Effect of Sodium Nitrite on Ischaemia and Reperfusion-Induced Arrhythmias in Anaesthetized Dogs: Is Protein S-Nitrosylation Involved?

Background and Purpose

To provide evidence for the protective role of inorganic nitrite against acute ischaemia and reperfusion-induced ventricular arrhythmias in a large animal model.

Experimental Approach

Dogs, anaesthetized with chloralose and urethane, were administered intravenously with sodium nitrite (0.2 µmolkg^-1min^-1) in two protocols. In protocol 1 nitrite was infused 10 min prior to and during a 25 min occlusion of the left anterior descending (LAD) coronary artery (NaNO₂-PO; n = 14), whereas in protocol 2 the infusion was started 10 min prior to reperfusion of the occluded vessel (NaNO₂-PR; n = 12). Control dogs (n = 15) were infused with saline and subjected to the same period of ischaemia and reperfusion. Severities of ischaemia and ventricular arrhythmias, as well as changes in plasma nitrate/nitrite (NOx) levels in the coronary sinus blood, were assessed throughout the experiment. Myocardial superoxide and nitrotyrosine (NT) levels were determined during reperfusion. Changes in protein S-nitrosylation (SNO) and S-glutathionylation were also examined.

Key Results

Compared with controls, sodium nitrite administered either pre-occlusion or pre-reperfusion markedly suppressed the number and severity of ventricular arrhythmias during occlusion and increased survival (0% vs. 50 and 92%) upon reperfusion. There were also significant decreases in superoxide and NT levels in the nitrite treated dogs. Compared with controls, increased SNO was found only in NaNO₂-PR dogs, whereas S-glutathionylation occurred primarily in NaNO₂-PO dogs.

Conclusions

Intravenous infusion of nitrite profoundly reduced the severity of ventricular arrhythmias resulting from acute ischaemia and reperfusion in anaesthetized dogs. This effect, among several others, may result from an NO-mediated reduction in oxidative stress, perhaps through protein SNO and/or S-glutathionylation.     

Determining the Mode of Action Involved in the Antimicrobial Activity of?Synthetic Peptides: A Solid-State NMR and FTIR Study

We have previously shown that leucine to lysine substitution(s) in neutral synthetic crown ether containing 14-mer peptide affect the peptide structure and its ability to permeabilize bilayers. Depending on the substitution position, the peptides adopt mainly either a α-helical structure able to permeabilize dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) vesicles (nonselective peptides) or an intermolecular β-sheet structure only able to permeabilize DMPG vesicles (selective peptides). In this study, we have used a combination of solid-state NMR and Fourier transform infrared spectroscopy to investigate the effects of nonselective α-helical and selective intermolecular β-sheet peptides on both types of bilayers. ³¹P NMR results indicate that both types of peptides interact with the headgroups of DMPC and DMPG bilayers. ²H NMR and Fourier transform infrared results reveal an ordering of the hydrophobic core of bilayers when leakage is noted, i.e., for DMPG vesicles in the presence of both types of peptides and DMPC vesicles in the presence of nonselective peptides. However, selective peptides have no significant effect on the ordering of DMPC acyl chains. The ability of these 14-mer peptides to permeabilize lipid vesicles therefore appears to be related to their ability to increase the order of the bilayer hydrophobic core.     

A Prospective Study of Selenium Concentration and Risk of Preeclampsia in Pregnant Iranian Women: a Nested Case–Control Study

Preeclampsia remains a leading cause of maternal and perinatal mortality and morbidity worldwide; however, its specific etiology still remains obscure. Some studies implicate poor maternal selenium status predisposing the mother to preeclampsia. This study was designed to determine changes in plasma selenium levels in women having preeclampsia as compared with those with normal pregnancy. In a nested case–control study, 650 normal primigravida in their first 24–28 weeks participated in the study. After 3 months of follow-up of all subjects, blood selenium levels were measured in 38 women presenting consecutively with preeclampsia and in 38 women having a normal pregnancy by atomic absorption spectrophotometry. Birth outcomes were recorded, such as gestational age at delivery, height, weight, birth head circumflex and 1-min Apgar score. Preeclampsia affects about 5.84 % of pregnancies, and in our study, there were no significant differences in age, anthropometric indices, and family history of preeclampsia between the preeclamptic and control groups. The selenium concentrations in plasma in women with preeclampsia were significantly lower as compared with those in women with normal pregnancy (70.63?±?21.41 versus 82.03?±?15.54 μg/L, p?<?0.05). Being in the bottom tertile of selenium concentration (less than 62.2 μg/L) was associated with greater risk of preeclampsia in pregnant women. The reduced selenium in the maternal circulations observed in the preeclamptic mothers support the hypothesis that insufficient selenium concentration may be a contributing factor to the pathophysiological mechanisms associated with preeclampsia, and optimizing the dietary selenium intake through supplementation could produce demonstrable clinical benefits.     

Effect of Supervised Students' Involvement on Diagnostic Accuracy in Hospitalized Medical Patients �� A Prospective Controlled Study

Background

During internships most medical students engage in history taking and physical examination during evaluation of hospitalized patients. However, the students'' ability for pattern recognition is not as developed as in medical experts and complete history taking is often not repeated by an expert, so important clues may be missed. On the other hand, students'' history taking is usually more extensive than experts'' history taking and medical students discuss their findings with a Supervisor. Thus the effect of student involvement on diagnostic accuracy is unclear. We therefore compared the diagnostic accuracy for patients in the medical emergency department with and without student involvement in the evaluation process.

Methodology/Principal Findings

Patients in the medical emergency department were assigned to evaluation by either a supervised medical student or an emergency department physician. We only included patients who were admitted to our hospital and subsequently cared for by another medical team on the ward. We compared the working diagnosis from the emergency department with the discharge diagnosis. A total of 310 patients included in the study were cared for by 41 medical students and 21 emergency department physicians. The working diagnosis was changed in 22% of the patients evaluated by physicians evaluation and in 10% of the patients evaluated by supervised medical students (p = .006). There was no difference in the expenditures for diagnostic procedures, length of stay in the emergency department or patient comorbidity complexity level.

Conclusion/Significance

Involvement of closely supervised medical students in the evaluation process of hospitalized medical patients leads to an improved diagnostic accuracy compared to evaluation by an emergency department physician alone.     

The Impact of Health Behaviours on Incident Cardiovascular Disease in Europeans and South Asians – A Prospective Analysis in the UK SABRE Study

Background

There is consistent evidence on the impact of health behaviours on risk of cardiovascular disease (CVD) in European populations. As South Asians in the UK have an excess risk of CVD and coronary heart disease (CHD) compared to Europeans, we investigated whether a similar association between combined health behaviours and risk of CVD and CHD among this high-risk group exists, and estimated the population impact.

Methods and Findings

In a prospective cohort of 1090 Europeans and 1006 South Asians (40–69 y) without prevalent CVD at baseline (1988–1990), followed up for 21 years to 2011, there were 601 incident CVD events [Europeans n = 255; South Asians n = 346] of which 520 were CHD events [n = 207 and 313 respectively]. Participants scored between 0 to 4 points for a composite score including four baseline healthy behaviours (non-smoker, moderate alcohol intake, physically active, frequent fruit/vegetable intake). Adjusted hazard ratios (95% confidence intervals) for incident CHD in Europeans who had three, two, one, and zero compared to four health behaviours were 1.33 (0.78–2.29), 1.96 (1.15–3.33), 1.36 (0.74–2.48) and 2.45 (1.18–5.10), respectively, p-trend = 0.025. In South Asians, corresponding HRs were 2.88 (1.33–6.24), 2.28 (1.06–4.91), 3.36 (1.53–7.39) and 3.48 (1.38–8.81), p-trend = 0.022. The results were similar for incident CVD; Europeans HR 2.12 (1.14–3.94), p–trend = 0.014; South Asians HR 2.73 (1.20–6.21), p-trend = 0.018. The population attributable fraction in Europeans was 43% for CHD and 28% for CVD. In South Asians it was 63% and 51% respectively.

Conclusions

Lack of adherence to four combined health behaviours was associated with 2 to 3-fold increased risk of incident CVD in Europeans and South Asians. A substantial population impact in the South Asian group indicates important potential for disease prevention in this high-risk group by adherence to healthy behaviours.     

Sequential Activation of Classic PKC and Estrogen Receptor α Is Involved in Estradiol 17?-D-Glucuronide-Induced Cholestasis

Estradiol 17ß-d-glucuronide (E17G) induces acute cholestasis in rat with endocytic internalization of the canalicular transporters bile salt export pump (Abcb11) and multidrug resistance-associated protein 2 (Abcc2). Classical protein kinase C (cPKC) and PI3K pathways play complementary roles in E17G cholestasis. Since non-conjugated estradiol is capable of activating these pathways via estrogen receptor alpha (ERα), we assessed the participation of this receptor in the cholestatic manifestations of estradiol glucuronidated-metabolite E17G in perfused rat liver (PRL) and in isolated rat hepatocyte couplets (IRHC). In both models, E17G activated ERα. In PRL, E17G maximally decreased bile flow, and the excretions of dinitrophenyl-glutathione, and taurocholate (Abcc2 and Abcb11 substrates, respectively) by 60% approximately; preadministration of ICI 182,780 (ICI, ERα inhibitor) almost totally prevented these decreases. In IRHC, E17G decreased the canalicular vacuolar accumulation of cholyl-glycylamido-fluorescein (Abcb11 substrate) with an IC50 of 91±1 µM. ICI increased the IC50 to 184±1 µM, and similarly prevented the decrease in the canalicular vacuolar accumulation of the Abcc2 substrate, glutathione-methylfluorescein. ICI also completely prevented E17G-induced delocalization of Abcb11 and Abcc2 from the canalicular membrane, both in PRL and IRHC. The role of ERα in canalicular transporter internalization induced by E17G was confirmed in ERα-knocked-down hepatocytes cultured in collagen sandwich. In IRHC, the protection of ICI was additive to that produced by PI3K inhibitor wortmannin but not with that produced by cPKC inhibitor Gö6976, suggesting that ERα shared the signaling pathway of cPKC but not that of PI3K. Further analysis of ERα and cPKC activations induced by E17G, demonstrated that ICI did not affect cPKC activation whereas Gö6976 prevented that of ERα, indicating that cPKC activation precedes that of ERα. Conclusion: ERα is involved in the biliary secretory failure induced by E17G and its activation follows that of cPKC.     

Is the Relationship between Common Mental Disorder and Adiposity Bidirectional? Prospective Analyses of a UK General Population-Based Study

The direction of the association between mental health and adiposity is poorly understood. Our objective was to empirically examine this link in a UK study. This is a prospective cohort study of 3 388 people (men) aged ≥ 18 years at study induction who participated in both the UK Health and Lifestyle Survey at baseline (HALS-1, 1984/1985) and the re-survey (HALS-2, 1991/1992). At both survey examinations, body mass index, waist circumference and self-reported common mental disorder (the 30-item General Health Questionnaire, GHQ) were measured. Logistic regression models were used to compute odds ratios (OR) and accompanying 95% confidence intervals (CI) for the associations between (1) baseline common mental disorder (QHQ score > 4) and subsequent general and abdominal obesity and (2) baseline general and abdominal obesity and re-survey common mental disorders. After controlling for a range of covariates, participants with common mental disorder at baseline experienced greater odds of subsequently becoming overweight (women, OR: 1.30, 1.03 – 1.64; men, 1.05, 0.81 – 1.38) and obese (women, 1.26, 0.82 – 1.94; men, OR: 2.10, 1.23 – 3.55) than those who were free of common mental disorder. Similarly, having baseline common mental health disorder was also related to a greater risk of developing moderate (1.57, 1.21 – 2.04) and severe (1.48, 1.09 – 2.01) abdominal obesity (women only). Baseline general or abdominal obesity was not associated with the risk of future common mental disorder. These findings of the present study suggest that the direction of association between common mental disorders and adiposity is from common mental disorder to increased future risk of adiposity as opposed to the converse.     

What Role Do Local Grocery Stores Play in Urban Food Environments? A Case Study of Hartford-Connecticut

Introduction

Research on urban food environments emphasizes limited access to healthy food, with fewer large supermarkets and higher food prices. Many residents of Hartford, Connecticut, which is often considered a food desert, buy most of their food from small and medium-sized grocery stores. We examined the food environment in greater Hartford, comparing stores in Hartford to those in the surrounding suburbs, and by store size (small, medium, and large).

Methods

We surveyed all small (over 1,000 ft²), medium, and large-sized supermarkets within a 2-mile radius of Hartford (36 total stores). We measured the distance to stores, availability, price and quality of a market basket of 25 items, and rated each store on internal and external appearance. Geographic Information System (GIS) was used for mapping distance to the stores and variation of food availability, quality, and appearance.

Results

Contrary to common literature, no significant differences were found in food availability and price between Hartford and suburban stores. However, produce quality, internal, and external store appearance were significantly lower in Hartford compared to suburban stores (all p<0.05). Medium-sized stores had significantly lower prices than small or large supermarkets (p<0.05). Large stores had better scores for internal (p<0.05), external, and produce quality (p<0.01). Most Hartford residents live within 0.5 to 1 mile distance to a grocery store.

Discussion

Classifying urban areas with few large supermarkets as ‘food deserts’ may overlook the availability of healthy foods and low prices that exist within small and medium-sized groceries common in inner cities. Improving produce quality and store appearance can potentially impact the food purchasing decisions of low-income residents in Hartford.     

Is Dynamic Autocrine Insulin Signaling Possible? A Mathematical Model Predicts Picomolar Concentrations of Extracellular Monomeric Insulin within Human Pancreatic Islets

Insulin signaling is essential for -cell survival and proliferation in vivo. Insulin also has potent mitogenic and anti-apoptotic actions on cultured -cells, with maximum effect in the high picomolar range and diminishing effect at high nanomolar doses. In order to understand whether these effects of insulin are constitutive or can be subjected to physiological modulation, it is essential to estimate the extracellular concentration of monomeric insulin within an intact islet. Unfortunately, the in vivo concentration of insulin monomers within the islet cannot be measured directly with current technology. Here, we present the first mathematical model designed to estimate the levels of monomeric insulin within the islet extracellular space. Insulin is released as insoluble crystals that exhibit a delayed dissociation into hexamers, dimers, and eventually monomers, which only then can act as signaling ligands. The rates at which different forms of insulin dissolve in vivo have been estimated from studies of peripheral insulin injection sites. We used this and other information to formulate a mathematical model to estimate the local insulin concentration within a single islet as a function of glucose. Model parameters were estimated from existing literature. Components of the model were validated using experimental data, if available. Model analysis predicted that the majority of monomeric insulin in the islet is that which has been returned from the periphery, and the concentration of intra-islet monomeric insulin varies from 50–300 pM when glucose is in the physiological range. Thus, our results suggest that the local concentration of monomeric insulin within the islet is in the picomolar ‘sweet spot’ range of insulin doses that activate the insulin receptor and have the most potent effects on -cells in vitro. Together with experimental data, these estimations support the concept that autocrine/paracrine insulin signalling within the islet is dynamic, rather than constitutive and saturated.     

How Do Local Folks Value Wild Meat,and Why It Matters? A Study in the Democratic Republic of Congo

Human Ecology - We elucidate the value orientations (VOs) towards wild meat/wildlife in the Tshopo Province of the Democratic Republic of Congo, distinguishing between the provincial capital and...     

“How Local Is Local?”—A Review of Practical and Conceptual Issues in the Genetics of Restoration

In plant conservation, restoration (the augmentation or reestablishment of an extinct population or community) is a valuable tool to mitigate the loss of habitat. However, restoration efforts can result in the introduction of novel genes and genotypes into populations when plant materials used are not of local origin. This movement is potentially important because many plant species are subdivided into populations that are adapted to local environmental conditions. Here we focus on genetic concerns arising from ongoing restoration efforts, where often little is known about “How local is local?” (i.e., the geographic or environmental scale over which plant species are adapted). We review the major issues regarding gene flow and local adaptation in the restoration of natural plant populations. Finally, we offer some practical, commonsense guidelines for the consideration of genetic structure when restoring natural plant populations.     

Effects of Antenatal Maternal Depression and Anxiety on Children’s Early Cognitive Development: A Prospective Cohort Study

Introduction

Studies have shown that depression or anxiety occur in 10–20% of pregnant women. These disorders are often undertreated and may affect mothers and children’s health. This study investigates the relation between antenatal maternal depression, anxiety and children’s early cognitive development among 1380 two-year-old children and 1227 three-year-old children.

Methods

In the French EDEN Mother-Child Cohort Study, language ability was assessed with the Communicative Development Inventory at 2 years of age and overall development with the Ages and Stages Questionnaire at 3 years of age. Multiple regressions and structural equation modeling were used to examine links between depression, anxiety during pregnancy and child cognitive development.

Results

We found strong significant associations between maternal antenatal anxiety and poorer children’s cognitive development at 2 and 3 years. Antenatal maternal depression was not associated with child development, except when antenatal maternal anxiety was also present. Both postnatal maternal depression and parental stimulation appeared to play mediating roles in the relation between antenatal maternal anxiety and children’s cognitive development. At 3 years, parental stimulation mediated 13.2% of the effect of antenatal maternal anxiety while postnatal maternal depression mediated 26.5%.

Discussion

The partial nature of these effects suggests that other mediators may play a role. Implications for theory and research on child development are discussed.     

Serum Autotaxin Is a Parameter for the Severity of Liver Cirrhosis and Overall Survival in Patients with Liver Cirrhosis – A Prospective Cohort Study

Background

Autotaxin (ATX) and its product lysophosphatidic acid (LPA) are considered to be involved in the development of liver fibrosis and elevated levels of serum ATX have been found in patients with hepatitis C virus associated liver fibrosis. However, the clinical role of systemic ATX in the stages of liver cirrhosis was unknown. Here we investigated the relation of ATX serum levels and severity of cirrhosis as well as prognosis of cirrhotic patients.

Methods

Patients with liver cirrhosis were prospectively enrolled and followed until death, liver transplantation or last contact. Blood samples drawn at the day of inclusion in the study were assessed for ATX content by an enzyme-linked immunosorbent assay. ATX levels were correlated with the stage as well as complications of cirrhosis. The prognostic value of ATX was investigated by uni- and multivariate Cox regression analyses. LPA concentration was determined by liquid chromatography-tandem mass spectrometry.

Results

270 patients were enrolled. Subjects with liver cirrhosis showed elevated serum levels of ATX as compared to healthy subjects (0.814±0.42 mg/l vs. 0.258±0.40 mg/l, P<0.001). Serum ATX levels correlated with the Child-Pugh stage and the MELD (model of end stage liver disease) score and LPA levels (r = 0.493, P = 0.027). Patients with hepatic encephalopathy (P = 0.006), esophageal varices (P = 0.002) and portal hypertensive gastropathy (P = 0.008) had higher ATX levels than patients without these complications. Low ATX levels were a parameter independently associated with longer overall survival (hazard ratio 0.575, 95% confidence interval 0.365–0.905, P = 0.017).

Conclusion

Serum ATX is an indicator for the severity of liver disease and the prognosis of cirrhotic patients.     

A “Prime-Pull” Vaccine Strategy Has a Modest Effect on Local and Systemic Antibody Responses to HIV gp140 in Mice

One potential strategy for the prevention of HIV infection is to induce virus specific mucosal antibody that can act as an immune barrier to prevent transmission. The mucosal application of chemokines after immunisation, termed “prime-pull”, has been shown to recruit T cells to mucosal sites. We wished to determine whether this strategy could be used to increase B cells and antibody in the vaginal mucosa following immunisation with an HIV antigen. BALB/c mice were immunised intranasally with trimeric gp140 prior to vaginal application of the chemokine CCL28 or the synthetic TLR4 ligand MPLA, without antigen six days later. There was no increase in vaginal IgA, IgG or B cells following the application of CCL28, however vaginal application of MPLA led to a significant boost in antigen specific vaginal IgA. Follow up studies to investigate the effect of the timing of the “pull” stimulation demonstrated that when given 14 days after the initial immunisation MPLA significantly increased systemic antibody responses. We speculate that this may be due to residual inflammation prior to re-immunisation. Overall we conclude that in contrast to the previously observed effect on T cells, the use of “prime-pull” has only a modest effect on B cells and antibody.     

A Prospective Cohort Study of Absconsion Incidents in Forensic Psychiatric Settings: Can We Identify Those at High-Risk?

Background

Incidents of absconsion in forensic psychiatric units can have potentially serious consequences, yet surprisingly little is known about the characteristics of patients who abscond from these settings. The few previous studies conducted to date have employed retrospective designs, and no attempt has been made to develop an empirically-derived risk assessment scale. In this prospective study, we aimed to identify predictors of absconsion over a two-year period and investigate the feasibility of developing a brief risk assessment scale.

Methods

The study examined a representative sample of 135 patients treated in forensic medium- and low-secure wards. At baseline, demographic, clinical, treatment-related, and offending/behavioural factors were ascertained from electronic medical records and the treating teams. Incidents of absconsion (i.e., failure to return from leave, incidents of escape, and absconding whilst on escorted leave) were assessed at a two-year follow-up. Logistic regression analyses were used to determine the strongest predictors of absconsion which were then weighted according to their ability to discriminate absconders and non-absconders. The predictive utility of a brief risk assessment scale based on these weighted items was evaluated using receiver operator characteristics (ROC).

Results

During the two-year follow-up period, 27 patients (20%) absconded, accounting for 56 separate incidents. In multivariate analyses, four factors relating to offending and behaviour emerged as the strongest predictors of absconsion: history of sexual offending, previous absconsion, recent inpatient verbal aggression, and recent inpatient substance use. The weighted risk scale derived from these factors had moderate-to-good predictive accuracy (ROC area under the curve: 0.80; sensitivity: 067; specificity: 0.71), a high negative predictive value (0.91), but a low positive predictive value (0.34).

Conclusion

Potentially-targetable recent behaviours, such as inpatient verbal aggression and substance use, are strong predictors of absconsion in forensic settings; the absence of these factors may enable clinical teams to identify unnecessarily restricted low-risk individuals.     

Prospective Study of Police Officer Spouse/Partners: A New Pathway to Secondary Trauma and Relationship Violence?

Introduction

It has been reported that posttraumatic stress disorder (PTSD) is associated with secondary spouse/partner (S/P) emotional distress and relationship violence.

Objective

To investigate the relationships between PTSD, S/P emotional distress and relationship violence among police recruits using a prospective design.

Methods

Two hypotheses were tested in 71 S/Ps: (1) Police officer reports of greater PTSD symptoms after 12 months of police service will be associated with greater secondary trauma symptoms among S/Ps; (2) Greater secondary trauma symptoms among S/Ps at 12 months will be associated with S/P reports of greater relationship violence.

Methods

71 police recruits and their S/Ps were assessed at baseline and 12 months after the start of police officer duty. Using linear and logistic regression, we analyzed explanatory variables for 12 month S/P secondary traumatic stress symptoms and couple violence, including baseline S/P variables and couple violence, as well as exposure and PTSD reports from both S/P and officer.

Results

S/P perception of officer PTSD symptoms predicted S/P secondary traumatic stress. OS/P secondary trauma was significantly associated with both total couple violence (.34, p = .004) and S/P to officer violence (.35, p = .003).

Conclusions

Although results from this relatively small study of young police officers and their S/Ps must be confirmed by larger studies in general populations, findings suggest that S/P perception of PTSD symptoms may play a key role in the spread of traumatic stress symptoms across intimate partner relationships and intimate partner violence in the context of PTSD.     

A Perspective on the History and Evolution of an Oceans and Human Health “Metadiscipline” in the USA

We review recent history and evolution of Oceans and Human Health programs and related activities in the USA from a perspective within the Federal government. As a result of about a decade of support by the US Congress and through a few Federal agencies, notably the National Science Foundation, National Institute of Environmental Health Sciences, and National Ocean and Atmospheric Administration, robust Oceans and Human Health (OHH) research and application activities are now relatively widespread, although still small, in a number of agencies and academic institutions. OHH themes and issues have been incorporated into comprehensive federal ocean research plans and are reflected in the new National Ocean Policy enunciated by Executive Order 13547. In just a decade, OHH has matured into a recognized “metadiscipline,” with development of a small, but robust and diverse community of science and practice, incorporation into academic educational programs, regular participation in ocean and coastal science and public health societies, and active engagement with public health decision makers. In addition to substantial increases in scientific information, the OHH community has demonstrated ability to respond rapidly and effectively to emergency situations such as those associated with extreme weather events (e.g., hurricanes, floods) and human-caused disasters (e.g., the Deep Water Horizon oil spill). Among many other things, next steps include development and implementation of agency health strategies and provision of specific services, such as ecological forecasts to provide routine early warnings for ocean health threats and opportunities for prevention and mitigation of these risks.