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.

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.

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.

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.

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.

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.

Proprioceptive control of extensor activity during fictive scratching and weight support compared to fictive locomotion.

At rest, extensor group I afferents produce oligosynaptic inhibition of extensor motoneurons. During locomotor activity, however, such inhibition is replaced by oligosynaptic excitation. Oligosynaptic excitation from extensor group I afferents plays a crucial role in the regulation of extensor activity during walking. In this study we investigate the possibility that this mechanism also regulates extensor muscle activity during other motor tasks. We show that the reflex pathways responsible for extensor group I oligosynaptic excitation during fictive locomotion can be activated during both fictive scratching and fictive weight support (tonic motor activity induced by contralateral scratching). These observations suggest that the excitatory group I oligosynaptic reflex pathways are open for transmission during several forms of motor activities. We also show that extensor group I input during fictive scratching can affect the amplitude and the timing of extensor activity in a pattern similar to that observed during locomotion. Most likely these effects involve the activation of the excitatory group I oligosynaptic reflex pathways. Accordingly, it is suggested that extensor group I oligosynaptic excitation during motor activities other than locomotion is also used to regulate extensor muscle activity. Furthermore, the similarity of effects from extensor group I input on the rhythmicity during scratching and locomotion supports the hypothesis that both rhythms are generated by a common network.

Activation of p38 mitogen-activated protein kinase alpha and beta by insulin and contraction in rat skeletal muscle: potential role in the stimulation of glucose transport.

The stress-activated p38 mitogen-activated protein kinase (MAPK) was recently shown to be activated by insulin in muscle and adipose cells in culture. Here, we explore whether such stimulation is observed in rat skeletal muscle and whether muscle contraction can also affect the enzyme. Insulin injection (2 U over 3.5 min) resulted in increases in p38 MAPK phosphorylation measured in soleus (3.2-fold) and quadriceps (2.2-fold) muscles. Increased phosphorylation (3.5-fold) of an endogenous substrate of p38 MAPK, cAMP response element binder (CREB), was also observed. After in vivo insulin treatment, p38 MAPKalpha and p38 MAPKbeta isoforms were found to be activated (2.1- and 2.4-fold, respectively), using an in vitro kinase assay, in immunoprecipitates from quadriceps muscle extracts. In vitro insulin treatment (1 nmol/l over 4 min) and electrically-induced contraction of isolated extensor digitorum longus (EDL) muscle also doubled the kinase activity of p38 MAPKalpha and p38 MAPKbeta. The activity of both isoforms was inhibited in vitro by 10 micromol/l SB203580 in all muscles. To explore the possible participation of p38 MAPK in the stimulation of glucose uptake, EDL and soleus muscles were exposed to increasing doses of SB203580 before and during stimulation by insulin or contraction. SB203580 caused a significant reduction in the insulin- or contraction-stimulated 2-deoxyglucose uptake. Maximal inhibition (50-60%) occurred with 10 micromol/l SB203580. These results show that p38 MAPKalpha and -beta isoforms are activated by insulin and contraction in skeletal muscle. The data further suggest that activation of p38 MAPK may participate in the stimulation of glucose uptake by both stimuli in rat skeletal muscle.

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.

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.

How do we approach the locomotor network in the mammalian spinal cord?

For a large number of vertebrate species it is now indisputable that spinal networks have the capability of generating the basic locomotor rhythm. However, because of technical difficulties, the rate of progress in defining the intrinsic properties of mammalian locomotor rhythm generators has been slow in comparison to that made in the study of such networks in lower vertebrates. Investigations on afferent and descending control of locomotor activity in mammals have demonstrated that many of these pathways interact with the rhythm generator. In this review we discuss how these interactions (resetting) can be used for outlining relevant spinal circuits as a basis for a future identification of individual neurons of the spinal locomotor networks. In this overview we have given particular emphasis to selected afferent systems to illustrate the possibilities and problems with this approach.

The effect of isradipine on theophylline pharmacokinetics in healthy volunteers.

The effects of isradipine 2.5 mg and 5 mg on the disposition of theophylline were investigated in a placebo-controlled, randomized, three-way, crossover trial. Eleven healthy, nonsmoking men each received a treatment of placebo, and isradipine 2.5 mg and 5 mg every 12 hours for 6 consecutive days. On the morning of day 6, 2 hours after the isradipine dose, theophylline (solution) 5.0 mg/kg was administered orally, and blood samples were collected over 24 hours. A 2-week washout period separated treatment sequences. Plasma samples were analyzed for theophylline using high-performance liquid chromatography. Using a two-way analysis of variance, no significant changes in apparent theophylline clearance were observed between placebo, and isradipine 2.5 and 5 mg (0.815 +/- 0.164, 0.870 +/- 0.212, and 0.827 +/- 0.164 ml/min/kg, respectively; p = 0.136). Similarly, no significant change in volume of distribution was noted. These findings suggest that isradipine at recommended dosages does not impair theophylline metabolism.

Patients' requests and satisfaction with services in an outpatient psychiatric setting.

OBJECTIVE: Patients in four major diagnostic categories were compared to determine if their satisfaction with outpatient services varied. Both overall satisfaction and the degree to which clients and therapists agreed on the importance of 16 aspects of treatment were examined. METHODS: The Patient Request Form (PRF) and the Client Satisfaction Questionnaire were used to interview 464 outpatients. The professional who was the primary contact for each patient filled out a therapist version of the PRF. Diagnoses were grouped into four major categories: anxiety disorders, affective disorders, schizophrenia, and other psychotic disorders. RESULTS: The diagnostic groups differed in overall satisfaction with treatment, treatment characteristics, patients' reasons for coming to the clinic, therapists' descriptions of treatment, and patient-therapist agreement on the importance of different aspects of treatment. Agreement between patients and providers was associated with higher levels of patients' satisfaction. Patients with schizophrenia or with other psychotic disorders had the lowest level of agreement with their therapists and also were the least satisfied. In all patient categories, therapists underestimated the importance to patients of having a reliable source of help. CONCLUSIONS: The greater dissatisfaction expressed by patients with schizophrenia and other psychotic disorders may be related to their therapists' undervaluing the nonbiological aspects of treatment such as social support. Combining medication with psychosocial approaches that have been adapted for patients with psychotic disorders is likely to improve the patients' satisfaction and compliance and increase the overall effectiveness of treatment.

[Recruitment of Montreal women of very low socioeconomic status for a randomized clinical study]. / Le recrutement d'un groupe de femmes montréalaises de status socio-économique très faible dans une étude clinique randomisée.

Studies show that it is difficult to recruit women of low socioeconomic status as clinical research participants. Such an objective was attained though as our results demonstrate in an evaluative study of a program implemented to lower the percentage of low birthweight in four CLSCs of the Island of Montreal between 1994 and 1996. The global recruitment strategy enabled us to reach 56.2% of our goal in 1994 and 77.4% in 1996. Two conclusions can be drawn from this result: the effectiveness of the three methods of recruitment varied according to each participating CLSC, and the global strategy, combined with the mobilization of community resources, was successful in enrolling women of low socioeconomic status.

Evaluating AIDS prevention for men having sex with men: the west European experience.

This article presents the major results of a Concerted Action of the European Community on "Assessing AIDS-prevention" concerning the male homo- and bisexual population. It discusses the methodologies and results of research projects undertaken in this area in the 1980's.

[Concepts of AIDS in relation to health and illness in homosexual men living in Quebec with AIDS]. / Les représentations du sida en rapport à la maladie chez des hommes Les représentations du sida en rapport à la santé et à la maladie chez des hommes québécois d'orientation homosexuelle vivant avec le sida.

Herzlich's (1969) theoretical framework was used to explore Acquired Immune Deficiency Syndrome (AIDS) from the point of view of affected individuals. Content analysis was performed on transcripts of interviews with eight French Canadian gay men living with AIDS. Results indicate that health and illness are socially constructed concepts and that health can coexist with illness. The authors discuss how Herzlich's framework can be used by nurses to better understand the individual's experience of illness and to guide the individual towards making behavioural changes that will generate health throughout the course of the illness.