Nonsmokers' responses to new warning labels on smokeless tobacco and electronic cigarettes: an experimental study.
Graphic warning labels are a tobacco control best practice that is mandated in the US for cigarettes under the 2009 Family Smoking Prevention and Tobacco Control Act. However, smokeless tobacco products are not required to carry graphic warning labels, and as of September 2014, electronic cigarettes in the US carry no warning labels and are aggressively marketed, including with "reduced harm" or "FDA Approved" messages. In this online experiment, 483 US adult non-users of tobacco were randomized to view print advertisements for moist snuff, snus, and e-cigarettes with either warning labels (current warning label, graphic warning label) or "endorsements" (a "lower risk" label proposed by a tobacco company, an "FDA Approved" label) or control (tobacco advertisement with no label, advertisement for a non-tobacco consumer products). Main outcome measures included changes in perceived harm, positive attitudes towards, openness to using, and interest in a free sample of moist snuff, snus, and e-cigarettes. The graphic warning label increased perceived harm of moist snuff and e-cigarettes. "Lower risk" and "FDA Approved" labels decreased perceived harm of moist snuff and snus respectively. Current warning label and graphic warning label significantly lowered positive attitudes towards e-cigarettes. In this sample of non-users of tobacco, 15% were interested in a free sample of alternative tobacco products (predominantly e-cigarettes). Proportion of participants interested in a free sample did not differ significantly across the conditions, but those interested in a free sample had significantly lower perceptions of harm of corresponding tobacco products. Regulatory agencies should not allow "lower risk" warning labels, which have similar effects to the "FDA Approved" label, which is prohibited, and should consider implementing graphic warning labels for smokeless tobacco products and e-cigarettes.


Investigation of the effects of opiate antagonists infused into the nucleus accumbens on feeding and sucrose drinking in rats.
Previous work has shown that opiate agonist infusion into the nucleus accumbens, a region implicated in reinforcement, stimulates food intake. In the present study, the effects of opiate antagonist infusion into this region were examined in two behavioral paradigms. In the feeding test, food-deprived animals were tested for intake of laboratory chow. In the sucrose intake test, sated animals familiar with a 20% sucrose solution were tested. Before these tests, the following drugs were bilaterally infused into the accumbens: naloxone (0, 1, 10 and 30 micrograms; equivalent to 2.8, 28 and 83 nmol, respectively), naltrexone (0, 0.2, 2 and 20 micrograms; 0.55, 5.5 and 55 nmol, respectively), beta-funaltrexamine (0 and 15 micrograms; 31 nmol), naloxonazine (0 and 10 micrograms; 15 nmol), naltrindole (trial 1: 0, 1, 10 and 20 micrograms; 2.2, 22 and 44 nmol, respectively; trial 2: 0, 0.1 and 0.5 micrograms; 0.22 and 1.1 nmol, respectively) and nor-binaltorphimine (0, 0.1, 1 and 10 micrograms; 0.14, 1.4 and 14 nmol, respectively). Naloxone and naltrexone both significantly reduced sucrose drinking and did not affect feeding. Naloxone infused into the dorsolateral striatum, as a control, had no effect on sucrose drinking. Accumbens infusion of the mu antagonist beta-funaltrexamine reduced both sucrose drinking and feeding. The mu 1 antagonist naloxonazine did not influence intake behaviors, with the exception of a decrease in duration of chow feeding. In contrast, the delta antagonist naltrindole markedly potentiated both sucrose drinking and duration of chow feeding. In a replication of this effect, systemic naltrexone given concurrently blocked the enhancement. The kappa antagonist nor-binaltorphimine did not influence any parameters of ingestive behavior. Although some treatments also decreased motor activities, the overall profile of behavior suggested specific effects on ingestive behavior. The putative contributions of mu and delta receptors within the nucleus accumbens to modulation of food reward are discussed.


Influence of weight reduction on plasma lipoproteins in obese patients.
To determine the influence of weight reduction on plasma lipoproteins, studies were carried out in 15 nondiabetic patients of varying degrees of obesity and four obese insulin-dependent diabetics. All studies were carried out on a metabolic ward and patients underwent three dietary periods: Period I, 4 to 5 weeks of weight maintenance in the obese state; Period II, caloric restriction to 1000 kcal/day to a weight loss of within 10% of ideal body weight; and Period III, again weight maintenance for 4 to 5 weeks near ideal body weight. Similar results were obtained for both nondiabetics and diabetics. Many patients had mildly elevated plasma triglycerides in Period I; they fell to the normal range in Period II and remained low in Period III. Total cholesterol levels decreased early in Period II, but levels began to rise near the end of caloric restriction, and in Period III, they were similar to Period I. Low density lipoprotein cholesterol levels followed a pattern similar to that of total cholesterol. High density lipoprotein cholesterol was relatively low in Period I (38 +/- 2 mg/dl +/- SEM); throughout weight loss, levels tended to rise, and in Period III, the average high density lipoprotein cholesterol was significantly higher (46 +/- 2 mg/dl).


Long-Term Dosimetry of Solar UV Radiation in Antarctica with Spores of Bacillus subtilis.
The main objective was to assess the influence of the seasonal stratospheric ozone depletion on the UV climate in Antarctica by using a biological test system. This method is based on the UV sensitivity of a DNA repair-deficient strain of Bacillus subtilis (TKJ 6321). In our field experiment, dried layers of B. subtilis spores on quartz discs were exposed in different seasons in an exposure box open to solar radiation at the German Antarctic Georg von Neumayer Station (70 degrees 37'S, 8 degrees 22'W). The UV-induced loss of the colony-forming ability was chosen as the biological end point and taken as a measure for the absorbed biologically harmful UV radiation. Inactivation constants were calculated from the resulting dose-response curves. The results of field experiments performed in different seasons indicate a strongly season-dependent trend of the daily UV-B level. Exposures performed at extremely depleted ozone concentrations (October 1990) gave higher biologically harmful UV-B levels than expected from the calculated season-dependent trend, which was determined at normal ozone values. These values were similar to values which were measured during the Antarctic summer, indicating that the depleted ozone column thickness has an extreme influence on the biologically harmful UV climate on ground.


A stage-specific factor confers Fab-7 boundary activity during early embryogenesis in Drosophila.
The Fab-7 boundary is required to ensure that the iab-6 and iab-7 cis-regulatory domains in the Drosophila Bithorax complex can function autonomously. Though Fab-7 functions as a boundary from early embryogenesis through to the adult stage, this constitutive boundary activity depends on subelements whose activity is developmentally restricted. In the studies reported here, we have identified a factor, called early boundary activity (Elba), that confers Fab-7 boundary activity during early embryogenesis. The Elba factor binds to a recognition sequence within a Fab-7 subelement that has enhancer-blocking activity during early embryogenesis, but not during mid-embryogenesis or in the adult. We found that the Elba factor is present in early embryos but largely disappears during mid-embryogenesis. We show that mutations in the Elba recognition sequence that eliminate Elba binding in nuclear extracts disrupt the early boundary activity of the Fab-7 subelement. Conversely, we find that early boundary activity can be reconstituted by multimerizing the Elba recognition site.


Mechanistic insights into the therapeutic use of high-dose allopurinol in angina pectoris.
The aim of this study was to evaluate the effect of high-dose allopurinol on vascular oxidative stress (OS) and endothelial function in subjects with stable coronary artery disease (CAD). Allopurinol, a xanthine oxidase inhibitor, prolongs the time to chest pain during exercise in angina. We sought to ascertain whether allopurinol also improves endothelial dysfunction in optimally treated CAD patients, because such an effect might be of value to reduce future cardiovascular mortality. The mechanism of the anti-ischemic effect of allopurinol could be related to its reducing xanthine oxidase-induced OS, and our second aim was to see whether allopurinol really does reduce vascular tissue OS in CAD patients. A randomized, double-blind, placebo-controlled, crossover study was conducted in 80 patients with CAD, comparing allopurinol (600 mg/day) with placebo. Endothelial function was assessed by forearm venous occlusion plethysmography, flow-mediated dilation, and pulse wave analysis. Vascular OS was assessed by intra-arterial co-infusion of vitamin C and acetylcholine. Compared with placebo, allopurinol significantly improved endothelium-dependent vasodilation, by both forearm venous occlusion plethysmography (93 ± 67% vs. 145 ± 106%, p = 0.006) and flow-mediated dilation (4.2 ± 1.8% vs. 5.4 ± 1.7%, p < 0.001). Vascular oxidative stress was completely abolished by allopurinol. Central augmentation index improved significantly with allopurinol (2.6 ± 7.0%, p < 0.001) but not with placebo. Our study demonstrates that, in optimally treated CAD patients, high-dose allopurinol profoundly reduces vascular tissue OS and improves 3 different measures of vascular/endothelial dysfunction. The former effect on OS might underpin the anti-ischemic effect of allopurinol in CAD. Both effects (on OS and endothelial dysfunction) increase the likelihood that high-dose allopurinol might reduce future cardiovascular mortality in CAD, over and above existing optimum therapy. (Exploring the therapeutic potential of xanthine oxidase inhibitor allopurinol in angina; ISRCTN15253766).


After the Global Fund: who can sustain the HIV/AIDS response in Peru and how?
Peru has received around $70 million from Global Fund to fight AIDS, Tuberculosis and Malaria (Global Fund). Recent economic growth resulted in grant ineligibility, enabling greater government funding, yet doubts remain concerning programme continuity. This study examines the transition from Global Fund support to increasing national HIV/AIDS funding in Peru (2004-2012) by analysing actor roles, motivations and effects on policies, identifying recommendations to inform decision-makers on priority areas. A conceptual framework, which informed data collection, was developed. Thirty-five in-depth interviews were conducted from October to December 2011 in Lima, Peru, among key stakeholders involved in HIV/AIDS work. Findings show that Global Fund involvement led to important breakthroughs in the HIV/AIDS response, primarily concerning treatment access, focus on vulnerable populations and development of a coordination body. Nevertheless, reliance on Global Fund financing for prevention activities via non-governmental organisations, compounded by lack of government direction and weak regional governance, diluted power and caused role uncertainty. Strengthening government and regional capacity and fostering accountability mechanisms will facilitate an effective transition to government-led financing. Only then can achievements gained from the Global Fund presence be maintained, providing lessons for countries seeking to sustain programmes following donor exit.


Functional magnetic resonance imaging in an animal model of pancreatic cancer.
To test the hypotheses that diffusion weighed (DW)- and transcatheter intraarterial perfusion (TRIP)-magnetic resonance imaging (MRI) can each be used to assess regional differences in tumor function in an animal pancreatic cancer model. VX2 tumors were implanted in pancreata of 6 rabbits. MRI and digital subtraction angiography (DSA) were performed 3 wk following implantation. With a 2-French catheter secured in the rabbit's gastroduodenal artery, each rabbit was transferred to an adjacent 1.5T MRI scanner. DW- and TRIP-MRI were performed to determine if necrotic tumor core could be differentiated from viable tumor periphery. For each, we compared mean differences between tumor core/periphery using a 2-tailed paired t-test (alpha = 0.05). Imaging was correlated with histopathology. Tumors were successfully grown in all rabbits, confirmed by necropsy. On DW-MRI, mean apparent diffusion coefficient (ADC) value was higher in necrotic tumor core (2.1 +/- 0.3 mm(2)/s) than in viable tumor periphery (1.4 +/- 0.5 mm(2)/s) (P < 0.05). On TRIP-MRI, mean perfusion values was higher in tumor periphery (110 +/- 47 relative units) than in tumor core (66 +/- 31 relative units) (P < 0.001). Functional MRI can be used to differentiate necrotic from viable tumor cells in an animal pancreatic cancer model using ADC (DW-MRI) and perfusion (TRIP-MRI) values.


Microbe-mediated host defence drives the evolution of reduced pathogen virulence.
Microbes that protect their hosts from pathogens are widespread in nature and are attractive disease control agents. Given that pathogen adaptation to barriers against infection can drive changes in pathogen virulence, 'defensive microbes' may shape disease severity. Here we show that co-evolving a microbe with host-protective properties (Enterococcus faecalis) and a pathogen (Staphylococcus aureus) within Caenorhabditis elegans hosts drives the evolution of reduced pathogen virulence as a by-product of adaptation to the defensive microbe. Using both genomic and phenotypic analyses, we discover that the production of fewer iron-scavenging siderophores by the pathogen reduces the fitness of the defensive microbe and underpins the decline in pathogen virulence. These data show that defensive microbes can shape the evolution of pathogen virulence and that the mechanism of pathogen resistance can determine the direction of virulence evolution.


The long-term impact of torture on the mental health of war-wounded refugees: findings and implications for nursing programmes.
Today, nurses from many disciplines are expected to provide nursing care to refugees severely traumatized in war and conflict. The general aim of this study was to explore the long-term impact of torture on the mental health of war-wounded refugees. The study group consisted of 22 tortured and 22 nontortured male refugees who had been injured in war. Standardized interview schedules, exploring different background characteristics, and three instruments for assessment of mental health were used: the Hopkins Symptom Checklist, the Post Traumatic Symptom Scale and a well-being scale. The prevalence of psychiatric symptoms was high in both groups. However, there were no significant differences in mental health between the tortured and the nontortured refugees. The patterns of associations between background characteristics and mental health were different in the two groups. The strongest associations with lower level of mental health were higher education in the tortured group and unemployment in the nontortured group. Methodological difficulties in research on sequelae of prolonged traumatization remain. Further studies within the caring sciences can broaden the present understanding of the impact of torture and other war traumas.


Interhemispheric transcallosal connectivity between the left and right planum temporale predicts musicianship, performance in temporal speech processing, and functional specialization.
Currently, there is strong evidence showing that musicianship favours functional and structural changes of the left planum temporale (PT), and that these cortical reorganizations facilitate the discrimination of temporal speech cues. Based on the proposition of a division of labour between the left and right PT, here we postulated that the musicians' advantage in processing temporal speech cues and PT specialization origin, at least in part, from increased white matter connectivity between the two auditory-related cortices. In particular, we assume that increased transcallosal PT connectivity might promote functional specialization and asymmetry of homotopic brain regions. With this purpose in mind, we applied diffusion tensor imaging and compared axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA) of the interhemispheric connection between the left and right PT in thirteen musicians and 13 nonmusicians. Furthermore, in the form of an addendum, we integrated cortical surface area values and blood oxygenation level dependent (BOLD) responses of the left PT that were collected in the context of two previous studies conducted with the same sample of subjects. Our results indicate increased connectivity between the left and right PT in musicians compared to nonmusicians, as indexed by reduced mean RD. We did not find significant between-group differences in FA and AD. Most notably, RD was related to the performance in the phonetic categorization task, musical aptitudes, as well as to BOLD responses in the left PT. Hence, we provide first evidence for a relationship between PT connectivity, musicianship, and phonetic categorization.


Incidence of autoimmune thyroiditis in interferon-alpha treated and untreated patients with chronic hepatitis C virus infection.
To clarify the relationship between interferon-alpha (IFN-alpha) therapy and autoimmune thyroiditis in chronic hepatitis C virus (HCV) infection, we investigated a selected number of patients without basal thyroid dysfunctions. 130 patients (average age: 20-70), with chronic HCV infection and without basal clinical and laboratory signs of autoimmune thyroiditis were divided into two groups: IFN-alpha treated (A) and untreated (B) patients. Group A received IFN-alpha (three million U.I./3 times a week) for six months; group B was followed for the same period. Thyroid peroxidase and thyroglobulin autoantibodies were measured by radioimmunoassay; thyroid function was measured by radioimmunoassay (free thyroxine and triiodothyronine) and immunoradiometric assay (thyroid stimulating hormone). After a 6-month period, thyroid autoantibodies positivity was documented in 21.1% of group A and in 10.3% of group B patients, both statistically relevant (p<0.001 and p<0.011, respectively). The comparison between the two groups was not statistically relevant (p=0.142). Our study showed a prevalence of de novo thyroid autoimmunity in chronic HCV patients treated with IFN-alpha, confirming previous data in literature. The lack of a significant difference between treated and untreated patients strongly suggests that the anti-thyroid autoimmune response is linked to the HCV infection itself. Moreover, IFN-alpha therapy probably does not represent a risk factor in renewing the autoimmune processes of the thyroid gland. Thyroid function and autoantibodies must be systematically monitored in patients with HCV infection, especially in female and IFN-alpha treated population, not only to verify the possible thyroid abnormalities but also to rule out concomitant autoimmune diseases.


Porphyrin complexes containing coordinated BOB groups: synthesis, chemical reactivity and the structure of [BOB(tpClpp)]2+.
The reactions of boron halides with free base porphyrins under conditions where partial hydrolysis of the boron halides can occur give diboron porphyrin complexes containing BOB moieties in which each boron is bonded to two porphyrin nitrogen atoms. BF(3).OEt(2) with H(2)(por) gives B(2)OF(2)(por) (por = tpp, ttp, tpClpp, oep) which has an asymmetric structure in which one boron lies in the porphyrin plane (B(ip)) while the other lies above it (B(oop)). BCl(3).MeCN with H(2)(por) gives B(2)O(2)(BCl(3))(2)(por) which contains a four-membered B(2)O(2) ring and is stable only in the presence of excess BCl(3). BBr(3) with Li(2)(tpClpp) gives the dicationic complex [B(2)O(tpClpp)](2+) as its [BBr(4)](-) salt, and is the first example of a boron porphyrin containing three-coordinate boron to be structurally characterised. B(2)O(2)(BCl(3))(2)(por) can be chromatographed on basic alumina to give the hydroxyboron complex B(2)O(OH)(2)(por), which is deduced from its NMR spectra and DFT calculations to have a structure analogous to B(2)OF(2)(por). The OH protons are shifted upfield to near delta -4 (B(oop)-OH) and -10 (B(ip)-OH) by the diamagnetic porphyrin ring current. The reaction of either B(2)O(2)(BCl(3))(2)(por) or B(2)O(OH)(2)(por) (por = ttp, tpClpp) with alcohols (ROH, R = Et, 4-C(6)H(4)CH(3)) gives B(2)O(OR)(2)(por), which can in turn be converted to B(2)O(OR)(OH)(por) by repeated chromatography. The reaction of PhBCl(2) with H(2)(por) (por = ttp, tpClpp) gives B(2)O(Ph)(OH)(por) which has been characterised by spectroscopy in concert with DFT calculations. It is a further example of the B(2)OF(2)(por) structural type, in which the phenyl group is coordinated to the out-of-plane boron and the OH group to the in-plane boron, as are its derivatives B(2)O(Ph)(X)(tpClpp) (X = F, OEt). Steric drivers for the facile hydrolysis of haloboron porphyrins relative to their dipyrromethene and expanded porphyrin counterparts are discussed.


Viral respiratory infections and the oropharyngeal bacterial microbiota in acutely wheezing children.
Acute viral wheeze in children is a major cause of hospitalisation and a major risk factor for the development of asthma. However, the role of the respiratory tract microbiome in the development of acute wheeze is unclear. To investigate whether severe wheezing episodes in children are associated with bacterial dysbiosis in the respiratory tract, oropharyngeal swabs were collected from 109 children with acute wheezing attending the only tertiary paediatric hospital in Perth, Australia. The bacterial community from these samples was explored using next generation sequencing and compared to samples from 75 non-wheezing controls. No significant difference in bacterial diversity was observed between samples from those with wheeze and healthy controls. Within the wheezing group, attendance at kindergarten or preschool was however, associated with increased bacterial diversity. Rhinovirus (RV) infection did not have a significant effect on bacterial community composition. A significant difference in bacterial richness was observed between children with RV-A and RV-C infection, however this is likely due to the differences in age group between the patient cohorts. The bacterial community within the oropharynx was found to be diverse and heterogeneous. Age and attendance at day care or kindergarten were important factors in driving bacterial diversity. However, wheeze and viral infection were not found to significantly relate to the bacterial community. Bacterial airway microbiome is highly variable in early life and its role in wheeze remains less clear than viral influences.


Hepatology outpatient service provision in secondary care: a study of liver disease incidence and resource costs.
This paper discusses the annual incidence of liver disease and resource costs in providing a hepatology service for all new outpatient referrals to a secondary care setting. In a retrospective study, we found that 200 patients (1 in 1,000 of the West Suffolk population) with a mean age of 52 years were referred per year. One-third of patients had cirrhosis (almost half due to alcohol). Annual incidence (per 100,000 population) were as follows: non-alcoholic fatty liver disease (29: of which 23.5 non-cirrhotic and 5.5 cirrhotic), hepatitis C (25), hepatitis B (3), alcohol-related cirrhosis (12.5), primary biliary cirrhosis (3.5), autoimmune hepatitis (3), primary sclerosing cholangitis (2), haemochromatosis (2), hepatocellular carcinoma (1.5) and oesophageal variceal haemorrhage (6.5). Using national indicative tariffs, the total annual hepatology budget was 130K pounds (58K pounds for resources and 72K pounds for clinic attendances). The greatest resource expenditure was on endoscopy (almost half for oesophageal varices) and radiological imaging (one-third of the total budget). These findings will help inform commissioners in hepatology service funding.


Application and assessment of optical clearing methods for imaging of tissue-engineered neural stem cell spheres.
Three-dimensional (3D) cell culture is an important tool that facilitates biological discoveries by bridging the divide between standard two-dimensional cell culture and the complex, high-cell-density in vivo environment. Typically, the internal structures of 3D tissue-engineered samples are visualized through an involved process of physical sectioning, immunostaining, imaging, and computational reconstruction. However, recent progress in tissue-clearing methods has improved optical-imaging-depth capabilities in whole embryos and brains by reducing tissue opacity and light scattering, thus decreasing the need for physical sectioning. In this study, we assessed the application of the recently published clearing techniques Clear(T2), Scale, and SeeDB to tissue-engineered neural spheres. We found that scaffold-free self-assembled adult hippocampal neural stem cell spheres of 100-μm diameter could be optically cleared and imaged using either Clear(T2) or Scale, while SeeDB only marginally improved imaging depth. The Clear(T2) protocol maintained sphere size, while Scale led to sample expansion, and SeeDB led to sample shrinkage. Additionally, using Clear(T2) we cleared and successfully imaged spheres of C6 glioma cells and spheres of primary cortical neurons. We conclude that Clear(T2) is the most effective protocol of those tested at clearing neural spheres of various cell types and could be applied to better understand neural cell interactions in 3D tissue-engineered samples.


Benchmarking circumferential resection margin (R1) resection rate for rectal cancer in the neoadjuvant era.
Circumferential resection margin (CRM) involvement (R1) is used to audit rectal cancer surgical quality. However, when downsizing chemoradiation (dCRT) is used, CRM audits both dCRT and surgery, its use reflecting a high casemix of locally advanced tumours. We aimed to evaluate predictors of R1 and benchmark R1 rates in the dCRT era, and to assess the influence of failure of steps in the multidisciplinary team (MDT) process to CRM involvement. A retrospective analysis of prospectively collected rectal cancer data was undertaken. Patients were classified according to CRM status. Uni- and multivariate analysis was undertaken of risk factors for R1 resection. The contribution of the steps of the MDT process to CRM involvement was assessed. Two hundred and ten rectal cancers were evaluated (68% T3 or T4 on preoperative staging). R1 (microscopic) and R2 (macroscopic) resections occurred in 20 (10%) and 6 patients (3%), respectively. Of several factors associated with R1 resections on univariate analysis, only total mesorectal excision (TME) specimen defects and threatened/involved CRM on preoperative imaging remained as independent predictors of R1 resections on multivariate analysis. Causes of R1 failure by MDT step classification found that less than half were associated with and only 15% solely attributable to a suboptimal TME specimen. Total mesorectal excision specimen defects and staging-predicted threatened or involved CRM are independent strong predictors of R1 resections. In most R1 resections, the TME specimen was intact. It is important to remember the contribution of both the local staging casemix and dCRT failure when using R1 rates to assess purely surgical competence.


Continuing professional development: learning that leads to change in individual and collective clinical practice.
The lack of effectiveness of traditional models of continuing professional development is increasingly recognised. While they can lead to increased knowledge of participants, research suggests that there is a general failure to produce meaningful and sustained changes in clinician behaviours. The aim of this study was to explore the effect of the Royal College of Veterinary Surgeons' (RCVS) new individual outcomes-focused approach to delivery of continuing professional development (CPD) through the reflective accounts of participant experiences. Content analysis of 12 summaries of their learning, produced by early pioneers of the Professional Key Skills (PKS) Module of the RCVS Certificate in Advanced Veterinary Practice, revealed that the benefits of the PKS-related professional development is best understood through 'a framework of 'stakeholder' dynamics', with impact and behavioural change at the individual participant level having an effect on practice team behaviours, leading to patient, owner and business benefits. It can be concluded that, at least for these early pioneers, this new model for CPD has resulted in changes that have gone beyond knowledge accumulation to changed practitioner behaviours and recognisable patient, owner and business benefits.


Long-term effects on survival after a 1-year multifactorial vascular risk factor intervention after stroke or TIA: secondary analysis of a randomized controlled trial, a 7-year follow-up study.
Stroke and coronary heart disease share the same risk factors, and a multifactorial intervention after stroke may potentially result in the same reduction in cardiovascular mortality as seen after coronary events. We aimed to evaluate the effect on survival 7 years after a 1-year multifactorial risk factor intervention, and identify clinical predictors for long-term survival in a hospital-based cohort of patients with first-ever stroke or transient ischemic attack (TIA). We performed a secondary analysis of a randomized controlled trial including patients between February 2007 and July 2008 comparing an intensive risk factor intervention vs usual care the first year poststroke to prevent cognitive impairment. From February 2014 to July 2016, all patients were invited to a follow-up. For patients dying throughout the follow-up period, date of death was obtained from the medical record. Examination at baseline and 1-year follow-up included extensive assessment of vascular risk factors and cognitive assessments. A total of 195 patients were randomized. Mean (SD) age was 71.6 (12.5) years, 53.3% were male, mean (SD) body mass index (BMI) was 25.6 (4.1) kg/m2. During follow-up, 35 patients in the intervention group and 41 in the control group died. Kaplan-Meier survival estimates show no significant difference in intention-to-treat (ITT) population or complete case (CC) population (log-rank P=0.29 vs log-rank P=0.07). In multivariable Cox proportional hazards regression analyses, lower age and higher BMI was independently associated with long-term survival, adjusted HR (95% CI) 1.08 (1.05-1.11) per year and 0.91 (0.85-0.97) per kg/m2. In this post hoc analysis, we found no significant effect on survival after 7 years of a multifactorial risk factor program given during the first year after first-ever stroke or TIA. Higher BMI was an independent predictor for long-term survival in this cohort.


Infertility evaluation and access to assisted reproductive technologies among male military veterans: analysis of the South Florida Veterans Affairs experience.
Recent legislation extended coverage for assisted reproductive technologies (ART) to male veterans within the United States Veterans Affairs (VA) healthcare system. We sought to characterize the appropriateness of male infertility diagnosis and access to assisted reproductive technologies (ART) among men within the local VA healthcare system after passage of the new legislation. We retrospectively identified male patients within the South Florida VA Network who underwent semen analysis (SA) or were diagnosed with infertility between January 1999 and June 2017. Men were classified by infertility diagnosis and sperm concentration/mL (normal, oligospermia <15, severe oligospermia <5 million, azoospermia). We compared the number of oligospermic men before versus after the legislation. Men who did not receive ART were characterized according to eligibility criteria of military service connection to the infertility diagnosis. Six hundred twenty-seven men underwent SA or were diagnosed with infertility. Among 474 men with SA, 206 (43.5%) were diagnosed with infertility and 268 (56.5%) were not. Additionally, 153 men received an infertility diagnosis without SA. More men had oligospermia and severe oligospermia after the legislation (1 vs. 6, 1 vs. 10). Of 10 men with severe oligospermia post-legislation, 7 did not proceed to ART consultation due to lack of military service connection to the infertility diagnosis. A substantial proportion of veterans with abnormal sperm concentrations were not diagnosed with infertility, while others carrying an infertility diagnosis did not undergo SA. Most patients clinically eligible for ART did not proceed with further evaluation due to lack of military service connection to their infertility diagnosis.


The effects of epidural block on the distribution of lymphocyte subsets and natural-killer cell activity in patients with and without pain.
Although epidural anesthesia prevents immune suppression during surgery, no reports have elucidated how epidural block affects immune response in nonsurgical patients. We examined changes in proportion of lymphocyte subsets and in natural-killer (NK) cell activity in patients with and without pain. Fifteen patients with pain (Pain group) and 15 preoperative patients without pain (Preoperative group) received three different treatments in random order: epidural block with 7 mL 1% lidocaine, epidural injection of an identical volume of normal saline, and IV injection of 1 mg/kg lidocaine. Blood samples were drawn before and after 30, 60, and 120 min of treatment. During epidural block at 30 and 60 min, both groups showed significantly decreased epinephrine, norepinephrine, and cortisol levels, and the proportion of NK cells decreased, whereas the CD4+/CD8+ ratio increased significantly. NK cell activity in both groups decreased significantly at 30 and 60 min. At 120 min, the variables had all returned to preblock values. During treatments with saline and IV lidocaine, neither group showed significant changes in any of the above variables. We conclude that epidural block causes a transient and significant alteration of lymphocyte subsets and NK cell activity regardless of pain status.


Public Awareness and Barriers to Seeking Medical Advice for Colorectal Cancer in the Gaza Strip: A Cross-Sectional Study.
Raising awareness of colorectal cancer (CRC) symptoms for early recognition, reduction of modifiable risk factors, and removing barriers to seeking medical help could lower its mortality. This study aimed to assess the level of public awareness of CRC in the Gaza Strip. This was a cross-sectional study conducted at three hospitals and 10 high schools between September and October 2017. The Arabic version of the validated Bowel Cancer Awareness Measure (BoCAM) questionnaire was used to evaluate awareness of CRC symptoms and risk factors, and barriers to seeking medical help. Adults (age ≥ 18 years) in three major hospitals and adolescents (ages 15 to 17 years) in 10 schools were recruited for face-to-face interviews to complete the BoCAM. Of 3,172 potential participants, 3,080 completed the BoCAM (response rate, 97.1%). Among these, 1,578 (51.2%) were adults and 1,614 (52.4%) were females. Persistent abdominal pain was the most commonly recognized CRC symptom (n = 1,899; 61.7%), whereas anorectal pain was the least common (n = 1,056; 34.3%). In total, 2,177 (70.7%) were not confident in recognizing CRC symptoms or signs. Having a bowel disease was the most frequently recognized CRC risk factor (n = 1,456; 47.3%) and diabetes the least recognized (n = 591; 19.2%). The overall mean scores ± standard deviations for recalling and recognizing CRC symptoms were 1.2 ± 1.3 and 4.3 ± 2.3, respectively (out of 9 points). The overall mean scores ± standard deviations for recalling and recognizing CRC risk factors were 0.7 ± 0.8 and 8.0 ± 3.1, respectively (out of 16 points). Emotional barriers were the most commonly reported barriers to seeking medical help, with feeling worried about what a doctor might find as the most common barrier (n = 1,522; 49.4%). Public awareness of CRC is suboptimal in Gaza. Improving CRC awareness with educational interventions is needed, including in local schools.


Cell death and tissue remodeling in planarian regeneration.
Many long-lived organisms, including humans, can regenerate some adult tissues lost to physical injury or disease. Much of the previous research on mechanisms of regeneration has focused on adult stem cells, which give rise to new tissue necessary for the replacement of missing body parts. Here we report that apoptosis of differentiated cells complements stem cell division during regeneration in the planarian Schmidtea mediterranea. Specifically, we developed a whole-mount TUNEL assay that allowed us to document two dramatic increases in the rate of apoptosis following amputation-an initial localized response near the wound site and a subsequent systemic response that varies in magnitude depending on the type of fragment examined. The latter cell death response can be induced in uninjured organs, occurs in the absence of planarian stem cells, and can also be triggered by prolonged starvation. Taken together, our results implicate apoptosis in the restoration of proper anatomical scale and proportion through remodeling of existing tissues. We also report results from initial mechanistic studies of apoptosis in planarians, which revealed that a S. mediterranea homolog of the antiapoptotic gene BCL2 is required for cell survival in adult animals. We propose that apoptosis is a central mechanism working in concert with stem cell division to restore anatomical form and function during metazoan regeneration.


Repurposing Mebendazole as a Replacement for Vincristine for the Treatment of Brain Tumors.
The microtubule inhibitor vincristine is currently used to treat a variety of brain tumors, including low-grade glioma and anaplastic oligodendroglioma. Vincristine, however, does not penetrate well into brain tumor tissue, and moreover, it displays dose-limiting toxicities, including peripheral neuropathy. Mebendazole, a Food and Drug Administration-approved anthelmintic drug with a favorable safety profile, has recently been shown to display strong therapeutic efficacy in animal models of both glioma and medulloblastoma. Importantly, appropriate formulations of mebendazole yield therapeutically effective concentrations in the brain. Mebendazole has been shown to inhibit microtubule formation, but it is not known whether its potency against tumor cells is mediated by this inhibitory effect. To investigate this, we examined the effects of mebendazole on GL261 glioblastoma cell viability, microtubule polymerization and metaphase arrest, and found that the effective concentrations to inhibit these functions are very similar. In addition, using mebendazole as a seed for the National Cancer Institute (NCI) COMPARE program revealed that the top-scoring drugs were highly enriched in microtubule-targeting drugs. Taken together, these results indicate that the cell toxicity of mebendazole is indeed caused by inhibiting microtubule formation. We also compared the therapeutic efficacy of mebendazole and vincristine against GL261 orthotopic tumors. We found that mebendazole showed a significant increase in animal survival time, whereas vincristine, even at a dose close to its maximum tolerated dose, failed to show any efficacy. In conclusion, our results strongly support the clinical use of mebendazole as a replacement for vincristine for the treatment of brain tumors.


The effects of a low extracellular concentration of potassium on the activity and numbers of Na+/K+ pumps in an EB-virus transformed human lymphocyte cell line.
The BM1A EB-virus transformed human lymphocyte cell line contains approximately 950,000 Na+/K(+)-ATPase sites per cell. The turnover number of each site is approx. 2240 molecules of rubidium per min. When cells are exposed to a low extracellular concentration of potassium the intracellular concentration of sodium rises, and the cells respond in the short term by increasing the Vmax of 86Rb+ uptake. In the longer term the cells respond by increasing both the Vmax of 86Rb+ uptake and the Bmax of [3H]ouabain binding. The suggestion that increases in the intracellular concentration of sodium is responsible for these changes is supported by the finding that monensin, which increases intracellular sodium without affecting intracellular potassium, is capable of inducing both the short- and long-term changes associated with a low external concentration of potassium.


Small intestine bleeding due to multifocal angiosarcoma.
We report a case of an 84-year-old male patient with primary small intestinal angiosarcoma. The patient initially presented with anemia and melena. Consecutive endoscopy revealed no signs of upper or lower active gastrointestinal bleeding. The patient had been diagnosed 3 years previously with an aortic dilation, which was treated with a stent. Computed tomography suggested an aorto-intestinal fistula as the cause of the intestinal bleeding, leading to operative stent explantation and aortic replacement. However, an aorto-intestinal fistula was not found, and the intestinal bleeding did not arrest postoperatively. The constant need for blood transfusions made an exploratory laparotomy imperative, which showed multiple bleeding sites, predominately in the jejunal wall. A distal loop jejunostomy was conducted to contain the small intestinal bleeding and a segmental resection for histological evaluation was performed. The histological analysis revealed a less-differentiated tumor with characteristic CD31, cytokeratin, and vimentin expression, which led to the diagnosis of small intestinal angiosarcoma. Consequently, the infiltrated part of the jejunum was successfully resected in a subsequent operation, and adjuvant chemotherapy with paclitaxel was planned. Angiosarcoma of the small intestine is an extremely rare malignant neoplasm that presents with bleeding and high mortality. Early diagnosis and treatment are essential to improve outcome. A small intestinal angiosarcoma is a challenging diagnosis to make because of its rarity, nonspecific symptoms of altered intestinal function, nonspecific abdominal pain, severe melena, and acute abdominal signs. Therefore, a quick clinical and histological diagnosis and decisive measures including surgery and adjuvant chemotherapy should be the aim.


Uridine adenosine tetraphosphate and purinergic signaling in cardiovascular system: An update.
Uridine adenosine tetraphosphate (Up4A), biosynthesized by activation of vascular endothelial growth factor receptor (VEGFR) 2, was initially identified as a potent endothelium-derived vasoconstrictor in perfused rat kidney. Subsequently, the effect of Up4A on vascular tone regulation was intensively investigated in arteries isolated from different vascular beds in rodents including rat pulmonary arteries, aortas, mesenteric and renal arteries as well as mouse aortas, in which Up4A produces vascular contraction. In contrast, Up4A produces vascular relaxation in porcine coronary small arteries and rat aortas. Intravenous infusion of Up4A into conscious rats or mice decreases blood pressure, and intravenous bolus injection of Up4A into anesthetized mice increases coronary blood flow, indicating an overall vasodilator influence in vivo. Although Up4A is the first dinucleotide described that contains both purine and pyrimidine moieties, its cardiovascular effects are exerted mainly through activation of purinergic receptors. These effects not only encompass regulation of vascular tone, but also endothelial angiogenesis, smooth muscle cell proliferation and migration, and vascular calcification. Furthermore, this review discusses a potential role for Up4A in cardiovascular pathophysiology, as plasma levels of Up4A are elevated in juvenile hypertensive patients and Up4A-mediated vascular purinergic signaling changes in cardiovascular disease such as hypertension, diabetes, atherosclerosis and myocardial infarction. Better understanding the vascular effect of the novel dinucleotide Up4A and the purinergic signaling mechanisms mediating its effects will enhance its potential as target for treatment of cardiovascular disease.


Functional characterization of mast cells generated in vitro from the mesenteric lymph node of rats infected with Nippostrongylus brasiliensis.
We have examined the biochemical and functional characteristics of mast cells grown in tissue culture from the mesenteric lymph node (MLN) of rats infected with the nematode Nippostrongylus brasiliensis and compared them with mast cells isolated from the small intestinal mucosa and peritoneal cavity of infected animals. Cultured mast cells (MC) and isolated intestinal mucosal mast cells (MMC) had a similar histamine content, and both contained type II protease (RMCP II) which was absent from peritoneal mast cells (PMC). PMC, MMC and cultured MC each responded to immunologically induced histamine secretion, but MMC and cultured MC were hyporesponsive to calcium ionophores and unresponsive to widely used PMC secretagogues including compound 48/80 and bee venom peptide 401. MMC and cultured MC also differed from PMC in their lack of responsiveness to the anti-allergic agent disodium cromoglycate. Thus, MC cultured from the MLN are distinct from PMC but have a biochemical and functional phenotype similar to that of intestinal MMC.


Long-term outcomes of provisional stenting compared with a two-stent strategy for bifurcation lesions: a meta-analysis of randomised trials.
The optimal interventional technique for addressing coronary bifurcation lesions is debatable. Long-term clinical outcomes with provisional stenting (PS) compared with a two-stent (TS) strategy for bifurcation lesions are scarce. We aim to perform the first meta-analysis of randomised controlled trials (RCTs) to explore long-term outcomes comparing both strategies. An electronic search was performed for online databases until August 2016 for RCTs comparing PS with TS for bifurcation lesions reporting outcomes at 1 year of follow-up or more. Random effects model risk ratios (RRs) were calculated for outcomes of interest. Eight RCTs with a total of 2778 patients reported long-term clinical outcomes. At mean follow-up of 3.0±1.6 years, PS was associated with lower risk of all-cause mortality (RR=0.66; 95% CI 0.45 to 0.98; p=0.04) compared with TS for bifurcation lesions. No difference was observed with PS compared with TS regarding major adverse cardiac events (MACE), myocardial infarction (MI), target lesion revascularisation (TLR) or stent thrombosis (ST). In a sensitivity analysis limited to trials with follow-up duration ≥3 years, PS was associated with lower risk of all-cause mortality (RR=0.57; 95% CI 0.36 to 0.88; p=0.01), MACE (RR=0.71; 95% CI 0.52 to 0.97; p=0.03) and MI (RR=0.45; 95% CI 0.21 to 0.96; p=0.04) compared with TS, at mean follow-up of 4.6±0.7 years. The risk of TLR and ST remained similar with both strategies (RR=0.81; 95% CI 0.57 to 1.15; p=0.24; and RR=0.75; 95% CI 0.19 to 2.84; p=0.67 respectively). Meta-regression analyses identified increased risk of MACE with PS in patients presenting with acute coronary syndrome (p=0.05). PS may be associated with a long-term mortality benefit compared with a TS strategy for coronary bifurcation lesions.


Caffeine, exercise and the brain.
Caffeine can improve exercise performance when it is ingested at moderate doses (3-6 mg/kg body mass). Caffeine also has an effect on the central nervous system (CNS), and it is now recognized that most of the performance-enhancing effect of caffeine is accomplished through the antagonism of the adenosine receptors, influencing the dopaminergic and other neurotransmitter systems. Adenosine and dopamine interact in the brain, and this might be one mechanism to explain how the important components of motivation (i.e. vigor, persistence and work output) and higher-order brain processes are involved in motor control. Caffeine maintains a higher dopamine concentration especially in those brain areas linked with 'attention'. Through this neurochemical interaction, caffeine improves sustained attention, vigilance, and reduces symptoms of fatigue. Other aspects that are localized in the CNS are a reduction in skeletal muscle pain and force sensation, leading to a reduction in perception of effort during exercise and therefore influencing the motivational factors to sustain effort during exercise. Because not all CNS aspects have been examined in detail, one should consider that a placebo effect may also be present. Overall, it appears that the performance-enhancing effects of caffeine reside in the brain, although more research is necessary to reveal the exact mechanisms through which the CNS effect is established.


RNA Interference Directed against the Transglutaminase Gene Triggers Dysbiosis of Gut Microbiota in Drosophila.
We recently reported that transglutaminase (TG) suppresses immune deficiency pathway-controlled antimicrobial peptides (IMD-AMPs), thereby conferring immune tolerance to gut microbes, and that RNAi of the TG gene in flies decreases the lifespan compared with non-TG-RNAi flies. Here, analysis of the bacterial composition of the Drosophila gut by next-generation sequencing revealed that gut microbiota comprising one dominant genus of Acetobacter in non-TG-RNAi flies was shifted to that comprising two dominant genera of Acetobacter and Providencia in TG-RNAi flies. Four bacterial strains, including Acetobacter persici SK1 and Acetobacter indonesiensis SK2, Lactobacillus pentosus SK3, and Providencia rettgeri SK4, were isolated from the midgut of TG-RNAi flies. SK1 exhibited the highest resistance to the IMD-AMPs Cecropin A1 and Diptericin among the isolated bacteria. In contrast, SK4 exhibited considerably lower resistance against Cecropin A1, whereas SK4 exhibited high resistance to hypochlorous acid. The resistance of strains SK1-4 against IMD-AMPs in in vitro assays could not explain the shift of the microbiota in the gut of TG-RNAi flies. The lifespan was reduced in gnotobiotic flies that ingested both SK4 and SK1, concomitant with the production of reactive oxygen species and apoptosis in the midgut, whereas the survival rate was not altered in gnotobiotic flies that mono-ingested either SK4 or SK1. Interestingly, significant amounts of reactive oxygen species were detected in the midgut of gnotobiotic flies that ingested SK4 and SK2, concomitant with no significant apoptosis in the midgut. In gnotobiotic flies that co-ingested SK4 and SK1, an additional unknown factor(s) may be required to cause midgut apoptosis.


Determination of electrical axis deviation.
While the determination of an abnormal electrical axis is not considered to be diagnostic, it will lend support to suspicions of abnormalities such as hypertrophy or intraventricular conduction defects. In some instances the recognition of axis deviation may be the first indication of underlying heart disease in an otherwise asymptomatic patient. Axis deviation can be determined easily in the critical care setting and should become as routine to the critical care nurse as the interpretation of a rhythm strip.


Interventions to Promote Healthy Eating, Physical Activity and Smoking in Low-Income Groups: a Systematic Review with Meta-Analysis of Behavior Change Techniques and Delivery/Context.
Healthy eating, physical activity and smoking interventions for low-income groups may have small, positive effects. Identifying effective intervention components could guide intervention development. This study investigated which content and delivery components of interventions were associated with increased healthy behavior in randomised controlled trials (RCTs) for low-income adults. Data from a review showing intervention effects in 35 RCTs containing 45 interventions with 17,000 participants were analysed to assess associations with behavior change techniques (BCTs) and delivery/context components from the template for intervention description and replication (TIDieR) checklist. The associations of 46 BCTs and 14 delivery/context components with behavior change (measures of healthy eating, physical activity and smoking cessation) were examined using random effects subgroup meta-analyses. Synergistic effects of components were examined using classification and regression trees (meta-CART) analyses based on both fixed and random effects assumptions. For healthy eating, self-monitoring, delivery through personal contact, and targeting multiple behaviors were associated with increased effectiveness. Providing feedback, information about emotional consequences, or using prompts and cues were associated with reduced effectiveness. In synergistic analyses, interventions were most effective without feedback, or with self-monitoring excluding feedback. More effective physical activity interventions included behavioral practice/rehearsal or instruction, focussed solely on physical activity or took place in home/community settings. Information about antecedents was associated with reduced effectiveness. In synergistic analyses, interventions were most effective in home/community settings with instruction. No associations were identified for smoking. This study identified BCTs and delivery/context components, individually and synergistically, linked to increased and reduced effectiveness of healthy eating and physical activity interventions. The identified components should be subject to further experimental study to help inform the development effective behavior change interventions for low-income groups to reduce health inequalities.


Analysis of non-cleaned QuEChERS extracts for the determination of pesticide residues in fruit, vegetables and cereals by gas chromatography-tandem mass spectrometry.
This paper investigated the possibility of leaving out the traditional clean-up step in the QuEChERS procedure and analysing non-cleaned extracts from fruit, vegetables and cereals with a combination of gas chromatography-tandem mass spectrometry (GC-MS/MS), back-flush technology and large-volume injection. By using calibration standards in cucumber matrix, recovery and precision were calculated in lettuce, orange and wheat for 109 pesticides at 0.01 and 0.1 mg kg(-1) in two sets of samples: one with and one without clean-up. For both spiking levels, 80-82% of the pesticides in the non-cleaned extracts and 80-84% of the pesticides in the cleaned extracts were within the acceptable recovery range of 70-120%. Precision data for both levels showed that 95% of the pesticides in the non-cleaned extracts and 93-95% of the pesticides in the cleaned extracts had RSDs below 20%. Recovery and precision data were determined using a two tailed t-test (p = 0.05). By using calibration standards in the respective matrix, we studied if the non-cleaned calibration standards gave an extra matrix effect compared with the cleaned standards by using the slope from calibration graphs and plotting the calculated extra matrix effect minus 100 for each compound. The results showed that for 79% of the pesticides, the extra matrix effect minus 100 was within the acceptable range of -20% to 20%. Five European Union proficiency tests on rye, mandarin, rice, pear and barley, respectively, from 2010 to 2012 were reanalysed omitting the clean-up step and showed satisfactory results. At least 70 injections of non-cleaned extracts were made without detecting any increased need for maintenance during the experimental period. Analysing non-cleaned QuEChERS extracts of lettuce, orange and wheat are possible under the conditions described in this paper because recovery, precision and specificity showed satisfactory results compared with samples subjected to traditional dispersive clean-up.


Risk management in outpatient surgery.
Outpatient surgery has become a national policy priority set by health care authorities (targets for more than 70% of outpatient procedures by 2022), making ambulatory hospitalization the new standard of care. This practice introduces new risks along the patient's course. Even though these risks are low and although the literature and data from insurance databases is reassuring, the risks in outpatient surgery remain poorly understood. Risks can be organizational in view of the many stages of the patient journey that must be formalized-medical, anesthetic or surgical-in view of planned discharge the same evening as the procedure, and medico-legal because of the importance of the discharge authorization and the information provided to the patient. A risk management approach (a priori or a posteriori) has become a mandatory part of a policy of continuous quality improvement and safety of care. The coordination of all the team members (surgeon, anesthesiologist, nursing and administrative staff and the patient's accompanying person) as well as the patient's active participation are essential to minimize risks and prevent complications.


A comparative analysis of safety and efficacy of different methods of tube placement for enteral feeding following major pancreatic resection. A non-randomized study.
Postoperative enteral nutrition is thought to reduce complications and speed recovery after pancreatic resection. There is little evidence on the best route for delivery of enteral nutrition. Currently we use percutaneous transperitoneal jejunostomy or percutaneous transperitoneal gastrojejunostomy, or the nasojejunal route to deliver enteral nutrition, according to surgeon preference. To compare morbidity, efficiency, and safety of these three routes for enteral nutrition following pancreaticoduodenectomy. Data were obtained from a prospectively maintained database, for all patients undergoing pancreatic resection between January 2007 and June 2008. One-hundred pancreatic resected patients underwent enteral nutrition: 93 had Whipple's operations and 7 had total pancreatectomies. Enteral nutrition was delivered by agreed protocol, starting within 24 h of operation and increasing over 2-3 days to meet full nutritional requirement. Delivery route of enteral nutrition was: percutaneous transperitoneal jejunostomy in 25 (25%), percutaneous transperitoneal gastrojejunostomy in 32 (32%) and nasojejunal in 43 (43%). The incidence of catheter-related complications was higher in percutaneous techniques: 24% in percutaneous transperitoneal jejunostomy and 34% in percutaneous transperitoneal gastrojejunostomy as compared to nasojejunal technique (12%). Median time to complete establishment of oral intake was 14, 14 and 10 days in percutaneous transperitoneal jejunostomy, percutaneous transperitoneal gastrojejunostomy, and nasojejunal groups, respectively. Nasojejunal tubes were removed at median 11 days (mean 11.5 days) compared to 5-6 weeks for percutaneous transperitoneal jejunostomy and percutaneous transperitoneal gastrojejunostomy. Commonest catheter-related complication in the percutaneous transperitoneal jejunostomy and percutaneous transperitoneal gastrojejunostomy was blockage (n=6; 10.5%), followed by pain after removal of feeding tube at 5-6 weeks (n=5; 8.8%), whereas in the nasojejunal group it was blockage (n=3; 7.0%), followed by displacement (n=2; 4.7%). Two patients died postoperatively in this cohort, however, there were no catheter-related mortalities. Enteral nutrition following pancreatic resection can be delivered in different ways. Nasojejunal feeding was associated with fewest and less serious complications. On current evidence surgeon preference is a reasonable way to decide enteral nutrition but a randomized controlled trial is needed to address this issue.


Maternal depressive symptoms and early childhood cognitive development: a meta-analysis.
Previous findings have been mixed regarding the relationship between maternal depressive symptoms and child cognitive development. The objective of this study was to systematically review relevant literature and to perform a meta-analysis. Three electronic databases (PubMed, EMBASE, PsycINFO) were searched. Initial screening was conducted independently by two reviewers. Studies selected for detailed review were read in full and included based on a set of criteria. Data from selected studies were abstracted onto a standardized form. Meta-analysis using the inverse variance approach and random-effects models was conducted. The univariate analysis of 14 studies revealed that maternal depressive symptoms are related to lower cognitive scores among children aged ⩽56 months (Cohen's d = -0.25, 95% CI -0.39 to -0.12). The synthesis of studies controlling for confounding variables showed that the mean cognitive score for children 6-8 weeks post-partum whose mothers had high depressive symptoms during the first few weeks postpartum was approximately 4.2 units lower on the Mental Developmental Index (MDI) of the Bayley Scales of Infant and Toddler Development (BSID) compared with children with non-symptomatic mothers (B̂ = -4.17, 95% CI -8.01 to -0.32). The results indicated that maternal depressive symptoms are related to lower cognitive scores in early infancy, after adjusting for confounding factors. An integrated approach for supporting child cognitive development may include program efforts that promote maternal mental health in addition to family economic wellbeing, responsive caregiving, and child nutrition.


Parent-child Relationships and Sexual Minority Youth: Implications for Adult Alcohol Abuse.
Sexual minority (lesbian, gay, bisexual, and same-sex attracted) youth and adults report elevated rates of alcohol use and abuse relative to their heterosexual peers; these differences are strongest for sexual minority girls and women. Although preliminary evidence suggests that unsupportive parenting and maladaptive parent-child relationship qualities are associated with concurrent substance use among sexual minority youth, questions remain about the long-term implications of these early familial experiences on drinking behaviors among sexual minority youth and adults. Nationally-representative prospective data (n = 14,800; 53.1% female; Wave 1 Mean age = 15.61; Wave 4 Mean age = 28.51) were used to test the longitudinal association between parent-child relationships and parental autonomy granting between the ages of 13-18, and sexual-orientation-related disparities in alcohol abuse during adulthood. The findings showed that adolescent same-sex attraction was associated with alcohol abuse during adulthood for sexual minority women and that deficits in parent-child relationship quality statistically mediated this association. No sexual orientation differences in alcohol abuse were found among men. The findings suggest that the quality of relationships with parents in early adolescence has long-lasting impact on sexual minority women's vulnerability for alcohol abuse. Early interventions that bolster supportive parent-child relationship qualities may have enduring consequences for sexual minority women's alcohol use across the life course.


Basics of health technology assessment.
This chapter begins with a brief introduction to health technology assessment (HTA). HTA is concerned with the systematic evaluation of the consequences of the adoption and use of new health technologies and improving the evidence on existing technologies. The objective of mainstream HTA is to support evidence-based decision and policy making that encourage the uptake of efficient and effective health care technologies. This chapter provides a basic framework for conducting an HTA, as well as some fundamental concepts and challenges in assessing health technologies. A case study of the assessment of drug-eluting stents in Ontario is presented to illustrate the HTA process. Whether HTA is beneficial (supporting timely access to needed technologies) or detrimental depends on three critical issues: when the assessment is performed, how it is performed, and how the findings are used.


Metathesis of alkanes and related reactions.
The transformation of alkanes remains a difficult challenge because of the relative inertness of the C-H and C-C bonds. The rewards for asserting synthetic control over unfunctionalized, saturated hydrocarbons are considerable, however, because converting short alkanes into longer chain analogues is usually a value-adding process. Alkane metathesis is a novel catalytic and direct transformation of two molecules of a given alkane into its lower and higher homologues; moreover, the process proceeds at relatively low temperature (ambient conditions or higher). It was discovered through the use of a silica-supported tantalum hydride, ([triple bond]SiO)(2)TaH, a multifunctional catalyst with a single site of action. This reaction completes the story of the metathesis reactions discovered over the past 40 years: olefin metathesis, alkyne metathesis, and ene-yne cyclizations. In this Account, we examine the fundamental mechanistic aspects of alkane metathesis as well as the novel reactions that have been derived from its study. The silica-supported tantalum hydride catalyst was developed as the result of systematic and meticulous studies of the interaction between oxide supports and organometallic complexes, a field of study denoted surface organometallic chemistry (SOMC). A careful examination of this surface-supported tantalum hydride led to the later discovery of alumina-supported tungsten hydride, W(H)(3)/Al(2)O(3), which proved to be an even better catalyst for alkane metathesis. Supported tantalum and tungsten hydrides are highly unsaturated, electron-deficient species that are very reactive toward the C-H and C-C bonds of alkanes. They show a great versatility in various other reactions, such as cross-metathesis between methane and alkanes, cross-metathesis between toluene and ethane, or even methane nonoxidative coupling. Moreover, tungsten hydride exhibits a specific ability in the transformation of isobutane into 2,3-dimethylbutane as well as in the metathesis of olefins or the selective transformation of ethylene into propylene. Alkane metathesis represents a powerful tool for making progress in a variety of areas, perhaps most notably in the petroleum and petrochemical fields. Modern civilization is currently confronting a host of problems that relate to energy production and its effects on the environment, and judicious application of alkane metathesis to the processing of fuels such as crude oil and natural gas may well afford solutions to these difficulties.


Epidemiology of perinatal depression in Portugal: categorical and dimensional approach.
The aim of the present study was to estimate depressive disorder and symptomatology prevalence and incidence in perinatal period in a population-based sample. Three-hundred and eighty six Portuguese women (mean age=30.08 years, SD=4.21) were interviewed with the Diagnostic Interview for Genetic Studies and completed Beck Depression Inventory-II/BDI-II and Postpartum Depression Screening Scale/PDSS, in pregnancy and postpartum. OPCRIT polydiagnostic system generated ICD-10 and DSM-IV diagnoses. One-month prevalence in pregnancy was of 2.3%/ICD-10 and 1.3%/DSM-IV; in postpartum it was of 16.6% and 11.7%. Pregnancy incidence was of 0%/ICD-10 and .3%/DSM-IV and in postpartum of 7.5%/ ICD-10 and 4.9%/DSM-IV. Depression pregnancy point-prevalence found with BDI-II cutoffs ranged from 13.7% to 19.4% in pregnancy and from .8% to 13.0% in postpartum and with PDSS from 14.2% to 17.9% in pregnancy and from 3.9% to 12.7% in postpartum. In the same sample, different diagnostic systems generated different prevalence and incidence rates. Higher prevalence rates were found using self-reported questionnaires. ICD-10 generated higher prevalence and incidence rates than DSM-IV.


RanBP9 Plays a Critical Role in Neonatal Brain Development in Mice.
RanBP9 is known to act as a scaffolding protein bringing together a variety of cell surface receptors and intracellular targets thereby regulating functions as diverse as neurite and axonal outgrowth, cell morphology, cell proliferation, myelination, gonad development, myofibrillogenesis and migration of neuronal precursors. Though RanBP9 is ubiquitously expressed in all tissues, brain is one of the organs with the highest expression levels of RanBP9. In the neurons, RanBP9 is localized mostly in the cytoplasm but also in the neurites and dendritic processes. We recently demonstrated that RanBP9 plays pathogenic role in Alzheimer's disease. To understand the role of RanBP9 in the brain, here we generated RanBP9 null mice by gene-trap based strategy. Most of Ran-/- mice die neonatally due to defects in the brain growth and development. The major defects include smaller cortical plate (CP), robustly enlarged lateral ventricles (LV) and reduced volume of hippocampus (HI). The lethal phenotype is due to a suckling defect as evidenced by lack of milk in the stomachs even several hours after parturition. The complex somatosensory system which is required for a behavior such as suckling appears to be compromised in Ran-/- mice due to under developed CP. Most importantly, RanBP9 phenotype is similar to ERK1/2 double knockout and the neural cell adhesion receptor, L1CAM knockout mice. Both ERK1 and L1CAM interact with RanBP9. Thus, RanBP9 appears to control brain growth and development through signaling mechanisms involving ERK1 and L1CAM receptor.


Hoxa2 selectively enhances Meis binding to change a branchial arch ground state.
Hox transcription factors (TFs) are essential for vertebrate development, but how these evolutionary conserved proteins function in vivo remains unclear. Because Hox proteins have notoriously low binding specificity, they are believed to bind with cofactors, mainly homeodomain TFs Pbx and Meis, to select their specific targets. We mapped binding of Meis, Pbx, and Hoxa2 in the branchial arches, a series of segments in the developing vertebrate head. Meis occupancy is largely similar in Hox-positive and -negative arches. Hoxa2, which specifies second arch (IIBA) identity, recognizes a subset of Meis prebound sites that contain Hox motifs. Importantly, at these sites Meis binding is strongly increased. This enhanced Meis binding coincides with active enhancers, which are linked to genes highly expressed in the IIBA and regulated by Hoxa2. These findings show that Hoxa2 operates as a tissue-specific cofactor, enhancing Meis binding to specific sites that provide the IIBA with its anatomical identity.


Image-based reconstruction of three-dimensional myocardial infarct geometry for patient-specific modeling of cardiac electrophysiology.
Accurate three-dimensional (3D) reconstruction of myocardial infarct geometry is crucial to patient-specific modeling of the heart aimed at providing therapeutic guidance in ischemic cardiomyopathy. However, myocardial infarct imaging is clinically performed using two-dimensional (2D) late-gadolinium enhanced cardiac magnetic resonance (LGE-CMR) techniques, and a method to build accurate 3D infarct reconstructions from the 2D LGE-CMR images has been lacking. The purpose of this study was to address this need. The authors developed a novel methodology to reconstruct 3D infarct geometry from segmented low-resolution (Lo-res) clinical LGE-CMR images. Their methodology employed the so-called logarithm of odds (LogOdds) function to implicitly represent the shape of the infarct in segmented image slices as LogOdds maps. These 2D maps were then interpolated into a 3D image, and the result transformed via the inverse of LogOdds to a binary image representing the 3D infarct geometry. To assess the efficacy of this method, the authors utilized 39 high-resolution (Hi-res) LGE-CMR images, including 36 in vivo acquisitions of human subjects with prior myocardial infarction and 3 ex vivo scans of canine hearts following coronary ligation to induce infarction. The infarct was manually segmented by trained experts in each slice of the Hi-res images, and the segmented data were downsampled to typical clinical resolution. The proposed method was then used to reconstruct 3D infarct geometry from the downsampled images, and the resulting reconstructions were compared with the manually segmented data. The method was extensively evaluated using metrics based on geometry as well as results of electrophysiological simulations of cardiac sinus rhythm and ventricular tachycardia in individual hearts. Several alternative reconstruction techniques were also implemented and compared with the proposed method. The accuracy of the LogOdds method in reconstructing 3D infarct geometry, as measured by the Dice similarity coefficient, was 82.10% ± 6.58%, a significantly higher value than those of the alternative reconstruction methods. Among outcomes of electrophysiological simulations with infarct reconstructions generated by various methods, the simulation results corresponding to the LogOdds method showed the smallest deviation from those corresponding to the manual reconstructions, as measured by metrics based on both activation maps and pseudo-ECGs. The authors have developed a novel method for reconstructing 3D infarct geometry from segmented slices of Lo-res clinical 2D LGE-CMR images. This method outperformed alternative approaches in reproducing expert manual 3D reconstructions and in electrophysiological simulations.


Vitamin D3 and 25-hydroxyvitamin D3 in pork and their relationship to vitamin D status in pigs.
The content of vitamin D in pork produced in conventional systems depends on the vitamin D concentration in the pig feed. Both vitamin D3 and 25-hydroxyvitamin D3 (25(OH)D3) are essential sources of dietary vitamin D; however, bioavailability assessed by serum 25(OH)D3 concentration is reported to be different between the two sources. Furthermore, the relationship between serum 25(OH)D3 level and the tissue content of vitamin D3 and 25(OH)D3 is unknown. The objective of this study was to investigate the potential of increasing the content of vitamin D in different pig tissues by increasing the levels of vitamin D3 and 25(OH)D3 in the pig feed for 49 d before slaughter. Concurrently, the 25(OH)D3 level in serum was investigated as a biomarker to assess the content of vitamin D3 and 25(OH)D3 in pig tissues. Adipose tissue, white and red muscle, the liver and serum were sampled from pigs fed feed containing either vitamin D3 or 25(OH)D3 at 5, 20, 35 or 50 µg/kg feed for 7 weeks before slaughter. The tissue 25(OH)D3 level was significantly higher in the pigs fed 25(OH)D3 compared with those fed vitamin D3, while the tissue vitamin D3 level was higher in the pigs fed vitamin D3 compared with those fed 25(OH)D3. The content of 25(OH)D3 in the different tissues fully correlated with the serum 25(OH)D3 level, whereas the correlation between the tissue content of vitamin D3 and serum 25(OH)D3 was dependent on the source of the ingested vitamin D3.


Whatever happened to clinical breast examinations?
The purpose of this study was to examine trends in the use of clinical breast examinations (CBE), mammography, and both tests between the years 1990 and 2000. Receipt of breast cancer screening tests (CBE, mammography, and both tests combined) for white, black, and Hispanic women in 1990, 1994, 1998, and 2000 were examined by sociodemographic, access, and health risk indicators using data from the National Health Interview Survey. The use of mammography increased from 1990 to 2000, but the proportion of women reporting a recent CBE decreased for almost all groups of women. Differential use of CBE by sociodemographic characteristics is consistent with what has been documented for mammography. Although the use of mammography has increased since 1990, there has been a downward trend in the use of CBE. Healthcare providers should be aware of the lower rates of CBE, particularly among women with compromised access to health care, and should not assume that women who get mammograms have received comprehensive screening for breast cancer.


Ataxia telangiectasia-mutated kinase deficiency exacerbates left ventricular dysfunction and remodeling late after myocardial infarction.
Ataxia telangiectasia-mutated kinase (ATM), a cell cycle checkpoint protein, is activated in response to DNA damage and oxidative stress. We have previously shown that ATM deficiency is associated with increased apoptosis and fibrosis and attenuation of cardiac dysfunction early (1-7 days) following myocardial infarction (MI). Here, we tested the hypothesis that enhanced fibrosis and apoptosis, as observed early post-MI during ATM deficiency, exacerbate cardiac dysfunction and remodeling in ATM-deficient mice late post-MI. MIs were induced in wild-type (WT) and ATM heterozygous knockout (hKO) mice by ligation of the left anterior descending artery. Left ventricular (LV) structural and functional parameters were assessed by echocardiography 14 and 28 days post-MI, whereas biochemical parameters were measured 28 days post-MI. hKO-MI mice exhibited exacerbated LV dysfunction as observed by increased LV end-systolic volume and decreased percent fractional shortening and ejection fraction. Infarct size and thickness were not different between the two genotypes. Myocyte cross-sectional area was greater in hKO-MI group. The hKO-MI group exhibited increased fibrosis in the noninfarct and higher expression of α-smooth muscle actin (myofibroblast marker) in the infarct region. Apoptosis and activation of GSK-3β (proapoptotic kinase) were significantly lower in the infarct region of hKO-MI group. Matrix metalloproteinase 2 (MMP-2) expression was not different between the two genotypes. However, MMP-9 expression was significantly lower in the noninfarct region of hKO-MI group. Thus ATM deficiency exacerbates cardiac remodeling late post-MI with effects on cardiac function, fibrosis, apoptosis, and myocyte hypertrophy.


Urine-based biomarkers for the early detection and surveillance of non-muscle invasive bladder cancer.
Bladder cancer has a very high frequency of recurrence and therefore requires lifelong surveillance, traditionally consisting of serial cystoscopy and cytology. These tests are both invasive and expensive, with considerable inter-user and inter-institutional variability. In addition, the sensitivity of cytology in detecting low-grade tumors is low. Therefore, there has been active investigation into urinary biomarkers that can either supplement or supplant these tests. At this point there are only six urine-based tests that are FDA-approved in bladder cancer surveillance, but a wide variety of other biomarkers are being studied. In this review, we examine the natural history of bladder cancer as well as the rationale and performance of an ideal urinary biomarker. The authors describe the FDA-approved biomarkers such as Bladder Tumor Antigen, ImmunoCyt, Nuclear Matrix Protein-22, and Fluorescent In Situ Hybridization, as well as the most promising investigational tests (i.e., Urinary bladder cancer test, BLCA-1, BLCA-4, hyaluronic acid, hyaluronidase, Lewis X antigen, microsatellite analysis, Quanticyt, soluble Fas, Survivin, and telomerase). The biological foundation, methodologies, and diagnostic performance of the biomarkers are discussed. The characteristics of the biomarkers are compared to urine cytology. At this time, urine biomarkers are utilized in a variety of clinical situations but their role is not well defined. The goal of identifying an optimal marker that will replace cystoscopy and/or cytology is still ongoing.


Natural killer T cell based Immunotherapy.
Natural killer T (NKT) cells play an important immunoregulatory role and are thought to bridge the innate and adaptive immune responses. Following activation through cognate interactions with lipid antigen presented in the context of CD1d molecules, NKT cells rapidly produce a plethora of cytokines and can also mediate cytotoxicity. Due to their potent effector functions, extensive research has been performed to increase our understanding on how to effectively modulate these cells. In fact, NKT cell agonists have been used as vaccine adjuvants to enhance antigen specific T and B cell responses to infections and malignancy. In this review, we will focus on recent advances in NKT cell-based vaccination strategies. Given the role that NKT cells play in autoimmune disease, infectious diseases, cancer, transplant immunology and dermatology, it is important to understand how to effectively guide their effector functions in order to develop novel immunotherapeutic strategies.


Growth factors for therapeutic angiogenesis in peripheral arterial disease.
Peripheral arterial disease is a common disease that has few treatment options. Angiogenesis is defined as the growth of new blood vessels from preexisting vasculature. Therapeutic angiogenesis is an investigational method that uses vascular growth to alleviate disorders of tissue ischemia, such as coronary artery disease and peripheral arterial disease. There have been tremendous changes in the field of therapeutic angiogenesis over the past decade, and there is much promise for the future. Initial preclinical work with cytokine growth factor delivery resulted in a great deal of enthusiasm, but larger clinical studies have failed to achieve similar success. With an increased understanding of the complex mechanisms involved in angiogenesis, gene therapy and cell therapy have moved to the forefront of therapeutic angiogenesis. Novel therapies which target multiple different angiogenic pathways are also being developed and tested. Therapeutic angiogenesis is an exciting field that continues to evolve. This review will focus on the different growth factors being used, their routes of delivery, the results of clinical trials, and some of the novel therapies being developed.


Maintenance of blastemal proliferation by functionally diverse epidermis in regenerating zebrafish fins.
Appendage regeneration in salamanders and fish occurs through formation and maintenance of a mass of progenitor tissue called the blastema. A dedicated epidermis overlays the blastema and is required for its proliferation and patterning, yet this interaction is poorly understood. Here, we identified molecularly and functionally distinct compartments within the basal epidermal layer during zebrafish fin regeneration. Proximal epidermal subtypes express the transcription factor lef1 and the blastemal mitogen shh, while distal subtypes express the Fgf target gene pea3 and wnt5b, an inhibitor of blastemal proliferation. Ectopic overexpression of wnt5b reduced shh expression, while pharmacologic introduction of a Hh pathway agonist partially rescued blastemal proliferation during wnt5b overexpression. Loss- and gain-of-function approaches indicate that Fgf signaling promotes shh expression in proximal epidermis, while Fgf/Ras signaling restricts shh expression from distal epidermis through induction of pea3 expression and maintenance of wnt5b. Thus, the fin wound epidermis spatially confines Hh signaling through the activity of Fgf and Wnt pathways, impacting blastemal proliferation during regenerative outgrowth.


Simulation of transcatheter aortic valve implantation under consideration of leaflet calcification.
Transcatheter aortic valve implantation (TAVI) is a minimally invasive off-pump procedure to replace diseased aortic heart valves. Known complications include paravalvular leaks, atrioventricular blocks, coronary obstruction and annular rupture. Careful procedure planning including appropriate stent selection and sizing are crucial. Few patient-specific geometric parameters, like annular diameters, annular perimeter and measurement of the distance to the coronary ostia, are currently used within this process. Biomechanical simulation allows the consideration of extracted anatomy and material parameters for the intervention, which may improve planning and execution phases. We present a simulation workflow using a fully segmented aortic root anatomy, which was extracted from pre-operative CT-scan data and apply individual material models and parameters to predict the procedure outcome. Our results indicate the high relevance of calcification location and size for intervention planning, which are not sufficiently considered at this time. Our analysis can further provide guidance for accurate, patient-specific device positioning and future adaptations to stent design.


Depression vulnerability within smoking research: How accurate are one-item screening items?
Epidemiological and large scale treatment studies within smoking research have utilized many one-item screening items to examine the influence of current depressive symptoms on smoking behavior and quitting. Little is known about that concurrent validity of screening items that may reflect depression vulnerability independent of current symptoms. The present paper evaluated the concurrent validity of two one-item screening items that were essential for diagnosing past episodes of major depression. Screening questions were administered to seventy-seven nicotine dependent participants via a telephone screening interview. Smokers then returned to the laboratory for a comprehensive structured assessment of depressive vulnerability. Vulnerability measures were clinician-diagnosed history of major depressive disorder and other self-reported depressive vulnerability factors. Telephone screening items accurately classified a clinician-diagnosed history of major depression, and predicted the number of recurrent depressive episodes, self-reported rumination, and self-reported depression-proneness (all p<0.05). Results support the utility of one-item screening questions as a "proxy" of a depressive vulnerability for smoking treatment studies that are not designed for comprehensive assessment procedures.


Report of the first international workshop on onchocerciasis-associated epilepsy.
Recently, several epidemiological studies performed in Onchocerca volvulus-endemic regions have suggested that onchocerciasis-associated epilepsy (OAE) may constitute an important but neglected public health problem in many countries where onchocerciasis is still endemic. On October 12-14th 2017, the first international workshop on onchocerciasis-associated epilepsy (OAE) was held in Antwerp, Belgium. The workshop was attended by 79 participants from 20 different countries. Recent research findings strongly suggest that O. volvulus is an important contributor to epilepsy, particularly in meso- and hyperendemic areas for onchocerciasis. Infection with O. volvulus is associated with a spectrum of epileptic seizures, mainly generalised tonic-clonic seizures but also atonic neck seizures (nodding), and stunted growth. OAE is characterised by an onset of seizures between the ages of 3-18 years. Multidisciplinary working groups discussed topics such as how to 1) strengthen the evidence for an association between onchocerciasis and epilepsy, 2) determine the burden of disease caused by OAE, 3) prevent OAE, 4) improve the treatment/care for persons with OAE and affected families, 5) identify the pathophysiological mechanism of OAE, and 6) deal with misconceptions, stigma, discrimination and gender violence associated with OAE. An OAE Alliance was created to increase awareness about OAE and its public health importance, stimulate research and disseminate research findings, and create partnerships between OAE researchers, communities, advocacy groups, ministries of health, non-governmental organisations, the pharmaceutical industry and funding organizations. Although the exact pathophysiological mechanism underlying OAE remains unknown, there is increasing evidence that by controlling and eliminating onchocerciasis, OAE will also disappear. Therefore, OAE constitutes an additional argument for strengthening onchocerciasis elimination efforts. Given the high numbers of people with epilepsy in O. volvulus-endemic regions, more advocacy is urgently needed to provide anti-epileptic treatment to improve the quality of life of these individuals and their families.


Assessing stability in mild and moderate Parkinson's disease: Can clinical measures provide insight?
This cross-sectional study aimed to investigate the relationship between accelerometer-derived measures of movement rhythmicity and clinical measures of mobility, balance confidence and gait difficulty in people with Parkinson's disease (PD). Twenty-nine independently-living PD patients (Hoehn & Yahr Stages 1-3) with no history of significant injury or orthopaedic/deep brain stimulation surgery were recruited from a database of patients who had expressed an interest to participate in research. Participants completed clinical assessments of mobility, postural stability, balance confidence and symptom severity, while head and trunk rhythmicity was evaluated during gait using accelerometers. Following data collection, patients were stratified based on disease stage into either a Mild (Hoehn & Yahr Stage 1) or Moderate (Hoehn & Yahr Stages 2-3) PD group. The results highlighted that the Moderate PD group had poorer quality of life, reduced balance confidence and increased gait and falls difficulty. Furthermore, for these patients, gait disability and the number of previous falls were both negatively correlated with multiple components of head and trunk rhythmicity. For the Mild PD group, six-meter walk time was positively correlated with ML head rhythmicity and linear regression highlighted a significant predictive relationship between these outcomes. For the Mild and Moderate PD groups, balance confidence respectively predicted anterior-posterior trunk rhythmicity and vertical head rhythmicity. While these findings demonstrate that falls history and the Gait and Falls questionnaire provide moderate insight into head and trunk rhythmicity in Moderate PD patients, objective and clinically-feasible measures of postural instability would assist with the management of these symptoms.


Iterative development of a web-based intervention for families of young children with type 1 diabetes: DIPPer Academy.
A new diagnosis of Type 1 diabetes mellitus (T1D) can be stressful for families as they are expected to learn a large amount of information regarding disease management and treatment in a short period of time. Currently, parents complete diabetes education at the time of diagnosis. However, this format may not be sustainable as rates of T1D climb. The current study aimed to develop an online platform to provide educational material in the form of video micro-lectures using an iterative, user-centered, design process. In the first stage of development, parents of young children with T1D identified information they felt most important to their child's T1D care. In the second stage, healthcare providers contributed qualitative and quantitative feedback regarding the educational material and video mock-ups. The third stage involved parents of young children with T1D providing feedback on the completed video micro-lectures. Providers and parents reported that the videos were highly useful, important to T1D care, and the majority would recommend them to other parents. The iterative design process used by the research team incorporated multiple perspectives and ultimately developed educational resources that were well-received by providers, researchers, and parents. This study used an iterative, user-centered design to develop a series of web-based videos for parents of young children with type 1 diabetes. Primary stakeholders, both healthcare providers and parents, described videos as highly important, useful, enjoyable, and would recommend these resources to others. Parents rated videos highly across a variety of presentations that ranged in development time and cost, indicating that researchers can feasibly and cost-effectively create web-based resources for parents.


The effects of inspiratory muscle training on plasma interleukin-6 concentration during cycling exercise and a volitional mimic of the exercise hyperpnea.
It is unknown whether the respiratory muscles contribute to exercise-induced increases in plasma interleukin-6 (IL-6) concentration, if this is related to diaphragm fatigue, and whether inspiratory muscle training (IMT) attenuates the plasma IL-6 response to whole body exercise and/or a volitional mimic of the exercise hyperpnea. Twelve healthy males were divided equally into an IMT or placebo (PLA) group, and before and after a 6-wk intervention they undertook, on separate days, 1 h of 1) passive rest, 2) cycling exercise at estimated maximal lactate steady state power (EX), and 3) volitional hyperpnea at rest, which mimicked the breathing and respiratory muscle recruitment patterns achieved during EX (HYPEX). Plasma IL-6 concentration remained unchanged during passive rest. The plasma IL-6 response to EX was reduced following IMT (main effect of intervention, P = 0.039) but not PLA (P = 0.272). Plasma IL-6 concentration increased during HYPEX (main effect of time, P < 0.01) and was unchanged postintervention. There was no evidence of diaphragm fatigue (measured by phrenic nerve stimulation) following each trial. In conclusion, plasma IL-6 concentration is increased during EX and HYPEX and this occurred in the absence of diaphragm fatigue. Furthermore, IMT reduced the plasma IL-6 response to EX but not HYPEX. These findings suggest that the respiratory muscles contribute to exercise-induced increases in plasma IL-6 concentration in the absence of diaphragm fatigue and that IMT can reduce the magnitude of the response to exercise but not a volitional mimic of the exercise hyperpnea.


Vitamin B-6 intake is related to physical performance in European older adults: results of the New Dietary Strategies Addressing the Specific Needs of the Elderly Population for Healthy Aging in Europe (NU-AGE) study.
Maintenance of high physical performance during aging might be supported by an adequate dietary intake of niacin, vitamins B-6 and B-12, and folate because these B vitamins are involved in multiple processes related to muscle functioning. However, not much is known about the association between dietary intake of these B vitamins and physical performance. The objectives of this study were to investigate the association between dietary intake of niacin, vitamins B-6 and B-12, and folate and physical performance in older adults and to explore mediation by niacin status and homocysteine concentrations. We used baseline data from the New Dietary Strategies Addressing the Specific Needs of the Elderly Population for Healthy Aging in Europe (NU-AGE) trial, which included n = 1249 healthy older adults (aged 65-79 y) with complete data on dietary intake measured with 7-d food records and questionnaires on vitamin supplement use and physical performance measured with the short physical performance battery and handgrip dynamometry. Associations were assessed by adjusted linear mixed models. Intake of vitamin B-6 was related to lower chair rise test time [β: -0.033 ± 0.016 s (log); P = 0.043]. Vitamin B-6 intake was also significantly associated with handgrip strength, but for this association, a significant interaction effect between vitamin B-6 intake and physical activity level was found. In participants with the lowest level of physical activity, higher intake of vitamin B-6 tended to be associated with greater handgrip strength (β: 1.5 ± 0.8 kg; P = 0.051), whereas in participants in the highest quartile of physical activity, higher intake was associated with lower handgrip strength (β: -1.4 ± 0.7 kg; P = 0.041). No evidence was found for an association between intake of niacin, vitamin B-12, or folate and physical performance or for mediation by niacin status or homocysteine concentrations. Vitamin B-6 intake was associated with better chair rise test time in a population of European healthy older adults and also with greater handgrip strength in participants with low physical activity only. Homocysteine concentrations did not mediate these associations. The NU-AGE trial was registered at clinicaltrials.gov as NCT01754012.


Genome-wide search reveals a novel GacA-regulated small RNA in Pseudomonas species.
Small RNAs (sRNAs) are widespread among bacteria and have diverse regulatory roles. Most of these sRNAs have been discovered by a combination of computational and experimental methods. In Pseudomonas aeruginosa, a ubiquitous Gram-negative bacterium and opportunistic human pathogen, the GacS/GacA two-component system positively controls the transcription of two sRNAs (RsmY, RsmZ), which are crucial for the expression of genes involved in virulence. In the biocontrol bacterium Pseudomonas fluorescens CHA0, three GacA-controlled sRNAs (RsmX, RsmY, RsmZ) regulate the response to oxidative stress and the expression of extracellular products including biocontrol factors. RsmX, RsmY and RsmZ contain multiple unpaired GGA motifs and control the expression of target mRNAs at the translational level, by sequestration of translational repressor proteins of the RsmA family. A combined computational and experimental approach enabled us to identify 14 intergenic regions encoding sRNAs in P. aeruginosa. Eight of these regions encode newly identified sRNAs. The intergenic region 1698 was found to specify a novel GacA-controlled sRNA termed RgsA. GacA regulation appeared to be indirect. In P. fluorescens CHA0, an RgsA homolog was also expressed under positive GacA control. This 120-nt sRNA contained a single GGA motif and, unlike RsmX, RsmY and RsmZ, was unable to derepress translation of the hcnA gene (involved in the biosynthesis of the biocontrol factor hydrogen cyanide), but contributed to the bacterium's resistance to hydrogen peroxide. In both P. aeruginosa and P. fluorescens the stress sigma factor RpoS was essential for RgsA expression. The discovery of an additional sRNA expressed under GacA control in two Pseudomonas species highlights the complexity of this global regulatory system and suggests that the mode of action of GacA control may be more elaborate than previously suspected. Our results also confirm that several GGA motifs are required in an sRNA for sequestration of the RsmA protein.