Predictors of clinicians' underuse of daily sedation interruption and sedation scales.

PURPOSE: The purpose of the study is to identify predictors of underuse of sedation scales and daily sedation interruption (DSI). METHODS: We surveyed all physicians and seven nurses in every Belgian intensive care unit (ICU), addressing practices and perceptions on guideline recommendations. Underuse was defined for sedation scales as use less than 3× per day and for DSI as never using it. Classification trees and logistic regressions identified predictors of underuse. RESULTS: Underuse of sedation scales and DSI was found for 16.6% and 32.5% of clinicians, respectively. Strongest predictors of underuse of sedation scales were agreeing that using them daily takes much time and being a physician (rather than a nurse). Further predictors were confidence in their ability to measure sedation levels without using scales, for physicians, and nurse/ICU bed ratios less than 1.98, for nurses. The strongest predictor of underuse of DSI among physicians was the perception that DSI impairs patients' comfort. Among nurses, lack of familiarity with DSI, region, and agreeing DSI should only be performed upon medical orders best predicted underuse. CONCLUSIONS: Workload considerations hamper utilization of sedation scales. Poor familiarity, for nurses, and negative perception of impact on patients' comfort, for physicians, both reduce DSI utilization. Targeting these obstacles is essential while designing quality improvement strategies to minimize sedative use.

Regulation of c-fos expression by the dopamine D1-D2 receptor heteromer.

The dopamine D1 and D2 receptors form the D1-D2 receptor heteromer in a subset of neurons and couple to the Gq protein to regulate intracellular calcium signaling. In the present study the effect of D1-D2 heteromer activation and disruption on neuronal activation in the rat brain was mapped. This was accomplished using the dopamine agonist SKF 83959 to activate the D1-D2 heteromer in combination with a TAT-D1 disrupting peptide we developed, and which has been shown to disrupt the D1/D2 receptor interaction and antagonize D1-D2 heteromer-induced cell signaling and behavior. Acute SKF 83959 administration to rats induced significant c-fos expression in the nucleus accumbens that was significantly inhibited by TAT-D1 pretreatment. No effects of SKF 83959 were seen in caudate putamen. D1-D2 heteromer disruption by TAT-D1 did not have any effects in any striatal subregions, but induced significant c-fos immunoreactivity in a number of cortical regions including the orbitofrontal cortex, prelimbic and infralimbic cortices and piriform cortex. The induction of c-fos by TAT-D1 was also evident in the anterior olfactory nucleus, as well as the lateral habenula and thalamic nuclei. These findings show for the first time that the D1-D2 heteromer can differentially regulate c-fos expression in a region-dependent manner either through its activation or through tonic inhibition of neuronal activity.

Corticosteroids in the management of brain-dead potential organ donors: a systematic review.

Summary Current guidelines recommend the administration of hormonal combination therapy including immunosuppressive doses of corticosteroids to donors with low left ventricular ejection fractions and to consider hormonal therapy administration to all donors. However, these recommendations are largely based on observational data. The aim of this systematic review (SR) was to assess the clinical efficacy and safety of corticosteroids in brain-dead potential organ donors. MEDLINE and EMBASE were searched from the earliest accessible date up to March 2013 with a qualified librarian. Studies comparing the effects of any corticosteroid with those of placebo, standard treatment, or another active comparator were sought. Two independent reviewers evaluated each citation retrieved and selected studies independently and in duplicate. A third independent reviewer resolved any disagreement. Outcomes included donor haemodynamics and oxygenation, organ procurement, recipient survival, and graft survival. This review included 11 randomized controlled trials (RCTs) and 14 observational studies. The majority used methylprednisolone and often combined it with other hormonal therapies. Ten out of the 11 RCTs yielded neutral results. However, in observational studies, use of corticosteroids generally resulted in improved donor haemodynamics and oxygenation status, increased organ procurement, and improved recipient and graft survival. Overall quality of included studies was poor, as most of them presented high risks of confounding. This SR highlights the low quality and conflicting evidence supporting the routine use of corticosteroids in the management of organ donors. A large trial evaluating the effect of corticosteroids on outcomes such as organ recovery and graft survival is warranted.

Profiling serum bile acid glucuronides in humans: gender divergences, genetic determinants, and response to fenofibrate.

Glucuronidation, catalyzed by uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, detoxifies cholestatic bile acids (BAs). We aimed to (i) characterize the circulating BA-glucuronide (BA-G) pool composition in humans, (ii) determine how sex and UGT polymorphisms influence this composition, and (iii) analyze the effects of the lipid-lowering drug fenofibrate on the circulating BA-G profile in 300 volunteers and 5 cholestatic patients. Eleven BA-Gs were determined in pre- and postfenofibrate samples. Men exhibited higher BA-G concentrations, and various genotype/BA-G associations were discovered in relevant UGT genes. The chenodeoxycholic acid-3G (CDCA-3G) concentration was associated with the UGT2B7 802C>T polymorphism. Glucuronidation assays confirmed the predominant role of UGT2B7 and UGT1A4 in CDCA-3G formation. Fenofibrate exposure increased the serum levels of five BA-G species, including CDCA-3G, and upregulated expression of UGT1A4, but not UGT2B7, in hepatic cells. This study demonstrated that fenofibrate stimulates BA glucuronidation in humans and thus reduces BA toxicity in the liver.

Reduced striatal dopamine D1-D2 receptor heteromer expression and behavioural subsensitivity in juvenile rats.

In adult rat striatum the dopamine D1-D2 receptor heteromer is expressed selectively in a subset of medium spiny neurons (MSNs) that coexpress the dopamine D1 and D2 receptors (D1R and D2R) as well as dynorphin (DYN) and enkephalin (ENK), with higher coexpression in nucleus accumbens (NAc) and much lower in the caudate putamen (CP). In the present study we showed that in neonatal striatal cultured neurons >90% exhibited the D1R/D2R-DYN/ENK phenotype. Similarly, in the striatum of juvenile rats (age 26-28 days) coexpression of D1R and D2R was also coincident with the expression of both DYN and ENK. Quantification of the number of striatal MSNs exhibiting coexpression of D1R and D2R in juvenile rats revealed significantly lower coexpression in NAc shell, but not core, and CP than in adult rats. However, within MSNs that coexpressed D1R and D2R, the propensity to form the D1-D2 receptor heteromer did not differ between age groups. Consistent with reduced coexpression of the D1R and D2R, juvenile rats exhibited subsensitivity to D1-D2 receptor heteromer-induced grooming following activation by SKF 83959. Given the proposed role of D1R/D2R-coexpressing MSNs in the regulation of thalamic output, and the recent discovery that these MSNs exhibit both inhibitory and excitatory capabilities, these findings suggest that the functional regulation of neurotransmission by the dopamine D1-D2 receptor heteromer within the juvenile striatum may be significantly different than in the adult.

Scientific and popular health knowledge in the education work of community health agents in Rio de Janeiro shantytowns.

Health education for socially marginalized populations challenges the efficacy of existing strategies and methods, and the pertinence of the educational and philosophical principles that underpin them. The Brazilian Community Health Agents Initiative (CHAI) hires residents of deprived marginalized communities to undertake health promotion and education in their communities. The ultimate goal of the CHAI is to connect populations with the public healthcare system by promoting social re-affiliation, protecting civil rights and enhancing equity of access to health services. In this article, we present the education work of community health agents through interplay between popular and scientific health knowledge in nine Rio de Janeiro shantytowns. A critical ethnographic research design, using thematic analysis, allowed us to explore agents' education work to enhance family health literacy in shantytowns. Local culture and social practices inspire Agents to create original strategies to reconcile forms of health knowledge in their work.

A multi-level study of the determinants of mental health service utilization.

BACKGROUND: Until now, research has focused on neighbourhood variations in mental health services and their relationships with local attributes, such as healthcare supply and socio-economic deprivation, without controlling for individual characteristics (age, sex, income, or education, for instance). Hence, this study is a major attempt to clarify the role played by individual and local attributes in the utilization of mental health services. The aim of this study was to disentangle individual and neighbourhood effects on mental health service use. METHODS: In this cross-sectional study, individual-level data on 423 participants with a frequent mental health disorder was recruited from the general population and linked to neighbourhood-level data at the census tract level from the 2006 Canadian Census. Neighbourhood variables included socio-economic deprivation, mean income, residential stability and the proportion of recent immigrants. Individual characteristics included gender, age, marital status, self-rated mental health and the number of diagnoses. Multi-level logistic regression was used to assess the effects of individual and neighbourhood characteristics simultaneously on mental health service use. RESULTS: The intraclass correlation coefficient indicated that 12.26% of the variance of mental health service utilization is at the neighbourhood level. Final analysis showed that at the individual level, being female, married, or self-rating mental health less than excellent increased healthcare use. At the neighbourhood level, deprived socio-economic neighbourhood decreased health service use (OR=0.71, P<0.05), while residential stability increased use (OR=1.24, P<0.05). CONCLUSIONS: Individual and neighbourhood characteristics determine mental health service utilization. Taking both into consideration allows better targeting of health service policy and planning and enables more accurate needs-based resource allocation. However, future research should continue to investigate the pathway through which neighbourhood affects health service utilization.

Elevated blood levels of inflammatory monocytes (CD14+ CD16+ ) in patients with complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a chronic pain disorder. Although its pathophysiology is not completely understood, neurogenic inflammation is thought to play a significant role. Microglia and astrocytes are activated following tissue injury or inflammation and have been reported to be both necessary and sufficient for enhanced nociception. Blood-borne monocytes/macrophages can infiltrate the central nervous system (CNS) and differentiate into microglia resulting in hypersensitivity and chronic pain. The primary aim of this study was to evaluate the proportion of the proinflammatory CD14(+) CD16(+) monocytes as well as plasma cytokine levels in blood from CRPS patients compared to age- and gender-matched healthy control individuals. Forty-six subjects (25 CRPS, 21 controls) were recruited for this study. The percentage of monocytes, T, B or natural killer (NK) cells did not differ between CRPS and controls. However, the percentage of the CD14(+) CD16(+) monocyte/macrophage subgroup was elevated significantly (P<0·01) in CRPS compared to controls. Individuals with high percentage of CD14(+) CD16(+) demonstrated significantly lower (P<0·05) plasma levels on the anti-inflammatory cytokine interleukin (IL)-10. Our data cannot determine whether CD14(+) CD16(+) monocytes became elevated prior to or after developing CRPS. In either case, the elevation of blood proinflammatoty monocytes prior to the initiating event may predispose individuals for developing the syndrome whereas the elevation of blood proinflammatory monocytes following the development of CRPS may be relevant for its maintenance. Further evaluation of the role the immune system plays in the pathogenesis of CRPS may aid in elucidating disease mechanisms as well as the development of novel therapies for its treatment.

Modulation of nutrient sensing nuclear hormone receptors promotes weight loss through appetite suppression in mice.

AIM: Peroxisome proliferator activated receptors (PPARs) are nuclear receptors involved in glucose and lipid metabolism. Three isoforms of PPARs have been identified with different tissue distribution and biological functions. Although the pharmacology of each receptor is well studied, the physiological effect of simultaneous activation of PPARalpha, gamma and delta is only starting to emerge. We sought to determine the biological effects of a novel PPAR pan activator and elucidate the physiological mechanisms involved. METHODS: Ob/ob, diet-induced obese (DIO) or PPARalpha knockout mice were administered a novel agonist that activates all PPARs to various degrees to determine the effect on body weight, body composition, food intake and energy expenditure. In addition, serum parameters including glucose, insulin, triglycerides and ketone bodies as well as tissue acylcarnitine were evaluated. The effect of the novel agonist on liver and skeletal muscle histopathology was also studied. RESULTS: We report that simultaneous activation of all PPARs resulted in substantial weight loss in ob/ob and DIO mice. Consistent with known PPAR pharmacology, we observed that agonist treatment increased lipid oxidation, although appetite suppression was mainly responsible for the weight loss. Agonist-induced weight loss was completely absent in PPARalpha knockout mice suggesting that PPARalpha pharmacology was the major contributor to weight regulation in mice. CONCLUSIONS: Our work provides evidence that simultaneous activation of PPARalpha, gamma and delta decreases body weight by regulating appetite. These effects of the pan agonist were completely absent in PPARalpha knockout mice, suggesting that PPARalpha pharmacology was the major contributor to weight loss.

C fragment of tetanus toxin hybrid proteins evaluated for muscle-specific transsynaptic mapping of spinal motor circuitry in the newborn mouse.

We investigated whether the non-toxic C fragment of tetanus toxin (TTC) fused to either beta-galactosidase or green fluorescent protein could be utilized to transsynaptically trace muscle-specific spinal circuitry in the neonatal mouse after i.m. injection into a single hindlimb muscle. We found that even with careful low volume injection (0.2-1.0 microl) into a single muscle (medial gastrocnemius), the TTC hybrid proteins spread rapidly to many other hindlimb muscles and to trunk musculature such that retrograde labeling of motoneurons could not be constrained to a single motoneuron pool. Retrogradely labeled motoneurons in the lower lumbar segments harboring the medial gastrocnemius motoneuron pool were first observed two hours after the medial gastrocnemius injection. Within the next 10 h, additional lumbar and lower thoracic motoneurons became labeled, and punctate labeling in the neuropil surrounding the motoneurons appeared. Many of the TTC hybrid protein-labeled puncta in the neuropil co-localized synaptotagmin, indicating that they represent presynaptic axon terminals onto motoneurons. Although this is consistent with retrograde transsynaptic passage, we found no evidence that the TTC hybrid proteins were transported further along premotor axons to label interneuron somata. The i.m. TTC injection procedure described here therefore provides an important tool for the study of presynaptic terminals onto motoneurons. However, additional technical modifications will be required to utilize TTC tracers for transsynaptic mapping of muscle-specific spinal motor circuitry in the neonatal mouse. We provide here a set of criteria for assessing the i.m. delivery of TTC tracers as a basis for future improvements in this technique.

Patients' perspectives on information received in outpatient psychiatry.

The purpose of this study is to develop a scale in order to determine the informational needs deemed most important by psychiatric outpatients, and to determine their level of satisfaction with information received. The 'Patients' Perspective on Information Questionnaire' (PPIQ) scale was created and given to a volunteer sample of 86 psychiatric outpatients. The Client satisfaction questionnaire (CSQ-8), assessing global satisfaction, was also completed to assess the convergent validity of the PPIQ-Satisfaction subscale. Internal consistency for the two PPIQ subscales (Information and Satisfaction) is excellent (alpha = 0.90 and 0.91). Convergent validity between the Satisfaction subscale and the CSQ is adequate (r = 0.5). The PPIQ reveals high importance ratings given to items such as 'side effects of medication' and 'confidentiality and access to chart'. Elevated satisfaction ratings are given to items from the conceptual category 'treatment information'. Dissatisfaction on the PPIQ is highest for components of 'information on service modality and organization'. The PPIQ appears to distinguish between information that is important to clients and their level of satisfaction with that information. Satisfaction on multiple components of information, such as treatment, service modality and organization, and clinical difficulties should be assessed to generate feedback to improve services.

Organization of common synaptic drive to motoneurones during fictive locomotion in the spinal cat.

The basic locomotor rhythm in the cat is generated by a neuronal network in the spinal cord. The exact organization of this network and its drive to the spinal motoneurones is unknown. The purpose of the present study was to use time (cumulant density) and frequency domain (coherence) analysis to examine the organization of the last order drive to motoneurones during fictive locomotion (evoked by application of nialamide and dihydroxyphenylalanine (DOPA)) in the spinal cat. In all cats, narrow central synchronization peaks (half-width < 3 ms) were observed in cumulants estimated between electroneurograms (ENGs) of close synergists, but not between nerves belonging to muscles acting on different joints or to antagonistic muscles. Coherence was not observed at frequencies above 100 Hz and was mainly observed between synergists. Intracellular recording was obtained from a population of 70 lumbar motoneurones. Significant short-term synchronization was observed between the individual intracellular recordings and the ENGs recorded from nerves of the same pool and of close synergists. Recordings from 34 pairs of motoneurones (10 pairs belonged to the same motor pool, 11 pairs to close synergists and 13 pairs to antagonistic pools) failed to reveal any short-lasting synchronization. These data demonstrate that short-term synchronization during fictive locomotion is relatively weak and is restricted to close synergists. In addition, coherence analysis failed to identify any specific rhythmic component in the locomotor drive that could be associated with this synchronization. These results resemble findings obtained during human treadmill walking and imply that the spinal interneurones participating in the generation of the locomotor rhythm are themselves weakly synchronized. The restricted synchronization within the locomotor drive to motoneuronal pools may be a feature of the locomotor generating networks that is related to the ability of these networks to produce highly adaptive patterns of muscle activity during locomotion.

Background and gender effects on survival in the TgN(SOD1-G93A)1Gur mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder. While most cases of ALS are sporadic, 10-15% are familial, and of these 15-20% possess a mutation in the gene that codes for the enzyme Cu/Zn superoxide dismutase (SOD1). In families of ALS patients with specific SOD1 mutations, affected members demonstrate significant heterogeneity of disease and a large variation in age of onset and severity, suggesting that there are genetic modifiers of disease expression. Transgenic mice expressing mutant forms of SOD1 demonstrate symptoms similar to those seen in patients with ALS. We have observed in our colony of G93A SOD1 transgenic mice a milder phenotype in mice in a C57BL/6J background than the C57BL/6JxSJL/J hybrid background used by Jackson Laboratories to maintain their colony. To investigate the effect of genetic background on phenotype, we have constructed congenic lines on two genetic backgrounds, C57BL/6J (B6) and SJL/J (SJL). We report the influence of background and gender on the survival of these congenic lines compared to the hybrid C57BL/6JxSJL/J background. The mean survival of G93A SOD1 mice in the hybrid B6/SJL background was 130 days, with females surviving significantly longer than males. When compared to the hybrid B6/SJL background, the survival of mice in the SJL background significantly decreased, and the gender difference in survival was maintained. On the other hand, mean survival in the B6 background significantly increased, and in contrast to the B6/SJL and SJL backgrounds, there was no difference in survival between males and females. Transgene copy numbers were verified in all animals to ensure that any phenotypic differences observed were not due to alterations in copy number. This is the first report of a shortened lifespan when the G93A SOD1 transgene is placed on the SJL/J background and an increased survival with the loss of gender influences when the transgene is placed on the C57BL/6J background.

Resistance to the orexigenic effect of ghrelin in dietary-induced obesity in mice: reversal upon weight loss.

BACKGROUND: Ghrelin, an endogenous ligand for growth hormone secretagogue receptor (GHS-R), is known to increase food intake in lean humans and rodents. In addition, ghrelin levels are increased by fasting in lean rodents and are elevated before meals in humans, suggesting an important role for ghrelin in meal initiation. However, in obese human, circulating ghrelin levels were found to be significantly reduced as compared to lean individuals. OBJECTIVES: To evaluate whether circulating ghrelin levels, as well as ghrelin sensitivity, are decreased in obese individuals in order to limit its effect on food intake. DESIGN: : Lean C57BL/6J mice fed a chow, a low- (LFD) or a high-fat diet (HFD) were used to determine ghrelin regulation and secretion as well as ghrelin sensitivity. MEASUREMENTS: Plasma ghrelin levels were measured in low- and high-fat fed mice. Ghrelin-induced food intake was measured in chow, low- and high-fat fed mice. RESULTS: We measured ghrelin levels in lean and diet-induced obese mice, fed on an LFD or an HFD, respectively. We observed that not only ghrelin secretion was reduced in obese mice but its diurnal regulation was also lost. In addition, we failed to observe any change in ghrelin secretion upon fasting and refeeding. Moreover, we observed that the sensitivity to the orexigenic effects of exogenous ghrelin was reduced in obese mice when compared to lean mice fed a chow or a LFD. The insensitivity of obese mice to ghrelin was improved upon weigh loss. CONCLUSION: : Altogether, these results indicate that ghrelin secretion and regulation is impaired in dietary-induced obesity in mice and suggest that ghrelin inhibition could prevent weight regain after weight loss.

Predictors of psychological distress in family caregivers of persons with psychiatric disabilities.

The purpose of the study was to determine the relationships of primary and secondary stressors, and informal and formal supports, to psychological distress in 154 family caregivers of persons with psychiatric disabilities. All caregivers were members of self-help groups located in the Province of Quebec in Canada. Psychological distress was significantly lower among older caregivers, those working full time, and those experiencing lower objective and subjective burdens. Contrary to the hypotheses, caregivers who perceived more support from friends and had more contacts with their relatives' primary mental health providers experienced a higher level of psychological distress.

Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle.

Inducible nitric oxide synthase (iNOS) is induced by inflammatory cytokines in skeletal muscle and fat. It has been proposed that chronic iNOS induction may cause muscle insulin resistance. Here we show that iNOS expression is increased in muscle and fat of genetic and dietary models of obesity. Moreover, mice in which the gene encoding iNOS was disrupted (Nos2-/- mice) are protected from high-fat-induced insulin resistance. Whereas both wild-type and Nos2-/- mice developed obesity on the high-fat diet, obese Nos2-/- mice exhibited improved glucose tolerance, normal insulin sensitivity in vivo and normal insulin-stimulated glucose uptake in muscles. iNOS induction in obese wild-type mice was associated with impairments in phosphatidylinositol 3-kinase and Akt activation by insulin in muscle. These defects were fully prevented in obese Nos2-/- mice. These findings provide genetic evidence that iNOS is involved in the development of muscle insulin resistance in diet-induced obesity.

Information as a distinct dimension for satisfaction assessment of outpatient psychiatric services.

The purpose of this study is to verify whether information on services would appear as a distinct dimension of satisfaction in a multidimensional scale. Data collection was performed in two phases: 263 patients received the original version of the questionnaire and 200 received an adapted version of the scale. The findings suggest that not only is it important to consider information as a distinct dimension of satisfaction but it is equally important to examine three categories, consisting of satisfaction with information on; patients' problems/illness; distinct treatment components such as medication and psychotherapy; and patients' treatment progress.