morbidity resulted from the catheter ablations. Tachycardia-induced cardiomyopathy is amenable to "curative" therapy with RFCA. Ventricular function returns to normal after the successful catheter ablation procedure.


Bioaffinity sensor based on nanoarchitectonic films: control of the specific adsorption of proteins through the dual role of an ethylene oxide spacer.
The identification and quantification of biomarkers or proteins is a real challenge in allowing the early detection of diseases. The functionalization of the biosensor surface has to be properly designed to prevent nonspecific interactions and to detect the biomolecule of interest specifically. A multilayered nanoarchitecture, based on polyelectrolyte multilayers (PEM) and the sequential immobilization of streptavidin and a biotinylated antibody, was elaborated as a promising platform for the label-free sensing of targeted proteins. We choose ovalbumin as an example. Thanks to the versatility of PEM films, the platform was built on two types of sensor surface and was evaluated using both optical- and viscoelastic-based techniques, namely, optical waveguide lightmode spectroscopy and the quartz crystal microbalance, respectively. A library of biotinylated poly(acrylic acids) (PAAs) was synthesized by grafting biotin moieties at different grafting ratios (GR). The biotin moieties were linked to the PAA chains through ethylene oxide (EO) spacers of different lengths. The adsorption of the PAA-EOn-biotin (GR) layer on a PEM precursor film allows tuning the surface density in biotin and thus the streptavidin adsorption mainly through the grafting ratio. The nonspecific adsorption of serum was reduced and even suppressed depending on the length of the EO arms. We showed that to obtain an antifouling polyelectrolyte the grafting of EO9 or EO19 chains at 25% in GR is sufficient. Thus, the spacer has a dual role: ensuring the antifouling property and allowing the accessibility of biotin moieties. Finally, an optimized platform based on the PAA-EO9-biotin (25%)/streptavidin/biotinylated-antibody architecture was built and demonstrated promising performance as interface architecture for bioaffinity sensing of a targeted protein, in our case, ovalbumin.


Family interactions among African American prostate cancer survivors.
Prostate cancer affects African Americans at a higher rate than any other ethnic group in the United States. Prostate cancer does not only affect the man with the disease but also affects those individuals who are closest to him, such as his family and friends. Open communication is valuable in coping with stressors that are affiliated with chronic illnesses. This article focuses on family and friend social support of men with prostate cancer. Data analysis revealed that support from family members and friends plays an important role in how men cope with their treatment and recovery from prostate cancer.


Does socioeconomic position moderate the effects of race on cardiovascular disease mortality?
Cardiovascular disease (CVD) rates differ markedly by minority status, with younger Blacks having some of the highest CVD mortality rates in the United States. A major objective of this study was to assess whether socioeconomic position moderates the effects of race or minority status on CVD mortality. The sample included 443 Black and 21,182 White men, and 415 Black and 24,929 White women, 45 years and older, who died of CVD from 1992-1998, and who had lived in the Twin Cities 5-county area. Using individual and neighborhood level measures of socioeconomic position, we hypothesized that socioeconomic position would moderate the effects of race on CVD mortality. Test hypotheses were analyzed using Poisson regression analysis. Socioeconomic position moderated the effects of race on CVD mortality among older men, but not in older women. Older Black men who lived in more impoverished neighborhoods had significantly and disproportionately higher CVD mortality rates than did older White men living in more impoverished neighborhoods; this was not the case among older Black and White men living in less impoverished neighborhoods. Race was independently related to CVD mortality among younger men and women, with younger Black men and women having significantly higher CVD mortality rates than younger White men and women. The Black-White rate for Black women was twice that of White women. Socioeconomic position as measured by neighborhood poverty can moderate the effects of race on CVD mortality in older Black and White men. This may not have been as apparent had socioeconomic position not been treated as a major variable of interest, and measured at multiple levels.


Bioresorbable vascular scaffold implantation for severely calcified lesions after excimer laser lesion preparation.
Bioresorbable vascular scaffolds (Absorb BVS, Abbott Vascular, Santa Clara, CA) temporarily elute antiproliferative drugs and provide vessel support, which then subsequently resorb to allow restoration of normal vessel function and architecture. To attain the best possible results with BVS, a dedicated implantation technique (PSP: adequate lesion preparation, proper sizing, postdilatation) is considered mandatory, and calcified lesions are one of the most challenging lesion subsets for BVS implantation. In five cases with severe calcifications refractory to balloon predilatation, we performed excimer laser catheter ablation (ELCA: Turbo Elite catheter; Spectranetics Corporation, Colorado Springs, CO, USA), which facilitated adequate lesion expansion with high-pressure noncompliant balloon inflation and BVS implantation. During the follow-up period (481 days [interquartile range: 445-579]), all patients continued dual antiplatelet therapy (DAPT) and there were no cases of cardiac death, myocardial infarction, or scaffold thrombosis. For treatment of severely calcified lesions with bioresorbable scaffolds, ELCA could be considered an effective potential strategy. After the procedure, prolonged DAPT was prescribed.


Lung cancer screening: nodule identification and characterization.
The accurate identification and characterization of small pulmonary nodules at low-dose CT is an essential requirement for the implementation of effective lung cancer screening. Individual reader detection performance is influenced by nodule characteristics and technical CT parameters but can be improved by training, the application of CT techniques, and by computer-aided techniques. However, the evaluation of nodule detection in lung cancer screening trials differs from the assessment of individual readers as it incorporates multiple readers, their inter-observer variability, reporting thresholds, and reflects the program accuracy in identifying lung cancer. Understanding detection and interpretation errors in screening trials aids in the implementation of lung cancer screening in clinical practice. Indeed, as CT screening moves to ever lower radiation doses, radiologists must be cognisant of new technical challenges in nodule assessment. Screen detected lung cancers demonstrate distinct morphological features from incidentally or symptomatically detected lung cancers. Hence characterization of screen detected nodules requires an awareness of emerging concepts in early lung cancer appearances and their impact on radiological assessment and malignancy prediction models. Ultimately many nodules remain indeterminate, but further imaging evaluation can be appropriate with judicious utilization of contrast enhanced CT or MRI techniques or functional evaluation by PET-CT.


Enhanced bone healing using collagen-hydroxyapatite scaffold implantation in the treatment of a large multiloculated mandibular aneurysmal bone cyst in a thoroughbred filly.
An unmet need remains for a bone graft substitute material that is biocompatible, biodegradable and capable of promoting osteogenesis safely in vivo. The aim of this study was to investigate the use of a novel collagen-hydroxyapatite (CHA) bone graft substitute in the clinical treatment of a mandibular bone cyst in a young horse and to assess its potential to enhance repair of the affected bone. A 2 year-old thoroughbred filly, presenting with a multilobulated aneurysmal bone cyst, was treated using the CHA scaffold. Post-operative clinical follow-up was carried out at 2 weeks and 3, 6 and 14 months. Cortical thickening in the affected area was observed from computed tomography (CT) examination as early as 3 months post-surgery. At 14 months, reduced enlargement of the operated mandible was observed, with no fluid-filled area. The expansile cavity was occupied by moderately dense mineralized tissue and fat and the compact bone was remodelled, with a clearer definition between cortex and medulla observed. This report demonstrates the promotion of enhanced bone repair following application of the CHA scaffold material in this craniomaxillofacial indication, and thus the potential of this material for translation to human applications.


Interactions of cytochrome c and [14C].
1. The interactions between cytochrome c (native and [(14)C]carboxymethylated) and monolayers of phosphatidylcholine, phosphatidic acid and cardiolipin at the air/water interface was investigated by measurements of surface radioactivity, pressure and potential. 2. On a subphase of 10mm-or m-sodium chloride, penetration of cytochrome c into egg phosphatidylcholine monolayers, as measured by an increase of surface pressure, and the number of molecules penetrating, as judged by surface radioactivity, were inversely proportional to the initial pressure of the monolayer and became zero at 20dynes/cm. The constant of proportionality was increased when the cytochrome c was carboxymethylated or decreased when the phospholipid was hydrogenated, but the cut-off point remained at 20dynes/cm. 3. Penetrated cytochrome c could be removed almost entirely by compression of the phosphatidylcholine monolayer above 20dynes/cm. 4. With phosphatidic acid and cardiolipin monolayers on 10mm-sodium chloride the binding of cytochrome c was much stronger and cytochrome c penetrated into films nearing the collapse pressure (>40dynes/cm.). The penetration was partly electrostatically facilitated, since it was decreased by carrying out the reaction on a subphase of m-sodium chloride, and the relationship between the surface pressure increment and the initial film pressure moved nearer to that observed with phosphatidylcholine. 5. Surface radioactivity determinations showed that [(14)C]carboxymethylated cytochrome c was still adsorbed on phosphatidic acid and cardiolipin monolayers after the cessation of penetration. This adsorption was primarily electrostatic in nature because it could be prevented and substantially reversed by adding m-sodium chloride to the subphase and there was no similar adsorption on phosphatidylcholine films. 6. The penetration into and adsorption on the three phospholipid monolayers was examined as a function of the pH of the subphase and compared with the state of ionization of both the phospholipid and the protein, and the area occupied by the latter at an air/water interface. 7. It is concluded that the binding of cytochrome c to phospholipids can only be partially understood by a consideration of the ionic interaction between the components and that subtle conformational changes in the protein must affect the magnitude and stability of the complex. 8. If cytochrome c is associated with a phospholipid in mitochondria then cardiolipin would fulfil the characteristics of the binding most adequately.


The bicyclams, a new class of potent human immunodeficiency virus inhibitors, block viral entry after binding.
The bicyclams represent a new class of highly potent and selective HIV inhibitors. Time-of-addition experiments have previously shown that these compounds interfere with an early event in the viral replicative cycle. Additional experiments have now been carried out in order to investigate in more detail the mechanism of action of these promising compounds. As described in this paper, PCR experiments revealed that no viral DNA was formed following viral infection, thus confining the target(s) of action of the bicyclams to an early stage of HIV infection. An assay, using pseudotype virions containing the envelope of HIV-1 and the genome of a plaque-forming virus (Cocal Virus), pointed to viral entry as the main target of the bicyclams. HIV-1 strains resistant to two prototype bicyclams, JM2763 and SID791 (JM3100), were raised. Results obtained with SID791 with respect to syncytium formation induced by SID791-sensitive and -resistant HIV-1 strains and the cross-resistance observed for dextran sulfate, suggest inhibition of binding and/or fusion as a plausible target of SID791. Additional experiments enabled us to exclude SID791 and JM2763 as binding inhibitors and to conclude that bicyclams block the entry of cell-bound virus. Furthermore, a monoclonal antibody recognising the V3 loop of wild-type gp120 did not bind to this region in the two bicyclam-resistant strains. Our results point to gp120 as a possible target for the HIV-inhibitory effects of the bicyclams.


Involvement of Caveolin-1 in repair of DNA damage through both homologous recombination and non-homologous end joining.
Caveolin-1 (Cav-1), the major component of caveolae, is a 21-24 kDa integral membrane protein that interacts with a number of signaling molecules. By acting as a scaffolding protein, Cav-1 plays crucial roles in the regulation of various physiologic and patho-physiologic processes including oncogenic transformation and tumorigenesis, and tumor invasion and metastasis. In the present study we sought to explore the role of Cav-1 in response to DNA damage and the mechanism involved. We found that the level of Cav-1 was up-regulated rapidly in cells treated with ionizing radiation. The up-regulation of Cav-1 following DNA damage occurred only in cells expressing endogenous Cav-1, and was associated with the activation of DNA damage response pathways. Furthermore, we demonstrated that the expression of Cav-1 protected cells against DNA damage through modulating the activities of both the homologous recombination (HR) and non-homologous end joining (NHEJ) repair systems, as evidenced by the inhibitory effects of the Cav-1-targeted siRNA on cell survival, HR frequency, phosphorylation of DNA-dependent protein kinase (DNA-PK), and nuclear translocation of epidermal growth factor receptor (EGFR) following DNA damage, and by the stimulatory effect of the forced expression of Cav-1 on NHEJ frequency. Our results indicate that Cav-1 may play a critical role in sensing genotoxic stress and in orchestrating the response of cells to DNA damage through regulating the important molecules involved in maintaining genomic integrity.


Primary Health Care for Aboriginal Australian Women in Remote Communities after a Pregnancy with Hyperglycaemia.
Hyperglycaemia in pregnancy contributes to adverse outcomes for women and their children. The postpartum period is an opportune time to support women to reduce cardiometabolic and diabetes risk in subsequent pregnancies. To identify strengths and gaps in current care for Aboriginal women after a pregnancy complicated by hyperglycaemia. A retrospective review of the 12 month postpartum care provided by primary health centres in remote Australia in 2013-2014 identified 195 women who experienced hyperglycaemia in pregnancy (gestational diabetes (GDM) (n = 147), type 2 diabetes (T2D) (n = 39), and unclear diabetes status (n = 9)). Only 80 women (54%) with GDM had postpartum glycaemic checks. Of these, 32 women were diagnosed with prediabetes (n = 24) or diabetes (n = 8). Compared to women with GDM, women with T2D were more likely to have their weight measured (75% vs. 52%, p <0.01), and smoking status documented as "discussed" (65% vs. 34%, p < 0.01). Most women (97%) accessed the health centre at least once in the 12 month postpartum period but, during these visits, only 52% of women had service provision, either structured or opportunistic, related to diabetes. High rates of dysglycaemia among women screened for T2D after GDM in the 12 month postpartum period highlight the need for increased screening and early intervention to prevent the development of T2D and its complications. Whilst a clear strength was high postpartum attendance, many women did not attend health services for diabetes screening or management.


Rubisco activase requires residues in the large subunit N terminus to remodel inhibited plant Rubisco.
The photosynthetic CO2 fixing enzyme ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) forms dead-end inhibited complexes while binding multiple sugar phosphates, including its substrate ribulose 1,5-bisphosphate. Rubisco can be rescued from this inhibited form by molecular chaperones belonging to the ATPases associated with diverse cellular activities (AAA+ proteins) termed Rubisco activases (Rcas). The mechanism of green-type Rca found in higher plants has proved elusive, in part because until recently higher-plant Rubiscos could not be expressed recombinantly. Identifying the interaction sites between Rubisco and Rca is critical to formulate mechanistic hypotheses. Toward that end here we purify and characterize a suite of 33 Arabidopsis Rubisco mutants for their ability to be activated by Rca. Mutation of 17 surface-exposed large subunit residues did not yield variants that were perturbed in their interaction with Rca. In contrast, we find that Rca activity is highly sensitive to truncations and mutations in the conserved N terminus of the Rubisco large subunit. Large subunits lacking residues 1-4 are functional Rubiscos but cannot be activated. Both T5A and T7A substitutions result in functional carboxylases that are poorly activated by Rca, indicating the side chains of these residues form a critical interaction with the chaperone. Many other AAA+ proteins function by threading macromolecules through a central pore of a disc-shaped hexamer. Our results are consistent with a model in which Rca transiently threads the Rubisco large subunit N terminus through the axial pore of the AAA+ hexamer.


The Population Structure of Pseudomonas aeruginosa Is Characterized by Genetic Isolation of exoU+ and exoS+ Lineages.
The diversification of microbial populations may be driven by many factors including adaptation to distinct ecological niches and barriers to recombination. We examined the population structure of the bacterial pathogen Pseudomonas aeruginosa by analyzing whole-genome sequences of 739 isolates from diverse sources. We confirmed that the population structure of P. aeruginosa consists of two major groups (referred to as Groups A and B) and at least two minor groups (Groups C1 and C2). Evidence for frequent intragroup but limited intergroup recombination in the core genome was observed, consistent with sexual isolation of the groups. Likewise, accessory genome analysis demonstrated more gene flow within Groups A and B than between these groups, and a few accessory genomic elements were nearly specific to one or the other group. In particular, the exoS gene was highly overrepresented in Group A compared with Group B isolates (99.4% vs. 1.1%) and the exoU gene was highly overrepresented in Group B compared with Group A isolates (95.2% vs. 1.8%). The exoS and exoU genes encode effector proteins secreted by the P. aeruginosa type III secretion system. Together these results suggest that the major P. aeruginosa groups defined in part by the exoS and exoU genes are divergent from each other, and that these groups are genetically isolated and may be ecologically distinct. Although both groups were globally distributed and caused human infections, certain groups predominated in some clinical contexts.


Regulation of the cell cycle by p53 after DNA damage in an amphibian cell line.
In mammalian cells, the p53 protein is a key regulator of the cell cycle following DNA damage. In the present study, we investigated the function of p53 in the A6 amphibian cell line. Using various specific Xenopus p53 monoclonal antibodies, we showed that Xenopus p53 accumulates after DNA damage, including gamma and UV irradiation or treatment with adriamycin. Such accumulation is accompanied by an increase in the apparent molecular weight of the protein. This change was shown to be the result of a phosphorylation event that occurs after DNA damage. Accumulation of Xenopus p53 is parallel to a drastic change in the cell cycle distribution. Brief exposure to adriamycin or gamma irradiation induces reversible growth arrest, whereas long-term exposure to adriamycin leads to apoptosis. Taken together, these results indicate that p53 has a similar behaviour in frog cells and mammalian cells, and that it conserves two activities, cell cycle arrest and apoptosis.


The failed exstrophy closure: strategy for management.
In the last 7 years, 29 boys and 11 girls have been referred with failure of their exstrophy closure; 38 patients had classic bladder exstrophy and 2 had cloacal exstrophy. Reclosure was performed for complete bladder dehiscence in 28 cases and for significant bladder prolapse in 10. Two patients underwent revision of the posterior urethra after primary closure due to a severe urethral stricture secondary to the use of para-exstrophy skin flaps. Six patients underwent posterior iliac osteotomy at the time of initial bladder closure and in 34 no osteotomy was performed. Thirty-seven patients underwent either posterior iliac osteotomy (15) or anterior innominate osteotomy (22). Epispadias repair together with reclosure of bladder exstrophy was done in 20 boys. The upper tract has remained normal in all patients. Fourteen have undergone subsequent bladder neck reconstruction. Seven patients have undergone simultaneous bladder neck reconstruction and augmentation cystoplasty and 1 has undergone augmentation cystoplasty and Mitrofanoff procedure; all are dry on intermittent self-catheterisation. The failed exstrophy reconstruction represents a formidable dilemma. However, a well planned reconstruction including osteotomy (even if previously performed), reclosure with or without epispadias repair or revision of the urethra can be performed with an excellent chance of proceeding with staged reconstruction.


Seasonal synchrony in incidences of common infectious diagnoses in early childhood among neighbouring regions.
Information on seasonal synchrony of influenza activity between neighbouring regions has been found useful for planning infection control measures. Seasonal synchrony of other infectious diseases is less known. We describe the seasonality and seasonal synchrony of three common childhood infectious diagnoses among three regions in Taiwan. A large, nationally representative sample of young children (N=128 651, age 0-4 years) was used to estimate the monthly incidences of acute respiratory infection, acute intestinal infection, and herpangina and hand, foot, and mouth disease (HFMD) in three regions of Taiwan between 2000 and 2005. Seasonality of monthly incidences was indicated by year-on-year intra-class correlations (ICCs). Between-region ICCs were used to describe seasonal synchrony of incidences between regions. We found evidence of seasonality in all three infectious diagnoses (p<0.05). Seasonal synchrony among the three regions was highest for acute respiratory infection (between-region ICC 0.91, 95% confidence interval (CI) 0.87-0.94), followed by herpangina and HFMD (between-region ICC 0.85, 95% CI 0.80-0.90), and acute intestinal infection (between-region ICC 0.69, 95% CI 0.59-0.79). We found strong evidence of seasonal synchrony in the incidences of acute respiratory infection, acute intestinal infection, and herpangina and HFMD between three neighbouring regions of Taiwan. An understanding of these disease patterns may inform future infection control measures.


Transcriptional regulation of limulus factor C: repression of an NFkappaB motif modulates its responsiveness to bacterial lipopolysaccharide.
Serine proteases play fundamental roles in invertebrate development, hemostasis, and innate immunity. This is exemplified by the limulus Factor C, which is a serine protease that binds a pathogen-associated molecule, lipopolysaccharide (LPS) to trigger a blood coagulation cascade. As a central molecule in the limulus innate immunity and hemostasis, Factor C gene expression has been detected in two major immune defense tissues, the amebocytes and hepatopancreas. Infection of the limulus with live Gram-negative bacteria induces a 2-3-fold increase in mRNA transcripts in both tissues. However, in vitro studies in Drosophila cell lines using Factor C promoter-reporter chimera DNA constructs, and site-directed mutagenesis of the promoter demonstrated that a proximal kappaB binding site, aided by an adjacent dorsal-like binding motif responds dramatically to LPS and dorsal transcription factor overexpression. Electrophoretic mobility shift assay further confirmed a strong interaction of the limulus kappaB motif with Rel proteins. However, deletion constructs of the Factor C promoter harboring different numbers of dorsal-like binding sites upstream of the kappaB motif as well as the electrophoretic mobility shift assay of these motifs with Rel proteins strongly suggest that the up-regulation of Factor C gene expression is attenuated during microbial challenge. The repression of the dramatic activation of this pathogen-responsive gene by LPS is probably effected via competition between the dorsal-like motifs over the proximal LPS-responsive kappaB unit, or through inhibition from the upstream repressive element(s), which accounts for the gene expression pattern observed in vivo. Our findings demonstrate that blood coagulation and innate immune response are integrated at the transcriptional level in this ancient organism, and that this LPS-responsive serine protease is controlled by an evolutionarily conserved NFkappaB pathway.


Level of Need, Divertibility, and Outcomes of Newly Admitted Nursing Home Residents.
To describe the level of need and divertibility of newly admitted nursing home residents, describe the factors that drive need, and describe the outcomes of residents across different levels of need. Retrospective cohort study. A total of 640 publicly funded nursing homes (also known as long-term care facilities) in Ontario, Canada. All newly admitted residents between January 1, 2010 and March 1, 2012. We categorized residents into 36 groups based on different levels of (1) cognitive impairment, (2) difficulty in activities of daily living (ADL), (3) difficulty in instrumental ADLs, and (4) whether or not they had a caregiver at home. Residents were then categorized as having low, intermediate, or high needs; applying results from previous "Balance of Care" studies, we also captured the proportion who could have been cost-effectively diverted into the community. We then contrasted the characteristics of residents across the needs and divertible groupings, and compared 4 outcomes among these groups: hospital admissions, emergency department visits, mortality, and return to home. A population-level cohort of 64,105 incident admissions was captured. About two-thirds had great difficulty performing ADLs (65%) and had mild to severe cognitive impairment (66%); over 90% had great difficulty with instrumental ADLs. Just less than 50% of the new admissions were considered to be residents with high care needs (cognitively impaired with great ADL difficulty), while only 4.5% (2880 residents) had low care needs (cognition and ADL intact). Those with dementia (71.0%) and previous stroke (21.5%) were over-represented in the high needs group. Those that cannot be divertible to anywhere else but an institution with 24 hour nursing care comprised 41.3% (n = 26,502) of residents. Only 5.4% (n = 3483), based on community resources available, could potentially be cost-effectively diverted to the community. Those at higher needs experienced higher rates of mortality, higher total cost across all health sectors, and lower rates of return to home. The majority of those admitted into nursing homes have high levels of need (driven largely by dementia and stroke) and could not have their needs met cost-effectively elsewhere, suggesting that the system is at capacity. Caring for the long-term care needs of the aging population should consider the balance of investments in institution and community settings.


Evaluation of tracheal diameter after surgical tracheostomy.
The aim of this study was to evaluate the narrowing of the trachea in head and neck surgical patients who had undergone elective tracheostomy. This is a prospective study. Twenty-five patients were included in this study. All these patients had a preoperative elective tracheotomy, preceding major head and neck surgery for head and neck malignancies. An x-ray of the lateral soft tissue neck was taken after a minimum of 6 weeks after the dissimulation of tracheotomy tube. Diameter of the trachea above the stoma (around 2 cm below the cricoid ring that can be clearly seen in lateral x-ray corresponding to the second tracheal ring) was taken as controls. Data were entered into a computer database and statistically analyzed using SPSS for Windows (version 12.0; SPSS, Chicago, Ill). In addition to descriptive statistics for all patients, inferential statistics were used to compare the 2 tracheal diameters across all patients and within the subgroups of men and women. Associations between outcome and other variables were evaluated statistically using an chi 2 test for the categorical data. Other parametric and nonparametric statistical tests were used when appropriate. Criterion for statistical significance was set at P < .05 (Student t test and 2-tailed test). From this study, 92% (23/25) patients developed narrowing of trachea, all less than 50%. Very early decanulation of tracheotomy shows low or no narrowing at all. There is gradual narrowing in patients in whom dissimulations were performed after 14 days. Ethnicities of Indian decent (13/25) predominate in this study population. Male patients in this study have shorter decanulation period compared with female. Elective surgical tracheotomy is a relatively safe procedure resulting in minimum asymptomatic tracheal stenosis.


ATM-mediated DNA damage signals mediate immune escape through integrin-αvβ3-dependent mechanisms.
Although the tumor microenvironment plays a critical role in tumor progression and metastasis, the relationship between chemotherapy resistance and modulation of the tumor microenvironment remains unclear. Here, we report a novel mechanism showing how constitutive DNA damage signals in therapy-resistant tumor cells suppress antitumor immunity in an integrin-αvβ3-dependent manner. Integrin-αvβ3 was upregulated on various therapy-resistant tumor cells through chronic activation of ATM/Chk2-and NFκB-mediated pathways. Inhibiting tumor-specific expression of integrin-αvβ3 improved therapeutic responses to anticancer drugs by stimulating endogenous host immune systems. Mechanistic investigations revealed that tumor-specific integrin-αvβ3 expression targeted dendritic cells, facilitating their ability to phagocytose viable therapy-resistant tumor cells and thereby impaired their ability to cross-prime antigen-specific T lymphocytes. Together, our results clarify the detrimental effects of constitutive DNA damage signals to chemosensitivity and antitumor immunity. Furthermore, these findings suggest that integrin-αvβ3 targeting may benefit patients' refractory to current anticancer regimens by defeating DNA damage signaling-induced immune escape.


Identification of novel methyltransferases, Bmt5 and Bmt6, responsible for the m3U methylations of 25S rRNA in Saccharomyces cerevisiae.
RNA contains various chemical modifications that expand its otherwise limited repertoire to mediate complex processes like translation and gene regulation. 25S rRNA of the large subunit of ribosome contains eight base methylations. Except for the methylation of uridine residues, methyltransferases for all other known base methylations have been recently identified. Here we report the identification of BMT5 (YIL096C) and BMT6 (YLR063W), two previously uncharacterized genes, to be responsible for m3U2634 and m3U2843 methylation of the 25S rRNA, respectively. These genes were identified by RP-HPLC screening of all deletion mutants of putative RNA methyltransferases and were confirmed by gene complementation and phenotypic characterization. Both proteins belong to Rossmann-fold-like methyltransferases and the point mutations in the S-adenosyl-L-methionine binding pocket abolish the methylation reaction. Bmt5 localizes in the nucleolus, whereas Bmt6 is localized predominantly in the cytoplasm. Furthermore, we showed that 25S rRNA of yeast does not contain any m5U residues as previously predicted. With Bmt5 and Bmt6, all base methyltransferases of the 25S rRNA have been identified. This will facilitate the analyses of the significance of these modifications in ribosome function and cellular physiology.


Timing characterization of 100 GHz passively mode-locked discrete mode laser diodes.
We report on the characterization of the timing stability of passively mode-locked discrete mode diode laser sources. These are edge-emitting devices with a spatially varying refractive index profile for spectral filtering. Two devices with a mode-locking frequency of 100 GHz are characterized. The first device is designed to support a comb of six modes and generates near Fourier limited 1.9 ps pulses. The second supports four primary modes resulting in a sinusoidal modulation of the optical intensity. Using a cross-correlation technique, we measured a 20 fs pulse to pulse timing jitter for the first device, while, for the second device, a mode-beating (RF) linewidth of 1 MHz was measured using heterodyne mixing in a semiconductor optical amplifier. Comparison of these results with those obtained for an equivalent Fabry-Perot laser indicates that the spectral filtering mechanism employed does not adversely affect the timing properties of these passively mode-locked devices.


Partial development of the corpus callosum.
To determine whether the MR findings of callosal dysgenesis suggest that the partially formed corpus callosum in humans is the result of arrested growth or delayed continued development. The MR scans of 25 patients with callosal dysgenesis were reviewed to determine whether the observed corpus callosum corresponded to the form and position of a portion of a normal corpus callosum, as suggested by a theory of arrested growth. In 10 of the 25 cases, the partially formed corpus callosum corresponded to a portion of a normal corpus callosum. In the remaining 15 cases, the partially formed corpus callosum was located posterior to the expected location of a normal genu and inferior to the expected location of a normal body. Corpus callosum dysgenesis in humans may be caused by arrested growth in some cases; in other cases it is most likely caused by delayed continued development that attempts to compensate for earlier abnormalities in the evolution of midline structures.


House dust mite-driven asthma and allergen-specific T cells depend on B cells when the amount of inhaled allergen is limiting.
Allergic asthma is a CD4 TH2-lymphocyte driven disease characterized by airway hyperresponsiveness and eosinophilia. B cells can present antigens to CD4 T cells and produce IgE immunoglobulins that arm effector cells; however, mouse models are inconclusive on whether B cells are necessary for asthma development. We sought to address the role of B cells in a house dust mite (HDM)-driven TH2-high asthma mouse model. Wild-type and B cell-deficient muMT mice were sensitized and challenged through the airways with HDM extracts. The antigen-presenting capacities of B cells were studied by using new T-cell receptor transgenic 1-DER mice specific for the Der p 1 allergen. In vitro-activated B cells from HDM-exposed mice presented antigen to 1-DER T cells and induced a TH2 phenotype. In vivo B cells were dispensable for activation of naive 1-DER T cells but necessary for full expansion of primed 1-DER T cells. At high HDM challenge doses, B cells were not required for development of pulmonary asthmatic features yet contributed to TH2 expansion in the mediastinal lymph nodes but not in the lungs. When the amount of challenge allergen was decreased, muMT mice had reduced asthma features. Under these limiting conditions, B cells contributed also to expansion of TH2 effector cells in the lungs and central memory T cells in the mediastinal lymph nodes. B cells are a major part of the adaptive immune response to inhaled HDM allergen, particularly when the amount of inhaled allergen is low, by expanding allergen-specific T cells.


Discourse on safe drug use: symbolic logics and ethical aspects.
Drug safety is not a matter for healthcare professionals alone. Patients are also involved, at three different levels: (i) in the behaviours patients adopt to reduce the adverse effects of the drugs; (ii) in regard to what some doctors say to their patients about drug risks; and (iii) in what the pharmaceutical industry says about self-medication and risks. This article will examine these aspects on the basis of information gathered in France during anthropological studies on drug use. (i) Patients' concerns about reducing adverse effects give rise to a series of behaviours relating to drug use. Patients start with the identification of what they regard as a risk inherent in the substances or linked to the uncontrolled use of drugs, and try to neutralize the risk by modifying or modulating the prescriptions in line with various parameters. Dimensions as varied as the nature of the prescribed drugs, the quantity, the dosage and the preservation of certain functions or organs are taken into account, and patients follow their own rules of conduct in order to reduce risks. These dimensions bring into play characteristics of both the drug and the individual, and take into account the effects or the risks of drugs in their physical, psychic, behavioural and social aspects. (ii) Doctors' discourse towards patients regarding the risks and possible effects of drugs is examined, in particular the discourse of those who choose to hide the undesirable effects of drugs from their patients with the aim of not jeopardizing the patient's compliance. This situation involves comparing two logics: ethics of care versus ethics of information. (iii) Regarding the pharmaceutical industry's discourse on self-medication and risks, although on the one hand it promotes self-medication on the basis of patients' growing desire for autonomy and competency, on the other hand it discourages the use of the home medicine cabinet for reasons of safety, which questions the ability of patients to use drugs properly. This article aims to demonstrate that the various behaviours and discourses relating to the risks of drugs are embedded with symbolic, ethical and cultural logics. As a consequence, above and beyond work carried out on the question of pharmacovigilance, examining the issue of safe drug use involves studying the human - social and cultural - aspects that govern part of the behaviours and practices relating to drug safety.


Locations of Physical Activity as Assessed by GPS in Young Adolescents.
To compare adolescents' physical activity at home, near home, at school, near school, and at other locations. Adolescents (N = 549) were ages 12 to 16 years (49.9% girls, 31.3% nonwhite or Hispanic) from 447 census block groups in 2 US regions. Accelerometers and Global Positioning System devices assessed minutes of and proportion of time spent in moderate to vigorous physical activity (MVPA) in each of the 5 locations. Mixed-effects regression compared MVPA across locations and demographic factors. Forty-two percent of adolescents' overall MVPA occurred at school, 18.7% at home, 18.3% in other (nonhome, nonschool) locations, and 20.6% near home or school. Youth had 10 more minutes (30% more) of overall MVPA on school days than on nonschool days. However, the percentage of location time spent in MVPA was lowest at school (4.8% on school days) and highest near home and near school (9.5%-10.4%). Girls had 2.6 to 5.5 fewer minutes per day of MVPA than boys in all locations except near school. Although a majority of adolescents' physical activity occurred at school, the low proportion of active time relative to the large amount of time spent at school suggests potential for increasing school-based activity. Increasing time spent in the neighborhood appears promising for increasing overall physical activity, because a high proportion of neighborhood time was active. Increasing youth physical activity to support metabolic health requires strategies for increasing use of physical activity-supportive locations (eg, neighborhoods) and environmental and program improvements in unsupportive locations (eg, schools, homes).


The matrilineal ancestry of Ashkenazi Jewry: portrait of a recent founder event.
Both the extent and location of the maternal ancestral deme from which the Ashkenazi Jewry arose remain obscure. Here, using complete sequences of the maternally inherited mitochondrial DNA (mtDNA), we show that close to one-half of Ashkenazi Jews, estimated at 8,000,000 people, can be traced back to only 4 women carrying distinct mtDNAs that are virtually absent in other populations, with the important exception of low frequencies among non-Ashkenazi Jews. We conclude that four founding mtDNAs, likely of Near Eastern ancestry, underwent major expansion(s) in Europe within the past millennium.


Comparison of the effects of the mother and an unfamiliar adult female on cortisol and behavioral responses of pre- and postweaning guinea pigs.
In the guinea pig, the presence of the mother, but not littermates, has been found to inhibit hypothalamic-pituitary-adrenal (HPA) responses during brief (30-60 min) exposure to novel surroundings both prior to and several weeks following the completion of weaning. In the present study, we found that an unfamiliar adult female inhibited plasma cortisol and vocalization responses of pre- and postweaning guinea pigs during a 60-min exposure to a novel environment. However, the presence of the mother still had a greater effect on the cortisol levels of the young, at least during the preweaning period. The moderating influence of the unfamiliar adult female on vocalizations and cortisol levels occurred despite behavioral interactions, such as heightened aggression and sexual behavior, not seen during tests with the mother. It is suggested that the unfamiliar adult female's effectiveness in reducing HPA activity during exposure to novelty may facilitate the change in patterns of social interaction occurring in recently weaned animals.


Direct experimental observation of mesoscopic fluorous domains in fluorinated room temperature ionic liquids.
Fluorinated room temperature ionic liquids (FRTILs) represent a class of solvent media that are attracting great attention due to their IL-specific properties as well as features stemming from their fluorous nature. Medium-to-long fluorous tails constitute a well-defined apolar moiety in the otherwise polar environment. Similarly to the case of alkyl tails, such chains are expected to result in the formation of self-assembled fluorous domains. So far, however, no direct experimental observation has been made of the existence of such structural heterogeneities on the nm scale. We report here the first experimental evidence of the existence of mesoscopic spatial segregation of fluorinated domains, on the basis of highly complementary X-ray and neutron scattering data sets (highlighting the importance of the latter probe) and NMR spectroscopy. Data are interpreted using atomistic molecular dynamics simulations, emphasizing the existence of a self-assembly mechanism that delivers segregated fluorous domains, where preferential solubilisation of fluorinated compounds can occur, thus paving the way for several smart applications.


Reduced model-based decision-making in schizophrenia.
Individuals with schizophrenia have a diminished ability to use reward history to adaptively guide behavior. However, tasks traditionally used to assess such deficits often rely on multiple cognitive and neural processes, leaving etiology unresolved. In the current study, we adopted recent computational formalisms of reinforcement learning to distinguish between model-based and model-free decision-making in hopes of specifying mechanisms associated with reinforcement-learning dysfunction in schizophrenia. Under this framework, decision-making is model-free to the extent that it relies solely on prior reward history, and model-based if it relies on prospective information such as motivational state, future consequences, and the likelihood of obtaining various outcomes. Model-based and model-free decision-making was assessed in 33 schizophrenia patients and 30 controls using a 2-stage 2-alternative forced choice task previously demonstrated to discern individual differences in reliance on the 2 forms of reinforcement-learning. We show that, compared with controls, schizophrenia patients demonstrate decreased reliance on model-based decision-making. Further, parameter estimates of model-based behavior correlate positively with IQ and working memory measures, suggesting that model-based deficits seen in schizophrenia may be partially explained by higher-order cognitive deficits. These findings demonstrate specific reinforcement-learning and decision-making deficits and thereby provide valuable insights for understanding disordered behavior in schizophrenia. (PsycINFO Database Record


Tight junction assembly during mouse blastocyst formation is regulated by late expression of ZO-1 alpha+ isoform.
The mouse preimplantation embryo has been used to investigate the de novo synthesis of tight junctions during trophectoderm epithelial differentiation. We have shown previously that individual components of the tight junction assemble in a temporal sequence, with membrane assembly of the cytoplasmic plaque protein ZO-1 occurring 12 hours before that of cingulin. Subsequently, two alternatively spliced isoforms of ZO-1 (alpha+ and alpha-), differing in the presence or absence of an 80 residue alpha domain were reported. Here, the temporal and spatial expression of these ZO-1 isoforms has been investigated at different stages of preimplantation development. ZO-1alpha- mRNA was present in oocytes and all preimplantation stages, whilst ZO-1alpha+ transcripts were first detected in embryos at the morula stage, close to the time of blastocoele formation. mRNAs for both isoforms were detected in trophectoderm and ICM cells. Immunoprecipitation of 35S-labelled embryos also showed synthesis of ZO-1alpha- throughout cleavage, whereas synthesis of ZO-1alpha+ was only apparent from the blastocyst stage. In addition, 33P-labelling showed both isoforms to be phosphorylated at the early blastocyst stage. The pattern and timing of membrane assembly of the two isoforms was also distinct. ZO-1alpha- was initially seen as punctate sites at the cell-cell contacts of compact 8-cell embryos. These sites then coalesced laterally along the membrane until they completely surrounded each cell with a zonular belt by the late morula stage. ZO-1alpha+ however, was first seen as perinuclear foci in late morulae before assembling at the tight junction. Membrane assembly of ZO-1alpha+ first occurred during the 32-cell stage and was zonular just prior to the early blastocyst stage. Immunostaining indicative of both isoforms was restricted to the trophectoderm lineage. Membrane assembly of ZO-1alpha+ and blastocoele formation were sensitive to brefeldin A, an inhibitor of intracellular trafficking beyond the Golgi complex. In addition, the tight junction transmembrane protein occludin co-localised with ZO-1alpha+ at the perinuclear sites in late morulae and at the newly assembled cell junctions. These results provide direct evidence from a native epithelium that ZO-1 isoforms perform distinct roles in tight junction assembly. Moreover, the late expression of ZO-1alpha+ and its apparent intracellular interaction with occludin may act as a final rate-limiting step in the synthesis of the tight junction, thereby regulating the time of junction sealing and blastocoele formation in the early embryo.


Anti-Th/To are common antinucleolar autoantibodies in Italian patients with scleroderma.
Patients with scleroderma (systemic sclerosis; SSc) can be classified into subsets based on autoantibody profile and clinical features. Specificities such as anti-Th/To and anti-fibrillarin (U3RNP) are detectable mainly by immunoprecipitation (IP), which is not widely used in clinical laboratories. We examined the autoantibody profiles and clinical manifestations in a cohort of Italian patients with SSc, focusing on anti-Th/To and anticentromere (ACA) antibodies, associated with limited cutaneous SSc (lcSSc). Sera from 216 consecutive patients with SSc were tested for ACA (by indirect immunofluorescence), antitopoisomerase I (topo I; by counterimmunoelectrophoresis), and anti-RNA polymerase III (RNAPIII; by ELISA). Forty-one sera negative for these specificities were tested by IP analysis of proteins ((35)S-methionine labeled K562 cell extract) and RNA (silver staining). Among 216 SSc patients analyzed, anti-topo I, ACA, and anti-RNAPIII were detected in 38% (81/216), 31% (67/216) and 7% (15/216), respectively. Among 41 sera negative for ACA, anti-topo I, and anti-RNAPIII and which were tested by IP, 14 were nucleolar stain-positive. Eight out of 14 (57%) showed anti-Th/To reactivity, but no anti-U3RNP was found. In comparison with ACA-positive patients, anti-Th/To-positive patients were younger (p = 0.0046) and more commonly were male (p = 0.0006). All 8 anti-Th/To-positive and all but one ACA-positive patients had lcSSc. Interstitial lung disease (ILD) and pericarditis were more frequent in anti-Th/To-positive patients. Anti-Th/To are common in antinucleolar antibody-positive Italian patients with SSc. Anti-Th/To and ACA patients had lcSSc, with excellent prognosis. The anti-Th/To group had frequent pericarditis and ILD, although impairment of pulmonary function appeared mild.


Effects of cyanobacterial lipopolysaccharides from microcystis on glutathione-based detoxification pathways in the zebrafish (Danio rerio) embryo.
Cyanobacteria ("blue-green algae") are recognized producers of a diverse array of toxic secondary metabolites. Of these, the lipopolysaccharides (LPS), produced by all cyanobacteria, remain to be well investigated. In the current study, we specifically employed the zebrafish (Danio rerio) embryo to investigate the effects of LPS from geographically diverse strains of the widespread cyanobacterial genus, Microcystis, on several detoxifying enzymes/pathways, including glutathione-S-transferase (GST), glutathione peroxidase (GPx)/glutathione reductase (GR), superoxide dismutase (SOD), and catalase (CAT), and compared observed effects to those of heterotrophic bacterial (i.e., E. coli) LPS. In agreement with previous studies, cyanobacterial LPS significantly reduced GST in embryos exposed to LPS in all treatments. In contrast, GPx moderately increased in embryos exposed to LPS, with no effect on reciprocal GR activity. Interestingly, total glutathione levels were elevated in embryos exposed to Microcystis LPS, but the relative levels of reduced and oxidized glutathione (i.e., GSH/GSSG) were, likewise, elevated suggesting that oxidative stress is not involved in the observed effects as typical of heterotrophic bacterial LPS in mammalian systems. In further support of this, no effect was observed with respect to CAT or SOD activity. These findings demonstrate that Microcystis LPS affects glutathione-based detoxification pathways in the zebrafish embryo, and more generally, that this model is well suited for investigating the apparent toxicophore of cyanobacterial LPS, including possible differences in structure-activity relationships between heterotrophic and cyanobacterial LPS, and teleost fish versus mammalian systems.


flu, a metastable gene controlling surface properties of Escherichia coli.
flu, a gene of Escherichia coli K-12, was discovered and mapped between his and shiA. It is shown that flu is a metastable gene that changes frequently between the flu+ and flu states. flu+ variants give stable homogeneous suspensions, are piliated, and form glossy colonies. flu variants aggregate, fluff and sediment from suspensions, are nonpiliated, and form frizzy colonies. flu+ and flu variants can be isolated from most strains. Implications of these observations are discussed, and it is demonstrated that flu+ variants of strain P678-54 yield three times more minicells than flu variants.


Impact of siRNA overhangs for dendrimer-mediated siRNA delivery and gene silencing.
Small interfering RNA (siRNA) have attracted considerable attention, as compelling therapeutics providing safe and competent delivery systems are available. Dendrimers are emerging as appealing siRNA delivery vectors thanks to their unique, well-defined architecture and the resulting cooperativity and multivalency confined within a nanostructure. We have recently disclosed the structurally flexible fifth-generation TEA-core PAMAM dendrimer (G5) as an effective nanocarrier for delivery of sticky siRNA bearing long complementary sequence overhangs (dA)n/(dT)n (n = 5 or 7). Here, using combined experimental/computational approaches, we successfully clarified (i) the underlying mechanisms of interaction between the dendrimer nanovector G5 and siRNA molecules bearing either complementary or noncomplementary sequence overhangs of different length and chemistry and (ii) the impact of siRNA overhangs contributing toward the improved delivery potency. Using siRNA with complementary overhangs offer the best action in term of gene silencing through the formation of concatemers, that is, supramolecular structures resulting from synergistic and cooperative binding via (dA)n/(dT)n bridges (n = 5 or 7). On the other hand, although siRNA bearing long, noncomplementary overhangs (dA)n/(dA)n or (dT)n/(dT)n (n = 5 or 7) are endowed with considerably higher gene silencing potency than normal siRNA with (dT)2/(dT)2, they remain less effective than their sticky siRNA counterparts. The observed gene silencing potency depends on length, nature, and flexibility of the overhangs, which behave as a sort of clamps that hold and interact with the dendrimer nanovectors, thus impacting siRNA delivery performance and, ultimately, gene silencing. Our findings can be instrumental in designing siRNA entities with enhanced capability to achieve effective RNA interference for therapeutic applications.


Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C.
Liver fibrosis is the main predictor of the progression of chronic hepatitis C, and its assessment by liver biopsy (LB) can help determine therapy. However, biopsy is an invasive procedure with several limitations. A new, noninvasive medical device based on transient elastography has been designed to measure liver stiffness. The aim of this study was to investigate the use of liver stiffness measurement (LSM) in the evaluation of liver fibrosis in patients with chronic hepatitis C. We prospectively enrolled 327 patients with chronic hepatitis C in a multicenter study. Patients underwent LB and LSM. METAVIR liver fibrosis stages were assessed on biopsy specimens by 2 pathologists. LSM was performed by transient elastography. Efficiency of LSM and optimal cutoff values for fibrosis stage assessment were determined by a receiver-operating characteristics (ROC) curve analysis and cross-validated by the jack-knife method. LSM was well correlated with fibrosis stage (Kendall correlation coefficient: 0.55; P < .0001). The areas under ROC curves were 0.79 (95% CI, 0.73-0.84) for F > or =2, 0.91 (0.87-0.96) for F > or =3, and 0.97 (0.93-1) for F=4; for larger biopsies, these values were, respectively, 0.81, 0.95, and 0.99. Optimal stiffness cutoff values of 8.7 and 14.5 kPa showed F > or =2 and F=4, respectively. In conclusion, noninvasive assessment of liver stiffness with transient elastography appears as a reliable tool to detect significant fibrosis or cirrhosis in patients with chronic hepatitis C.


Hyperventilation alters colonic motor and sensory function: effects and mechanisms in humans.
BACKGROUND & AIMS. Hyperventilation-induced hypocapnia affects hemodynamic function and enhances colonic motility. The aims of this study were to determine the effects of hypocapnic hyperventilation on colonic motility and sensation in health and to explore the putative neurohumoral mechanisms. In experiment 1, colonic tone, sensation, plasma levels of cortisol, beta-endorphin, selected gut neuropeptides, norepinephrine, epinephrine, and splanchnic blood volume were measured during two sequences of hypocapnic hyperventilation. In experiment 2, colonic tone and sensation were assessed during eucapnic hyperventilation and abdominal compression. Hypocapnic hyperventilation, but not eucapnic hyperventilation or abdominal compression, significantly increased colonic tone and sensitivity to balloon distention (P = 0.017) without altering humoral mediators or splanchnic blood volume. Plasma norepinephrine level increased (P = 0.017) and splanchnic blood volume decreased (P = 0.028) during 5 minutes after hyperventilation, consistent with homeostatic responses. Increased colonic tone and sensation during hypocapnic hyperventilation are not caused by colonic compression. These effects of hyperventilation are not mediated humorally but may result from direct metabolic effects of hypocapnia on colonic muscle or from changes in central autonomic control of colonic smooth muscle.


Association of RAGE gene four single nucleotide polymorphisms with the risk, invasion, metastasis and overall survival of gastric cancer in Chinese.
Objectives: The receptor for advanced glycation end products (RAGE) is an oncogenic trans-membranous receptor expressed in many cells. The aim of this study was to clarify the association between RAGE gene 4 single nucleotide polymorphisms (SNPs) and the risk, invasion, metastasis and overall survival of gastric cancer. Methods and Results: We performed a hospital-based case-control study involving 369 gastric cancer patients and 493 cancer free controls. Four widely-studied SNPs, rs1800625 (T-429C), rs1800624 (T-374A), rs2070600 (Gly82Ser) and rs184003 (G1704T) in RAGE gene, were genotyped by the polymerase chain reaction - ligase detection reaction method. The RAGE gene rs1800625 TT genotype and T allele were significantly associated with a reduced risk of gastric cancer (TT vs. CC: adjusted odds ratio [OR]: 0.72, 95% CI: 0.55-0.95, p=0.021; T vs. C: adjusted OR: 0.67, 95% CI: 0.46-0.97, p=0.032). No hints of significance were detected for the other three SNPs in association with gastric cancer risk. Moreover, rs1800625 and rs184003 were significantly associated with tumor clinical stage (p=0.010 and 0.032, respectively). Survival curves differed significantly between the genotypes of rs1800625. Conclusions: RAGE gene SNP rs1800625 was significantly associated with gastric cancer risk, and rs1800625 and rs184003 were related to tumor clinical stage, indicating that RAGE gene may be a gastric cancer-susceptibility gene.


Mobile health units. Design and implementation considerations.
The decision to provide health care services with a mobile van is one which educational and service facilities are increasingly pursuing. The benefits include: The potential to increase the availability of services to underserved populations where access to care is perceived to be one reason for underuse of available services. The opportunity to increase and broaden the educational experiences of students in a training program. The opportunity to develop a sense of social responsibility in the health care provider. The process of deciding to pursue a van purchase is complicated, and administrators may best be served by obtaining experienced consultants to help them fully comprehend the issues involved. After the decision to purchase a mobile unit is made, it is necessary to focus on van requirements and design to meet federal, state, and city codes concerning motor vehicles and health requirements. Some modifications of one's standard practices are needed because of these codes. Being aware of them in advance will allow a smooth project completion. This article provides information about some of the steps required to implement a mobile unit. The approximate time from initial concept to van delivery was 1 year, with one fully dedicated project coordinator working to assure the project's success in such a short time frame. Seeing the gratified personnel and students who serve the children on the "Smiling Faces, Going Places" Mobile Dental Van of the NYUCD (see Figure 2), and knowing the children would otherwise not have received such services, allows the health care professionals involved to feel the development of this van is an exciting mechanism for delivery of health care to individuals who would otherwise go without.


Training Preferences of School Food Service Staff Vary by Role in the School Nutrition Program.
Professional development has been identified as a critical component for school nutrition professionals (SNPs) to successfully implement school meal standards in the United States. However, training needs may vary based on different factors. This study examined (1) the topics of highest priority for SNPs; (2) preferred learning methods; (3) where and when trainings should be conducted; and (4) whether responses differ according to important factors including position type, school locale (urban vs. rural), or job experience. Participants completed surveys that included questions on demographics and preferences for learning methods and training topics (n = 492). Descriptive statistics characterized survey responses. Chi square tests assessed differences in learning method and training topic preferences by participant role, locale, and job experience; Cramer's V assessed the strength of association for each chi square result. Qualitative responses to open-ended questions were analyzed using an inductive thematic analysis method. Nearly all training topic preferences were significantly different (p < 0.001 using Bonferroni method) when stratified by role. Significant differences were also observed for school locale and years of experience, but to a lesser degree. There was less variation in learning method preferences across staff role. Qualitative results (n = 93) identified three key themes related to training needs: role-specific trainings, innovative learning methods, and geographic access. The combination of quantitative and qualitative analysis indicate that professional development for SNPs should mostly be conducted in-person, be easily accessible, and include hands-on activities. Further, training should be tailored by job role and address situational barriers unique to the geographic area.


Host-guest chemistry with water-soluble gold nanoparticle supraspheres.
The uptake of molecular guests, a hallmark of the supramolecular chemistry of cages and containers, has yet to be documented for soluble assemblies of metal nanoparticles. Here we demonstrate that gold nanoparticle-based supraspheres serve as a host for the hydrophobic uptake, transport and subsequent release of over two million organic guests, exceeding by five orders of magnitude the capacities of individual supramolecular cages or containers and rivalling those of zeolites and metal-organic frameworks on a mass-per-volume basis. The supraspheres are prepared in water by adding hexanethiol to polyoxometalate-protected 4 nm gold nanoparticles. Each 200 nm assembly contains hydrophobic cavities between the estimated 27,400 gold building blocks that are connected to one another by nanometre-sized pores. This gives a percolated network that effectively absorbs large numbers of molecules from water, including 600,000, 2,100,000 and 2,600,000 molecules (35, 190 and 234 g l-1) of para-dichorobenzene, bisphenol A and trinitrotoluene, respectively.


Competition for actin between two distinct F-actin networks defines a bistable switch for cell polarization.
Symmetry-breaking polarization enables functional plasticity of cells and tissues and is yet not well understood. Here we show that epithelial cells, hard-wired to maintain a static morphology and to preserve tissue organization, can spontaneously switch to a migratory polarized phenotype after relaxation of the actomyosin cytoskeleton. We find that myosin II engages actin in the formation of cortical actomyosin bundles and thus makes it unavailable for deployment in the process of dendritic growth normally driving cell motility. Under low-contractility regimes, epithelial cells polarize in a front-back manner owing to the emergence of actin retrograde flows powered by dendritic polymerization of actin. Coupled to cell movement, the flows transport myosin II from the front to the back of the cell, where the motor locally 'locks' actin in contractile bundles. This polarization mechanism could be employed by embryonic and cancer epithelial cells in microenvironments where high-contractility-driven cell motion is inefficient.


Expressed Vomeronasal Type-1 Receptors (V1rs) in Bats Uncover Conserved Sequences Underlying Social Chemical Signaling.
In mammals, social and reproductive behaviors are mediated by chemical cues encoded by hyperdiverse families of receptors expressed in the vomeronasal organ. Between species, the number of intact receptors can vary by orders of magnitude. However, the evolutionary processes behind variation in receptor number, and its link to fitness-related behaviors are not well understood. From vomeronasal transcriptomes, we discovered the first evidence of intact vomeronasal type-1 receptor (V1r) genes in bats, and we tested whether putatively functional bat receptors were orthologous to those of related taxa, or whether bats have evolved novel receptors. Instead of lineage-specific duplications, we found that bat V1rs show high levels of orthology to those of their relatives, and receptors are under comparative levels of purifying selection as non-bats. Despite widespread vomeronasal organ loss in bats, V1r copies have been retained for >65 million years. The highly conserved nature of bat V1rs challenges our current understanding of mammalian V1r function and suggests roles other than conspecific recognition or mating initiation in social behavior.


Evaluation of leaf aqueous extract and synthesized silver nanoparticles using Nerium oleander against Anopheles stephensi (Diptera: Culicidae).
Green nanoparticle synthesis has been achieved using environmentally acceptable plant extract and ecofriendly reducing and capping agents. The present study was carried out to establish the larvicidal activity of synthesized silver nanoparticles (AgNPs) using leaf extract of Nerium oleander (Apocynaceae) against the first to fourth instar larvae and pupae of malaria vector, Anopheles stephensi (Diptera: Culicidae). Nanoparticles are being used in many commercial applications. It was found that aqueous silver ions can be reduced by the aqueous extract of the plant parts to generate extremely stable silver nanoparticles in water. The results were recorded from UV-Vis spectrum, Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and energy-dispersive X-ray (EDX) spectroscopy analysis. The production of the AgNPs synthesized using leaf extract of N. oleander was evaluated through a UV-Vis spectrophotometer in a wavelength range of 200 to 700 nm. This revealed a peak at 440 nm in N. oleander leaf extracts, indicating the production of AgNPs. The FTIR spectra of AgNPs exhibited prominent peaks at 509.12 cm(-1) (C-H bend alkenes), 1,077.05 cm(-1) (C-O stretch alcohols), 1,600.63 cm(-1) (N-H bend amines), 2,736.49 and 2,479.04 cm(-1) (O-H stretch carboxylic acids), and 3,415.31 cm(-1) (N-H stretching due to amines group). An SEM micrograph showed 20-35-nm-size aggregates of spherical- and cubic-shaped nanoparticles. EDX showed the complete chemical composition of the synthesized nanoparticles of silver. Larvicidal activity of aqueous leaf extract of N. oleander and synthesized AgNPs was carried out against Anopheles stephensi, and the results showed that the highest larval mortality was found in the synthesized AgNPs against the first to fourth instar larvae and pupae of Anopheles stephensi with the following values: LC(50) of instar larvae 20.60, 24.90, 28.22, and 33.99 ppm; LC(90) of instar larvae 41.62, 50.33, 57.78, and 68.41 ppm; and LC(50) and LC(90) of pupae 39.55 and 79.10 ppm, respectively. The aqueous leaf extract exhibited larval toxicity against the first to fourth instar larvae and pupae of Anopheles stephensi with the following values: LC(50) of instar larvae 232.90, 273.71, 318.94, and 369.96 ppm; LC(90) of instar larvae 455.95, 563.10, 639.86, and 730.30 ppm; and LC(50) and LC(90) of pupae 426.01 and 805.13 ppm, respectively. The chi-square value was significant at p < 0.05 level. The possible larvicidal activity may be due to penetration of nanoparticles through a membrane. The results could suggest that the use of plant N. oleander to synthesize silver nanoparticles is a rapid, environmentally safer, and greener approach for mosquito control. This could lead us to a new possibility in vector-control strategy.