Relative contribution of the dorsal raphe nucleus and ventrolateral periaqueductal gray to morphine antinociception and tolerance in the rat.

The dorsal raphe nucleus (DRN) is embedded in the ventral part of the caudal periaqueductal gray (PAG). Electrical or chemical activation of neurons throughout this region produces antinociception. The objective of this manuscript is to determine whether the ventrolateral PAG and DRN are distinct antinociceptive systems. This hypothesis was tested by determining the antinociceptive potency of microinjecting morphine into each structure (Experiment 1), creating a map of effective microinjection sites that produce antinociception (Experiment 2) and comparing the development of antinociceptive tolerance to repeated microinjections of morphine into the ventrolateral PAG and DRN (Experiment 3). Morphine was more potent following cumulative injections (1.0, 2.2, 4.6 & 10 µg/0.2 µL) into the ventrolateral PAG (D50  = 3.3 µg) compared to the lateral (4.3 µg) or medial DRN (5.8 µg). Antinociception occurred following 94% of the morphine injections into the ventrolateral PAG, whereas only 68.3% and 78.3% of the injections into the lateral and medial aspects of the DRN produced antinociception. Repeated microinjections of morphine into the ventrolateral PAG produced tolerance as indicated by a 528% difference in potency between morphine and saline pretreated rats. In contrast, relatively small changes in potency occurred following repeated microinjections of morphine into the lateral and medial aspects of the DRN (107% and 49%, respectively). These data indicate that the ventrolateral PAG and DRN are distinct antinociceptive structures. Antinociception is greater with injections into the ventrolateral PAG compared to the DRN, but this antinociception disappears rapidly because of the development of tolerance.

Walk@Work: An automated intervention to increase walking in university employees not achieving 10,000 daily steps.

OBJECTIVE: This study assessed the workday step counts of lower active (<10,000 daily steps) university employees using an automated, web-based walking intervention (Walk@Work). METHODS: Academic and administrative staff (n=390; 45.6±10.8years; BMI 27.2±5.5kg/m(2); 290 women) at five campuses (Australia [x2], Canada, Northern Ireland and the United States), were given a pedometer, access to the website program (2010-11) and tasked with increasing workday walking by 1000 daily steps above baseline, every two weeks, over a six week period. Step count changes at four weeks post intervention were evaluated relative to campus and baseline walking. RESULTS: Across the sample, step counts significantly increased from baseline to post-intervention (1477 daily steps; p=0.001). Variations in increases were evident between campuses (largest difference of 870 daily steps; p=0.04) and for baseline activity status. Those least active at baseline (<5000 daily steps; n=125) increased step counts the most (1837 daily steps; p=0.001), whereas those most active (7500-9999 daily steps; n=79) increased the least (929 daily steps; p=0.001). CONCLUSIONS: Walk@Work increased workday walking by 25% in this sample overall. Increases occurred through an automated program, at campuses in different countries, and were most evident for those most in need of intervention.

Biofeedback-assisted relaxation in type 2 diabetes.

OBJECTIVE: The objective of this randomized controlled study was to determine the effects of biofeedback and relaxation on blood glucose and HbA1c (A1C) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes were randomized to either 10 sessions of biofeedback (electromyograph and thermal) and relaxation or 3 sessions of education. All sessions were individual. A total of 39 participants were entered, and 30 completed the 3-month protocol. Average blood glucose, A1C, forehead muscle tension, and peripheral skin temperature were assessed, and inventories measuring depression and anxiety were administered pre-randomization and after completion of treatment/control. RESULTS: Biofeedback and relaxation were associated with significant decreases in average blood glucose, A1C, and muscle tension compared with the control group. At 3-month follow-up, the treatment group continued to demonstrate lower blood glucose and A1C. Both groups decreased scores on the depression and anxiety inventories. Patients with depression had higher blood glucose levels and tended to drop out of the study. CONCLUSIONS: This study supports the use of biofeedback and relaxation in patients with type 2 diabetes for up to 3 months after treatment. Further research is necessary to determine the long-term effects of biofeedback and the effects of mood on patients' responses to treatment.

Behavioral interventions for adolescents with type 1 diabetes: how effective are they?

OBJECTIVE: To evaluate the effectiveness of behavioral interventions for adolescents with type 1 diabetes based on a systematic review of the literature. RESEARCH DESIGN AND METHODS: The literature was identified by searching 11 electronic databases, hand-searching 3 journals from their start dates, and contacting individual researchers. Only articles that reported evaluations of behavioral (including educational and psychosocial) interventions for adolescents (age range 9-21 years) with type 1 diabetes that included a control group were included in the present review. Data summarizing the key features of the interventions and their effects were extracted from each article. Where possible, effect sizes for the randomized control trials (RCTs) were calculated. RESULTS: The search process identified 64 reports of empirical studies. Of these, 35 studies included a control group, and 24 were RCTs. Effect sizes could be calculated for 18 interventions. The overall mean effect size calculated across all outcomes was 0.33 (median 0.21), indicating that these interventions have a small- to medium-sized beneficial effect on diabetes management. Interventions that were theoretically based were significantly more effective than those that were not (P<0.05, 1-tailed). CONCLUSIONS: Research to date indicates that these interventions are moderately effective. Several methodological weaknesses to be avoided in future studies are noted. It is also recommended that investigators use the reach, efficacy, adoption, implementation, and maintenance (RE-AIM) framework to guide the design of future studies, which should result in more disseminable interventions. RE-AIM assesses the intervention's reach, or percent or representativeness of patients willing to participate; efficacy across a range of outcomes; adoption, or the percent and representativeness of settings willing to implement the intervention; implementation, or the consistency of the delivery of the intervention as intended; and maintenance, or the extent to which delivery of the intervention becomes a routine part of health care in the medical setting.

Dependent censoring in piecewise exponential survival models.

There are often reasons to suppose that there is dependence between the time to event and time to censoring, or dependent censoring, for survival data, particularly when considering medical data. This is because the decision to treat or not is often made according to prognosis, usually with the most ill patients being prioritised. Due to identifiability issues, sensitivity analyses are often used to assess whether independent censoring can lead to misleading results. In this paper, a sensitivity analysis method for piecewise exponential survival models is presented. This method assesses the sensitivity of the results of standard survival models to small amounts of dependence between the time to failure and time to censoring variables. It uses the same assumption about the dependence between the time to failure and time to censoring as previous sensitivity analyses for both standard parametric survival models and the Cox model. However, the method presented in this paper allows the use of more flexible models for the marginal distributions whilst remaining computationally simple. A simulation study is used to assess the accuracy of the sensitivity analysis method and identify the situations in which it is suitable to use this method. The study found that the sensitivity analysis performs well in many situations, but not when the data have a high proportion of censoring.

Effects of educational and psychosocial interventions for adolescents with diabetes mellitus: a systematic review.

BACKGROUND: Insulin-dependent diabetes mellitus, also known as type 1 diabetes, is a life-threatening condition and is the third most common chronic illness among young people. As a result of minimal or non-existent insulin production, people with diabetes must take over the normally automatic task of regulation of blood glucose levels. This is achieved by a complex regimen involving multiple, daily administrations of insulin coordinated with dietary intake and energy expenditure and monitored by blood glucose testing. OBJECTIVES: To examine the effectiveness of educational and psychosocial interventions for adolescents with type 1 diabetes designed to improve their diabetes management. Specifically, it addressed the following research questions: (1) Do educational and psychosocial interventions for adolescents with type 1 diabetes have beneficial effects on biological and psychosocial outcomes? (2) Are there types or features of interventions that have been shown to be more effective than others? (3) What evidence is there of the cost-effectiveness of interventions? METHODS: A search strategy was formulated, piloted and refined. Three journals were handsearched, 11 electronic databases were searched and personal contacts, flyers, conferences and websites were used to notify the research community of the review to access further literature. This process generated 10,535 abstracts, which, after screening, resulted in 367 articles identified for retrieval. This number was augmented by hand-searching, personal contact and exploding references, and a final total of 457 articles were scrutinised. Of these, 64 reports describing 62 studies were identified as empirical papers evaluating educational or psychosocial interventions. The relevant data were extracted from the papers and summary tables for each study were prepared. Where possible, effect sizes were computed for outcomes from studies that included a randomised control group (CG) and other relevant information. RESULTS: A descriptive analysis of the 62 studies was undertaken. Most studies (67.7%) were conducted in the USA and 41% were randomised controlled trials (RCTs), none of which were UK-based. Only 48% of the reports provided an explicit theoretical rationale for the intervention. The mean number of participants was 53.8. The studies took place in various settings, evaluated a variety of interventions, involved various interventionists, addressed various components and assessed the effects by a range of outcomes, including measures of metabolic control and psychological and behavioural outcomes. Follow-up assessments were relatively rare. RESULTS - THE EFFECTIVENESS OF INTERVENTIONS: The 25 RCTs were examined in more detail and three of the most effective were described in depth. Effect sizes could be calculated for 14 studies. The mean (pooled) effect size for psychosocial outcomes was 0.37 and 0.33 for glycated haemoglobin with outliers (0.08 without outliers), indicating that these interventions have small to medium beneficial effects on diabetes management outcomes. A narrative review of the 21 pre-post studies with no CG was performed, including evaluations of interventions conducted at summer camps, interventions for poorly controlled patients and educational interventions. All studies reported beneficial effects. RESULTS - COST-EFFECTIVENESS: Few studies addressed economic considerations associated with interventions, and the lack of information on costs and the diversity of outcomes included by investigators impeded cost- effectiveness comparisons. Shorter hospitalisation at diagnosis is at least as effective in achieving control and avoiding complications in adolescence as longer stays. Home care may result in improved outcomes but may not be cheaper than hospital care at diagnosis. Targeting poorly controlled subjects may reduce adverse events and hospitalisations and may be more cost-effective than generic interventions. There is a need for rigorous cost-effectiveness studies of educational and psychosocial interventions for adolescents with type 1 diabetes that include longer-term considerations. CONCLUSIONS: The following conclusions were drawn from this review: (1) Educational and psychosocial interventions have small to medium beneficial effects on various diabetes management outcomes. (2) Well-designed trials of such interventions are needed in the UK (no completed RCTs of educational or psychosocial interventions for adolescents with type 1 diabetes conducted in the UK were found). (3) The evidence, arising primarily from studies in the USA, provides a starting point for the design of interventions in the UK. (4) Quantitative and narrative analysis of the evidence suggested that interventions are more likely to be effective if they demonstrate the inter-relatedness of the various aspects of diabetes management. (ABSTRACT TRUNCATED)

Systematic review concerning the age of introduction of complementary foods to the healthy full-term infant.

OBJECTIVES: To evaluate existing data from published studies investigating outcomes (growth, nutritional status and morbidity) in relation to the age of introduction of complementary foods to the healthy full-term infant. To assess the methodological quality of current scientific evidence on which infant feeding recommendations are based. SEARCH STRATEGY: A database was created following a search of electronic databases MEDLINE and BIDS, a handsearch of relevant journals and consultation with international experts in infant feeding practices. The search was conducted during a 6-month period and encompassed the years 1982-1998. INCLUSION CRITERIA: Randomised/non-randomised controlled trials and cohort studies investigating the relationship to the health of full-term infants of the introduction of complementary foods to childhood health. DATA COLLECTION AND ANALYSIS: Assessment of studies for inclusion and their compliance with methodological criteria was undertaken independently by two reviewers and discrepancies were resolved by discussion. RESULTS: From over 400 published papers identified, 33 met specific inclusion criteria. Significant differences in baseline characteristics of subjects in included studies meant that data were not amenable to meta-analysis. The consensus of the authors was that, of the 33 included publications, 13 contained data supporting the current WHO recommendations which attempt to accommodate all infants, including those whose nutritional requirements are not met by exclusive breast-feeding for 6 months. An equal number contained data that would support a recommendation for delaying the introduction of complementary foods until 6 months of age within the study population. The remaining seven were unable to provide evidence to support a change from the current WHO infant feeding recommendations which state that 'infants should be fed exclusively on breast milk from birth to 4-6 months of age'. None of the studies met all the methodological criteria. CONCLUSIONS: This review has shown that there is a lack of clear evidence to either support or refute a change to the current recommendations for the age of introduction of complementary foods to the breast milk or formula fed infant. Whilst exclusive breast feeding for the first 6 months of life can support growth and development in some infants, sub-groups have been identified within certain populations who may require complementary feeding prior to this age.

Weaning preterm infants: a randomised controlled trial.

OBJECTIVE: To assess the effect on growth and iron status in preterm infants of a specially devised weaning strategy compared with current best practices in infant feeding. The preterm weaning strategy recommended the early onset of weaning and the use of foods with a higher energy and protein content than standard milk formula, and foods that are rich sources of iron and zinc. SUBJECTS AND DESIGN: In a blinded, controlled study, 68 preterm infants (mean (SD) birth weight 1470 (430) g and mean (SD) gestational age 31.3 (2.9) weeks) were randomised to either the preterm weaning strategy group (n = 37) or a current best practice control group (n = 31), from hospital discharge until 1 year gestation corrected age (GCA). MAIN OUTCOME MEASURES: Weight, supine length, occipitofrontal head circumference, and intakes of energy, protein, and minerals were determined at 0, 6, and 12 months GCA. Levels of haemoglobin, serum iron, and serum ferritin were assayed at 0 and 6 months GCA. RESULTS: Significant positive effects of treatment included: greater increase in standard deviation length scores and length growth velocity; increased intake of energy, protein, and carbohydrate at 6 months GCA and iron at 12 months GCA; increased haemoglobin and serum iron levels at 6 months GCA. CONCLUSIONS: The preterm weaning strategy significantly influenced dietary intakes with consequent beneficial effects on growth in length and iron status. This strategy should be adopted as the basis of feeding guidelines for preterm infants after hospital discharge.

Flight deck design and pilot selection: anthropometric considerations.

Safe and successful operation of flight displays and controls is, in part, dependent on the anthropometric characteristics of the pilots with respect to the design of a particular aircraft. This paper describes the approach required to optimise this fit and provides guidelines for both those responsible for design and those who select pilot recruits. The major results reported are those for a British population, although the aircraft considered (Boeing 737-200, 747, 757 and Lockheed TriStar) are used by airlines throughout the world. The study shows that limitations in design considerably reduce the pool of potential recruits with the appropriate anthropometric characteristics. The selection criteria, based on functional seated eye height, might exclude 73% of the British, 19-65-year-old female population and 13% of the male population.

A repeated measurements model with applications in psychology.

The multivariate Burr distribution is discussed in relation to the analysis of repeated measures data in psychology. The ease of coping with censored and missing observations is particularly highlighted. A numerical example involving test scores of low IQ institutional patients is used to illustrate the method.

Functionally selective signaling for morphine and fentanyl antinociception and tolerance mediated by the rat periaqueductal gray.

Functionally selective signaling appears to contribute to the variability in mechanisms that underlie tolerance to the antinociceptive effects of opioids. The present study tested this hypothesis by examining the contribution of G protein-coupled receptor kinase (GRK)/Protein kinase C (PKC) and C-Jun N-terminal kinase (JNK) activation on both the expression and development of tolerance to morphine and fentanyl microinjected into the ventrolateral periaqueductal gray of the rat. Microinjection of morphine or fentanyl into the periaqueductal gray produced a dose-dependent increase in hot plate latency. Microinjection of the non-specific GRK/PKC inhibitor Ro 32-0432 into the periaqueductal gray to block mu-opioid receptor phosphorylation enhanced the antinociceptive effect of morphine but had no effect on fentanyl antinociception. Microinjection of the JNK inhibitor SP600125 had no effect on morphine or fentanyl antinociception, but blocked the expression of tolerance to repeated morphine microinjections. In contrast, a microinjection of Ro 32-0432 blocked the expression of fentanyl, but not morphine tolerance. Repeated microinjections of Ro 32-0432 blocked the development of morphine tolerance and inhibited fentanyl antinociception whether rats were tolerant or not. Repeated microinjections of SP600125 into the periaqueductal gray blocked the development of tolerance to both morphine and fentanyl microinjections. These data demonstrate that the signaling molecules that contribute to tolerance vary depending on the opioid and methodology used to assess tolerance (expression vs. development of tolerance). This signaling difference is especially clear for the expression of tolerance in which JNK contributes to morphine tolerance and GRK/PKC contributes to fentanyl tolerance.

Correlates of constipation in people with Parkinson's.

PURPOSE: To investigate clinical, demographic and dietary factors associated with constipation in a sample of community dwelling people with Parkinson's disease, recruited through a specialist outpatient clinic. Partners/carers provided a convenience control group. SCOPE: Participants completed a baseline questionnaire (background information, diet and exercise, activities of daily living: mobility and manual dexterity, health-related quality of life (SF-12), stool frequency and characteristics, extent of concern due to constipation, laxative taking), and a four-week stool diary. The Rome criterion was used to determine constipation status. Multiple regression methods were used to explore the correlates of constipation. Baseline data were provided by 121 people with Parkinson's, (54 controls), of whom 73% (25%) met the Rome criterion. Prospective diary data from 106 people with Parkinson's (43 controls) showed lower proportions: 35% (7%) meeting the Rome criterion. Among all study subjects, i.e. Parkinson's patients and controls taken together, the presence of constipation is predicted by having Parkinson's disease (p = .003; odds ratio 4.80, 95% CI 1.64-14.04) and mobility score (p = .04; odds ratio 1.15, 95% CI 1.01-1.31), but not by dietary factors. Amongst people with Parkinson's constipation is predicted by number of medications (p = .027). Laxative taking masks constipation, and is significantly associated with wearing protection against bowel incontinence (p = .009; odds ratio 4.80, 95% CI: 1.48-15.52). CONCLUSIONS: Constipation is disease-related, not a lifestyle factor. More research is needed on optimal management and laxative use.

A Weibull-based score test for heterogeneity.

The Weibull distribution is a natural starting point in the modelling of failure times in reliability, material strength data and many other applications that involve lifetime data. In recent years there has been a growing interest in modelling heterogeneity within this context. A natural approach is to consider a mixture, either discrete or continuous, of Weibull distributions. A judicious choice of mixing distribution yields a tractable and flexible generalization of the Weibull distribution. In this note a score test for detecting heterogeneity in this context is discussed and illustrated using some infant nutrition data.

Helminthosporium maydis T Toxin Decreased Calcium Transport into Mitochondria of Susceptible Corn.

The effects of purified Helminthosporium maydis T (HmT) toxin on active Ca(2+) transport into isolated mitochondria and microsomal vesicles were compared for a susceptible (T) and a resistant (N) strain of corn (Zea mays). ATP, malate, NADH, or succinate could drive (45)Ca(2+) transport into mitochondria of corn roots. Ca(2+) uptake was dependent on the proton electrochemical gradient generated by the redox substrates or the reversible ATP synthetase, as oligomycin inhibited ATP-driven Ca(2+) uptake while KCN inhibited transport driven by the redox substrates. Purified native HmT toxin completely inhibited Ca(2+) transport into T mitochondria at 5 to 10 nanograms per milliliter while transport into N mitochondria was decreased slightly by 100 nanograms per milliliter toxin. Malate-driven Ca(2+) transport in T mitochondria was frequently more inhibited by 5 nanograms per milliliter toxin than succinate or ATP-driven Ca(2+) uptake. However, ATP-dependent Ca(2+) uptake into microsomal vesicles from either N or T corn was not inhibited by 100 nanograms per milliliter toxin. Similarly, toxin had no effect on proton gradient formation ([(14)C]methylamine accumulation) in microsomal vesicles. These results show that mitochondrial and not microsomal membrane is a primary site of HmT toxin action. HmT toxin may inhibit formation of or dissipate the electrochemical proton gradient generated by substrate-driven electron transport or the mitochondrial ATPase, after interacting with a component(s) of the mitochondrial membrane in susceptible corn.

[Feeding habits of a sample of children under 20 months of age in Madrid]. / Hábitos alimenticios de una muestra de niños menores de 20 meses en Madrid.

OBJECTIVE: To know the feeding habits of children of different socioeconomic groups during the first year and a half of life in Madrid. PATIENTS AND METHODS: The mothers of 344 children between 3 and 19 months who attended two vaccination centers of the Regional Health Authorities of Madrid were interviewed in detail using the dietary history method supplemented with questions on milk feeding and weaning. The sample was stratified into three socioeconomic groups, low middle and high, each group comprising about a third of the sample. RESULTS: In general, children were fed according to actual pediatric recommendations. Deviations were that breast-feeding was stopped too early, complementary feeding was introduced somewhat early and mothers were often found not to understand gluten nor did they know which products contain it. The children in this study were remarkably similarly fed regardless of socioeconomic group. CONCLUSIONS: The pediatrician should know where mothers may deviate from the recommendations to prevent feeding errors because o misunderstanding or ignorance.

Nutritional composition of home-prepared baby meals in Madrid. Comparison with commercial products in Spain and home-made meals in England.

The nutritional value of 50 home-prepared meat-based baby meals for infants of 7 and 8 months old in Madrid was evaluated. Chemical analysis showed the meals to have a low energy density (mean 50 kcal 100 g-1), mainly due to the low fat content of the meals (mean 2.5 g 100 kcal-1). Protein content was high in proportion to the energy provided (mean 9.1 g 100 kcal-1). The addition of fat would have considerably improved the relation between the three macronutrients. About 20% of the meals had a higher than desired sodium level (> 200 mg 100 kcal-1) when assessed against guidelines for commercial baby meals. The English home-made baby meals had a higher energy density, a lower protein content, the same low fat content, and a wider range between minimum and maximum values observed for each nutrient compared to the Spanish home-prepared meals. The commercial baby meals had a higher energy density, a better ratio between the macronutrients and a smaller variation in the nutrient content.

Metabolic response to fasting in experimental intrauterine growth retardation induced by surgical and nonsurgical maternal stress.

Experimental intrauterine growth retardation was produced by two groups of neonatal rats by maternal sham surgery or by maternal obligatory exercise during the last 5 days of gestation (forced swim). Both experimental groups of neonates had lower plasma glucose and higher plasma insulin levels than controls after a 4-hour fast. Fetal stunting may be produced by a variety of maternal stresses in the rat and may be associated with alterations in the hormonal and glycemic response to fasting. Studies of the metabolic effects of experimental intrauterine growth retardation must be interpreted with caution if control animals have been subjected to intrauterine stress.