Regional differences of tachykinin effects on smooth muscle and pacemaker potentials of the stomach, duodenum, ileum and colon of an emetic model, the house musk shrews.

BACKGROUND AND AIMS: The contractile effects of tachykinins on the gastrointestinal tract are well-known, but how they modulate slow-waves, particularly in species capable of emesis, remains largely unknown. We aimed to elucidate the effects of tachykinins on myoelectric and contractile activity of isolated gastrointestinal tissues of the Suncus murinus. METHODS: The effects of substance P (SP), neurokinin (NK)A, NKB and selective NK1 (CP122,721, CP99,994), NK2 (SR48,968, GR159,897) and NK3 (SB218,795, SB222,200) receptor antagonists on isolated stomach, duodenum, ileum and colon segments were studied. Mechanical contractile activity was recorded using isometric force displacement transducers. Electrical pacemaker activity was recorded using a microelectrode array. RESULTS: Compared with NKA, SP induced larger contractions in stomach tissue and smaller contractions in intestinal segments, where oscillation magnitudes increased in intestinal segments, but not the stomach. CP122,721 and GR159,897 inhibited electrical field stimulation-induced contractions of the stomach, ileum and colon. NKB and NK3 had minor effects on contractile activity. The inhibitory potencies of SP and NKA on the peristaltic frequency of the colon and ileum, respectively, were correlated with those on electrical pacemaker frequency. SP, NKA and NKB inhibited pacemaker activity of the duodenum and ileum, but increased that of the stomach and colon. SP elicited a dose-dependent contradictive pacemaker frequency response in the colon. CONCLUSION: This study revealed distinct effects of tachykinins on the mechanical and electrical properties of the stomach and colon vs. the proximal intestine, providing a unique aspect on neuromuscular correlation in terms of the effects of tachykinin on peristaltic and pacemaker activity in gastrointestinal-related symptoms.

Fast Ion-Beam Inactivation of Viruses, Where Radiation Track Structure Meets RNA Structural Biology.

Here we show an interplay between the structures present in ionization tracks and nucleocapsid RNA structural biology, using fast ion-beam inactivation of the severe acute respiratory syndrome coronavirus (SARS-CoV) virion as an example. This interplay could be a key factor in predicting dose-inactivation curves for high-energy ion-beam inactivation of virions. We also investigate the adaptation of well-established cross-section data derived from radiation interactions with water to the interactions involving the components of a virion, going beyond the density-scaling approximation developed previously. We conclude that solving one of the grand challenges of structural biology - the determination of RNA tertiary/quaternary structure - is linked to predicting ion-beam inactivation of viruses and that the two problems can be mutually informative. Indeed, our simulations show that fast ion beams have a key role to play in elucidating RNA tertiary/quaternary structure.

Experience of clinical services shapes attitudes to mental health data sharing: findings from a UK-wide survey.

BACKGROUND: Routinely-collected mental health data could deliver novel insights for mental health research. However, patients' willingness to share their mental health data remains largely unknown. We investigated factors influencing likelihood of sharing these data for research purposes amongst people with and without experience of mental illness. METHODS: We collected responses from a diverse sample of UK National Health Service (NHS) users (n = 2187) of which about half (n = 1087) had lifetime experience of mental illness. Ordinal logistic regression was used to examine the influence of demographic factors, clinical service experience, and primary mental illness on willingness to share mental health data, contrasted against physical health data. RESULTS: There was a high level of willingness to share mental (89.7%) and physical (92.8%) health data for research purposes. Higher levels of satisfaction with the NHS were associated with greater willingness to share mental health data. Furthermore, people with personal experience of mental illness were more willing than those without to share mental health data, once the variable of NHS satisfaction had been controlled for. Of the mental illnesses recorded, people with depression, obsessive-compulsive disorder (OCD), personality disorder or bipolar disorder were significantly more likely to share their mental health data than people without mental illness. CONCLUSIONS: These findings suggest that positive experiences of health services and personal experience of mental illness are associated with greater willingness to share mental health data. NHS satisfaction is a potentially modifiable factor that could foster public support for increased use of NHS mental health data in research.

Involvement of TRPV1 and TRPA1 in the modulation of pacemaker potentials in the mouse ileum.

BACKGROUND: The roles of transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and subfamily A, member 1 (TRPA1) in mechanisms of gastrointestinal motility are complex. This study aimed to clarify the effects of several TRPV1 and TRPA1 ligands on the electrical potentials generated by pacemaker cells in the mouse-isolated ileum. METHOD: The pacemaker potentials of ileal segments of mice were recorded extracellularly using a 60-channel microelectrode array. The dominant frequencies, average waveform periods and propagation velocities were quantified. The effects of TRPV1 and TRPA1 agonist and antagonist were compared with the baseline recordings. RESULTS: The electrophysiological recordings showed that capsaicin (30 µM to 3 mM), resiniferatoxin (300 µM), capsazepine (100-300 µM), allyl isothiocyanate (300 µM), isovelleral (300 µM), icilin (300 µM), A-967,079 (10 µM), AP18 (20 µM) and HC-030,031 (50 µM) significantly reduced the pacemaker frequency and increased the waveform period relative to the baseline. Conversely, ruthenium red (300 µM) significantly increased the pacemaker frequency and reduced the waveform period. Capsaicin (3 mM) and AP18 (20 µM) also significantly reduced the propagation velocity. However, all tested antagonists failed to inhibit the effects of agonists. AMG9810 (300 µM), but not A-967,079 (300 µM), significantly inhibited the increases in pacemaker frequency caused by increased temperatures. CONCLUSION: Our findings suggest that TRPV1 and TRPA1 play a minor role in regulating pacemaker potentials and that at non-specific actions at other TRP and ion channels most likely contributed to the overall effects on the electrophysiological recordings that we observed.

Parenchyma-stromal interleukin-1 alpha and interleukin-6 overexpressions in ameloblastoma correlate with the aggressive phenotype.

INTRODUCTION: Ameloblastoma is a benign but locally invasive odontogenic epithelial neoplasm with a high recurrence rate after treatment. The two main subsets encountered clinically are unicystic (UA) and solid/multicystic ameloblastoma (SMA). Currently neoplastic progression of many tumour types are believed to be related to parenchyma-stromal cell-cell interactions mediated by cytokines notably interleukins (IL). However their roles in ameloblastoma remain ill-understood. MATERIALS AND METHODS: Thirty-nine formalin-fixed paraffin-embedded ameloblastoma cases comprising unicystic ameloblastoma (n=19) and solid/multicystic ameloblastoma (n=20) were subjected to IHC staining for IL-1α, IL-1ß, IL-6 and IL-8. A semi-quantitative method was used to evaluate the expression levels of these cytokines according to cell types in the tumoural parenchyma and stroma. RESULTS: Major findings were upregulations of IL-1α and IL-6 in SMA compared to UA. Both cytokines were heterogeneously detected in the tumoural parenchyma and stroma. Within the neoplastic epithelial compartment, IL-1α expression was more frequently detected in PA-like cells in UA whereas it was more frequently encountered in SR-like cells in SMA. IL-6 demonstrated higher expression levels in the stromal compartment of SMA. IL-1ß and IL-8 were markedly underexpressed in both tumour subsets. CONCLUSIONS: Overexpression of IL-1α in SMA suggests that this growth factor might play a role in promoting bone resorption and local invasiveness in this subtype. The expression levels of IL-1α and IL-6 in three cellular localizations indicate that parenchymal-stromal components of ameloblastoma interact reciprocally via IL-1α and IL-6 to create a microenvironment conducive for tumour progression.

Morphoregulatory functions of the RNA-binding motif protein 3 in cell spreading, polarity and migration.

RNA-binding proteins are emerging as key regulators of transitions in cell morphology. The RNA-binding motif protein 3 (RBM3) is a cold-inducible RNA-binding protein with broadly relevant roles in cellular protection, and putative functions in cancer and development. Several findings suggest that RBM3 has morphoregulatory functions germane to its roles in these contexts. For example, RBM3 helps maintain the morphological integrity of cell protrusions during cell stress and disease. Moreover, it is highly expressed in migrating neurons of the developing brain and in cancer invadopodia, suggesting roles in migration. We here show that RBM3 regulates cell polarity, spreading and migration. RBM3 was present in spreading initiation centers, filopodia and blebs that formed during cell spreading in cell lines and primary myoblasts. Reducing RBM3 triggered exaggerated spreading, increased RhoA expression, and a loss of polarity that was rescued by Rho kinase inhibition and overexpression of CRMP2. High RBM3 expression enhanced the motility of cells migrating by a mesenchymal mode involving extension of long protrusions, whereas RBM3 knockdown slowed migration, greatly reducing the ability of cells to extend protrusions and impairing multiple processes that require directional migration. These data establish novel functions of RBM3 of potential significance to tissue repair, metastasis and development.

Genetic risk of major depressive disorder: the moderating and mediating effects of neuroticism and psychological resilience on clinical and self-reported depression.

BACKGROUND: Polygenic risk scores (PRS) for depression correlate with depression status and chronicity, and provide causal anchors to identify depressive mechanisms. Neuroticism is phenotypically and genetically positively associated with depression, whereas psychological resilience demonstrates negative phenotypic associations. Whether increased neuroticism and reduced resilience are downstream mediators of genetic risk for depression, and whether they contribute independently to risk remains unknown. METHODS: Moderating and mediating relationships between depression PRS, neuroticism, resilience and both clinical and self-reported depression were examined in a large, population-based cohort, Generation Scotland: Scottish Family Health Study (N = 4166), using linear regression and structural equation modelling. Neuroticism and resilience were measured by the Eysenck Personality Scale Short Form Revised and the Brief Resilience Scale, respectively. RESULTS: PRS for depression was associated with increased likelihood of self-reported and clinical depression. No interaction was found between PRS and neuroticism, or between PRS and resilience. Neuroticism was associated with increased likelihood of self-reported and clinical depression, whereas resilience was associated with reduced risk. Structural equation modelling suggested the association between PRS and self-reported and clinical depression was mediated by neuroticism (43-57%), while resilience mediated the association in the opposite direction (37-40%). For both self-reported and clinical diagnoses, the genetic risk for depression was independently mediated by neuroticism and resilience. CONCLUSIONS: Findings suggest polygenic risk for depression increases vulnerability for self-reported and clinical depression through independent effects on increased neuroticism and reduced psychological resilience. In addition, two partially independent mechanisms - neuroticism and resilience - may form part of the pathway of vulnerability to depression.

Intelligence and neuroticism in relation to depression and psychological distress: Evidence from two large population cohorts.

BACKGROUND: Neuroticism is a risk factor for selected mental and physical illnesses and is inversely associated with intelligence. Intelligence appears to interact with neuroticism and mitigate its detrimental effects on physical health and mortality. However, the inter-relationships of neuroticism and intelligence for major depressive disorder (MDD) and psychological distress has not been well examined. METHODS: Associations and interactions between neuroticism and general intelligence (g) on MDD, self-reported depression, and psychological distress were examined in two population-based cohorts: Generation Scotland: Scottish Family Health Study (GS:SFHS, n=19,200) and UK Biobank (n=90,529). The Eysenck Personality Scale Short Form-Revised measured neuroticism and g was extracted from multiple cognitive ability tests in each cohort. Family structure was adjusted for in GS:SFHS. RESULTS: Neuroticism was strongly associated with increased risk for depression and higher psychological distress in both samples. Although intelligence conferred no consistent independent effects on depression, it did increase the risk for depression across samples once neuroticism was adjusted for. Results suggest that higher intelligence may ameliorate the association between neuroticism and self-reported depression although no significant interaction was found for clinical MDD. Intelligence was inversely associated with psychological distress across cohorts. A small interaction was found across samples such that lower psychological distress associates with higher intelligence and lower neuroticism, although effect sizes were small. CONCLUSIONS: From two large cohort studies, our findings suggest intelligence acts a protective factor in mitigating the effects of neuroticism on psychological distress. Intelligence does not confer protection against diagnosis of depression in those high in neuroticism.

Associations of the CYP3A5*3 and CYP3A4*1G polymorphisms with the pharmacokinetics of oral midazolam and the urinary 6ß-hydroxycortisol/cortisol ratio as markers of CYP3A activity in healthy male Chinese.

WHAT IS KNOWN AND OBJECTIVE: The oral plasma clearance of midazolam and the ratio of 6ß-hydroxycortisol (6ß-OHF) to cortisol (F) in urine are two potential markers for evaluating CYP3A activity in vivo. We assessed the influence of two common CYP3A polymorphisms on the pharmacokinetics of oral midazolam and urinary ratio of 6ß-OHF/F in healthy Chinese. METHODS: Single oral 15 mg doses of midazolam were given to 20 healthy male Chinese subjects who were genotyped for the CYP3A5*3 and CYP3A4*1G polymorphisms. The plasma concentrations of midazolam were determined by LC/MS/MS. Morning urine samples were collected after overnight fasting, and urine F and 6ß-OHF concentrations were measured using UPLC. RESULTS AND DISCUSSION: There were no significant correlations between the pharmacokinetic parameters of midazolam and urinary ratios of 6ß-OHF/F. The CYP3A polymorphisms examined had no significant associations with the urinary ratios of 6ß-OHF/F or the pharmacokinetics of midazolam. However, diplotype analysis suggested that CYP3A5 expressers with the CYP3A4*1/*1G genotype (n = 3) had significantly lower midazolam AUC0-∞ values (210·0 ± 33·5 vs. 313·9 ± 204·6 h∙ng/mL, P = 0·044) and higher CL/F values (1·16 ± 0·16 vs. 0·88 ± 0·48 L/h/kg, P = 0·005) compared to subjects with the CYP3A4*1/*1 genotype (n = 4), which is consistent with some previous studies with tacrolimus. WHAT IS NEW AND CONCLUSION: There were no significant associations between midazolam pharmacokinetic parameters and urinary ratios of 6ß-OHF/F and the two CYP3A polymorphisms were not associated with the urinary ratios of 6ß-OHF/F or midazolam pharmacokinetic parameters. The possible association of CYP3A5*3 and CYP3A4*1G polymorphisms on CYP3A activity and their potential interaction require confirmation in a larger study.

Prospective longitudinal voxel-based morphometry study of major depressive disorder in young individuals at high familial risk.

BACKGROUND: Previous neuroimaging studies indicate abnormalities in cortico-limbic circuitry in mood disorder. Here we employ prospective longitudinal voxel-based morphometry to examine the trajectory of these abnormalities during early stages of illness development. METHOD: Unaffected individuals (16-25 years) at high and low familial risk of mood disorder underwent structural brain imaging on two occasions 2 years apart. Further clinical assessment was conducted 2 years after the second scan (time 3). Clinical outcome data at time 3 was used to categorize individuals: (i) healthy controls ('low risk', n = 48); (ii) high-risk individuals who remained well (HR well, n = 53); and (iii) high-risk individuals who developed a major depressive disorder (HR MDD, n = 30). Groups were compared using longitudinal voxel-based morphometry. We also examined whether progress to illness was associated with changes in other potential risk markers (personality traits, symptoms scores and baseline measures of childhood trauma), and whether any changes in brain structure could be indexed using these measures. RESULTS: Significant decreases in right amygdala grey matter were found in HR MDD v. controls (p = 0.001) and v. HR well (p = 0.005). This structural change was not related to measures of childhood trauma, symptom severity or measures of sub-diagnostic anxiety, neuroticism or extraversion, although cross-sectionally these measures significantly differentiated the groups at baseline. CONCLUSIONS: These longitudinal findings implicate structural amygdala changes in the neurobiology of mood disorder. They also provide a potential biomarker for risk stratification capturing additional information beyond clinically ascertained measures.

The experience of older people living independently in Singapore.

BACKGROUND: Globally, older people are living independently either alone or with their spouse, population continues to age. In Singapore, some may live with an unrelated older person in a public rental apartment. In Asia, these older people are associated with increased risks of poor health and social isolation, have poorer social support and a poor quality of life. Few studies have explored why these older people choose such living arrangements, the challenges they encountered and what has helped or may help them overcome these challenges. AIM: To explore older people's experiences of living independently or with an unrelated older person. METHODS: This descriptive qualitative study involved face-to-face interviews with 25 informants, 65 years or older in Singapore. Thematic analysis was adopted. RESULTS: Five themes emerged: (1) making own choice--participants decided to live apart from their families, (2) contending with concerns--the availability of external resources for participants was shrinking, (3) coping with the available assistance--depending on available external resources from the community, (4) holding on to their values--participants rely on their internal resources to manage, and (5) preparing for the inevitable--participants were planning for their final years of life and for their death. CONCLUSION: Older people have such living arrangements for many reasons. They attain well-being and quality of life by devising strategies, tapping on their limited external resources and relying on their values to manage their diminishing resources and the foreseeable death. IMPLICATIONS FOR NURSING AND/OR HEALTH POLICY: Understanding older people's experiences may help nurses and health professionals to develop health promotion programmes that support older people's everyday needs and help them to stay healthy. Public health policy must support older people to live in a safe environment near their extended family to reduce their need to relocate.

Relaxation effect of a novel Danshensu/tetramethylpyrazine derivative on rat mesenteric arteries.

Danshen (Radix Salviae miltiorrhizae) and ChuanXiong (Ligusticum wallichii) are two traditional herbal medicines commonly used in China for the treatment of cardiovascular diseases. The active components in Danshen and ChuanXiong are Danshensu (DSS, (R)-3, 4-dihydroxyphenyllactic acid) and tetramethylpyrazine (TMP), respectively. In the present study, a new compound named ADTM, which is a conjugation of DSS and TMP, was synthesized and its effect on the contractility of rat mesenteric arteries was examined. The relaxation effect of ADTM on rat mesenteric arteries was studied using myography. The effects of ADTM on Ca(2+) channels were measured by Ca(2+) imaging and patch-clamp techniques. The results showed that ADTM caused a concentration-dependent relaxation of rat mesenteric arteries. This relaxation effect was not affected by the removal of endothelium or inhibitors of nitric oxide synthase, cyclooxygenase, guanylyl cyclase and adenylyl cyclase. Potassium channel blockers including tetraethylammonium, iberiotoxin, apamin, 4-aminopyridine, BaCl2 and glibenclamide also failed to inhibit the relaxation response to ADTM. ADTM inhibited CaCl2-induced contractions and reduced the Ca(2+) influx in isolated mesenteric arterial muscle cells. Our results suggest that ADTM may be a novel relaxing agent. Its mechanism of action involves the direct blockade of voltage-gated Ca(2+) channels in vascular smooth muscle cells, resulting in a decrease in Ca(2+) influx into the cells.

Meta-analysis of association between ALDH2 rs671 polymorphism and essential hypertension in Asian populations.

BACKGROUND: Mitochondrial aldehyde dehydrogenase-2 (ALDH2) is an enzyme that oxidizes acetaldehyde into acetic acid during alcohol metabolism. Many studies indicate that the rs671 GG genotype in the ALDH2 gene may play a critical role in increasing the risk of essential hypertension (EH) associated with alcohol consumption, which predominantly occurs in men. However, the literature is inconclusive in this regard. This meta-analysis aims to derive a more precise estimation of the relationship between the rs671 polymorphism and EH for both male and female drinkers and nondrinkers. METHODS: Ten cohort and case-control studies were included in the analysis with a total of 12,161 subjects; 7,062 patients and 5,099 healthy controls. RESULTS: Our results show that the rs671 GG genotype was associated with an increased risk of EH compared with the AG+AA genotype (OR = 1.27, 95 % CI = 1.17-1.37, p < 0.00001). When comparing male and female subjects, only among male individuals was a higher risk of EH found in the GG genotype compared with the AG+ AA genotype (OR = 1.59, 95 % CI = 1.40-1.80, p < 0.00001). By contrast, among female subjects, the risk of EH in the rs671 GG genotype did not differ from that detected in the AA + GG genotype. The proportion of patients with EH was significantly higher for the GG genotype carriers than for the AG+AA genotype carriers, both in the subset of drinkers (OR = 1.51, 95 % CI = 1.23-1.86, p < 0.0001) and in that of nondrinkers (OR = 1.22, 95 % CI = 1.01-1.47, p = 0.03). In addition, among carriers of the GG genotype, the risk of EH among the drinkers was similar to that found in the nondrinkers' subset (OR = 1.12, 95 %CI = 0.89-1.41, p = 0.34). CONCLUSION: Our meta-analysis demonstrates that the rs671 GG genotype increases the risks of EH, especially in men, and is independent of alcohol consumption.

Exploring faculty perceptions towards electronic health records for nursing education.

BACKGROUND: The use of electronic health records in nursing education is rapidly increasing worldwide. The successful implementation of electronic health records for nursing education software program relies on students as well as nursing faculty members. AIMS: This study aimed to explore the experiences and perceptions of nursing faculty members using electronic health records for nursing education software program, and to identify the influential factors for successful implementation of this technology. METHODS: This exploratory qualitative study was conducted using in-depth individual interviews at a university in Singapore. Seven faculty members participated in the study. The data were gathered and analysed at the end of the semester in the 2012/2013 academic year. RESULTS: The participants' perceptions of the software program were organized into three main categories: innovation, transition and integration. The participants perceived this technology as innovative, with both values and challenges for the users. In addition, using the new software program was perceived as transitional process. The integration of this technology required time from faculty members and students, as well as support from administrators. LIMITATIONS: The software program had only been implemented for 2-3 months at the time of the interviews. Consequently, the participants might have lacked the necessary skill and competence and confidence to implement it successfully. In addition, the unequal exposure to the software program might have had an impact on participants' perceptions. CONCLUSION: The findings show that the integration of electronic health records into nursing education curricula is dependent on the faculty members' experiences with the new technology, as well as their perceptions of it. Hence, cultivating a positive attitude towards the use of new technologies is important. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Electronic health records are significant applications of health information technology. Health informatics competency should be included as a required competency component in faculty professional development policy and programmes.

Uptake and protective effects of ergothioneine in human endothelial cells.

Ergothioneine is a thiourea derivative of histidine found in food, especially mushrooms. Experiments in cell-free systems and chemical assays identified this compound as a powerful antioxidant. Experiments were designed to test the ability of endothelial cells to take up ergothioneine and hence benefit from protection against oxidative stress. Reverse-transcription polymerase chain reaction and Western blotting demonstrated transcription and translation of an ergothioneine transporter in human brain microvascular endothelial cells (HBMECs). Uptake of [(3)H]ergothioneine occurred by the organic cation transporter novel type-1 (OCTN-1), was sodium-dependent, and was reduced when expression of OCTN-1 was silenced by small interfering RNA (siRNA). The effect of ergothioneine on the production of reactive oxygen species (ROS) in HBMECs was measured using dichlorodihydrofluorescein and lucigenin, and the effect on cell viability was studied using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. ROS production and cell death induced by pyrogallol, xanthine oxidase plus xanthine, and high glucose were suppressed by ergothioneine. The antioxidant and cytoprotective effects of ergothioneine were abolished when OCTN-1 was silenced using siRNA. The expression of NADPH oxidase 1 was decreased, and those of glutathione reductase, catalase, and superoxide dismutase enhanced by the compound. In isolated rat basilar arteries, ergothioneine attenuated the reduction in acetylcholine-induced relaxation caused by pyrogallol, xanthine oxidase plus xanthine, or incubation in high glucose. Chronic treatment with the compound improved the response to acetylcholine in arteries of rats with streptozotocin-induced diabetes. In summary, ergothioneine is taken up by endothelial cells via OCTN-1, where the compound then protects against oxidative stress, curtailing endothelial dysfunction.