Prefrontal circuits encode both general danger and specific threat representations.

Behavioral adaptation to potential threats requires both a global representation of danger to prepare the organism to react in a timely manner but also the identification of specific threatening situations to select the appropriate behavioral responses. The prefrontal cortex is known to control threat-related behaviors, yet it is unknown whether it encodes global defensive states and/or the identity of specific threatening encounters. Using a new behavioral paradigm that exposes mice to different threatening situations, we show that the dorsomedial prefrontal cortex (dmPFC) encodes a general representation of danger while simultaneously encoding a specific neuronal representation of each threat. Importantly, the global representation of danger persisted in error trials that instead lacked specific threat identity representations. Consistently, optogenetic prefrontal inhibition impaired overall behavioral performance and discrimination of different threatening situations without any bias toward active or passive behaviors. Together, these data indicate that the prefrontal cortex encodes both a global representation of danger and specific representations of threat identity to control the selection of defensive behaviors.

Prevalence, specific and non-specific determinants of complementary medicine use in Switzerland: Data from the 2017 Swiss Health Survey.

OBJECTIVES: To determine the prevalence of use of complementary medicine (CM) in Switzerland in 2017, its development since the 2012 Swiss Health Survey, and to examine specific and non-specific sociodemographic, lifestyle and health-related determinants of CM use as compared to determinants of conventional health care use. MATERIALS AND METHODS: We used data of 18,832 participants from the cross-sectional Swiss Health Survey conducted by the Swiss Federal Statistical Office in 2017 and compared these data with those from 2012. We defined four CM categories: (1) traditional Chinese medicine, including acupuncture; (2) homeopathy; (3) herbal medicine; (4) other CM therapies (shiatsu, reflexology, osteopathy, Ayurveda, naturopathy, kinesiology, Feldenkrais, autogenic training, neural therapy, bioresonance therapy, anthroposophic medicine). Independent determinants of CM use and of conventional health care use were assessed using multivariate weighted logistic regression models. RESULTS: Prevalence of CM use significantly increased between 2012 and 2017 from 24.7% (95% CI: 23.9-25.4%) to 28.9% (95% CI: 28.1-29.7%), respectively, p<0.001). We identified the following independent specific determinants of CM use: gender, nationality, age, lifestyle and BMI. Female gender and nationality were the most specific determinants of CM use. Current smoking, being overweight and obesity were determinants of non-use of CM, while regular consumption of fruits and/or vegetables and regular physical activity were determinants of CM use. CONCLUSION: Prevalence of CM use significantly increased in Switzerland from 2012 to 2017. Gender, nationality, age, lifestyle and BMI were independent specific determinants of CM use as compared to conventional health care use. Healthier lifestyle was associated with CM use, which may have potentially significant implications for public health and preventive medicine initiatives. The nationality of CM users underlines the role of culture in driving the choice to use CM but also raises the question of whether all populations have equal access to CM within a same country.

Lung function fluctuation patterns unveil asthma and COPD phenotypes unrelated to type 2 inflammation.

BACKGROUND: In all chronic airway diseases, the dynamics of airway function are influenced by underlying airway inflammation and bronchial hyperresponsiveness along with limitations in reversibility owing to airway and lung remodeling as well as mucous plugging. The relative contribution of each component translates into specific clinical patterns of symptoms, quality of life, exacerbation risk, and treatment success. OBJECTIVE: We aimed to evaluate whether subgrouping of patients with obstructive airway diseases according to patterns of fluctuation in lung function allows identification of specific phenotypes with distinct clinical characteristics. METHODS: We applied the novel method of fluctuation-based clustering (FBC) to twice-daily FEV1 measurements recorded over a 1-year period in a mixed group of 134 adults with mild-to-moderate asthma, severe asthma, or chronic obstructive pulmonary disease from the European BIOAIR cohort. RESULTS: Independently of clinical diagnosis, FBC divided patients into 4 fluctuation-based clusters with progressively increasing alterations in lung function that corresponded to patterns of increasing clinical severity, risk of exacerbation, and lower quality of life. Clusters of patients with airway disease with significantly elevated levels of biomarkers relating to remodeling (osteonectin) and cellular senescence (plasminogen activator inhibitor-1), accompanied by a loss of airway reversibility, pulmonary hyperinflation, and loss of diffusion capacity, were identified. The 4 clusters generated were stable over time and revealed no differences in levels of markers of type 2 inflammation (blood eosinophils and periostin). CONCLUSION: FBC-based phenotyping provides another level of information that is complementary to clinical diagnosis and unrelated to eosinophilic inflammation, which could identify patients who may benefit from specific treatment strategies or closer monitoring.

Euphrasia Eye Drops in Preterm Neonates With Ocular Discharge: A Randomized Double-Blind Placebo-Controlled Trial.

Aim: To investigate whether the early administration of Euphrasia eye drops® in preterm neonates presenting with ocular discharge fosters the resolution of the ocular discharge and reduces the need for topical antibiotic therapy, as compared to placebo. Methods: We conducted a randomized double-blind placebo-controlled trial at the University Children's Hospital Bern, Switzerland. Preterm neonates with white, yellow, or green ocular discharge were included. Infants were randomly assigned (1:1) to the Euphrasia arm (Euphrasia eye drops®, Weleda AG, Arlesheim) or the placebo arm (NaCl 0.9%). Euphrasia or placebo was administrated at a dose of one drop in each eye four times a day over a period of 96 h. The primary outcome was the treatment success, defined as no ocular discharge at 96 h and no use of topical antibiotic therapy during the 96-h intervention. Results: A total of 114 neonates were screened and 84 were randomized. Among neonates in the Euphrasia arm, 22 (55.0%) achieved our primary outcome compared to 21 (51.2%) in the placebo arm (p = 0.85). In the Euphrasia arm, time to resolution of reddening tended to fall within the shorter bracket of 24 to 48 h (24 (92.3%) vs. 12 (80.0%) in the placebo arm, p = 0.34) and relapse or first signs of reddening during the 96-h intervention tended to be lower [3 (7.9%) eyes vs. 8 (18.2%) eyes in the placebo arm, p = 0.17]. Tearing at 96 h tended to be lower in the Euphrasia arm [5 (12.8%) eyes in the Euphrasia arm vs. 12 (27.3%) eyes in the placebo arm, p = 0.10]. Discussion: Euphrasia did not significantly improve treatment success, defined as no ocular discharge at 96 h and no use of topical antibiotic therapy during the 96-h intervention. However, results suggest that Euphrasia may be of benefit for symptoms such as reddening and tearing, and thus improve the comfort of patients. Trial Registration: The trial is registered at the US National Institutes of Health (ClinicalTrials.gov) NCT04122300 and at the portal for human research in Switzerland SNCTP000003490.

Eurythmy therapy versus slow movement fitness in the treatment of fatigue in metastatic breast cancer patients: study protocol for a randomized controlled trial.

BACKGROUND: Cancer-related fatigue (CRF) is the most taxing symptom for many breast cancer patients during and after therapy. In patients with metastatic disease, the prevalence of CRF exceeds 75%. Currently, there is no gold standard for the treatment of CRF. Physical activity can reduce CRF and is recommended during and after cancer treatment, but may be too burdensome for patients with metastatic breast cancer. The aim of this study is to assess the effect on fatigue of eurythmy therapy (ERYT) compared to slow movement fitness (CoordiFit) in metastatic breast cancer patients. METHODS: The ERYT/CoordiFit study is a randomized controlled, open-label, two-arm, multi-center Swiss clinical trial. A sample of 196 patients presenting with CRF will be recruited by oncologists from the departments of clinical oncology at each local study site. All participants will be randomly allocated to the intervention or control group in a 1:1 ratio. The control group is an active control intervention (CoordiFit) in order to control for potential non-intended effects such as therapist-patient interaction and participation in a program. Both ERYT and CoordiFit exercises are easy to learn, and the training sessions will follow the same frequency and duration schedule, i.e., 13 standardized therapy sessions of 45 min (once a week for 6 weeks and then once every second week) during the total intervention period of 20 weeks. The primary endpoint of the study is the change from baseline over the whole intervention period (i.e., including measurements at baseline, weeks 8, 14, and 20) in the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) subscale score. DISCUSSION: This study is the first-known randomized clinical trial assessing eurythmy therapy in the treatment of fatigue in metastatic breast cancer patients. Given the distress that fatigue causes patients, it is important to validate treatment options. If eurythmy therapy proves beneficial in CRF as part of this randomized controlled clinical trial, the study may be very impactful with implications not only for metastatic breast cancer patients but also for other cancer patients, health care personnel, scientists, and funding and regulatory bodies. TRIAL REGISTRATION: The ERYT/CoordiFit trial was registered at the US National Institutes of Health (ClinicalTrials.gov) on July 18, 2019, #NCT04024267 , and in the portal for human research in Switzerland on December 3, 2019, #SNCTP000003525 .

Association of long-term exposure to traffic-related PM10 with heart rate variability and heart rate dynamics in healthy subjects.

BACKGROUND: Epidemiological evidence on the influence of long-term exposure to traffic-related particulate matter (TPM10) on heart rate variability (HRV) is weak. OBJECTIVE: To evaluate the association of long-term exposure (10 years) with TPM10 on the regulation of the autonomic cardiovascular system and heart rate dynamics (HRD) in an aging general population, as well as potential modifying effects by the a priori selected factors sex, smoking status, obesity, and gene variation in selected glutathione S-transferases (GSTs). METHODS: We analyzed data from 1593 SAPALDIA cohort participants aged ≥ 50 years. For each participant, various HRV and HRD parameters were derived from 24-hour electrocardiogram recordings. Each parameter obtained was then used as the outcome variable in multivariable mixed linear regression models in order to evaluate the association with TPM10. Potential modifying effects were assessed using interaction terms. RESULTS: No association between long-term exposure to TPM10 and HRV/HRD was observed in the entire study population. However, HRD changes were found in subjects without cardiovascular morbidity and both HRD and HRV changes in non-obese subjects without cardiovascular morbidity. Subjects without cardiovascular morbidity with homozygous GSTM1 gene deletion appeared to be more susceptible to the effects of TPM10. CONCLUSION: This study suggests that long-term exposure to TPM10 triggers adverse changes in the regulation of the cardiovascular system. These adverse effects were more visible in the subjects without cardiovascular disease, in whom the overall relationship between TPM10 and HRV/HRD could not be masked by underlying morbidities and the potential counteracting effects of related drug treatments.

Prefrontal-Periaqueductal Gray-Projecting Neurons Mediate Context Fear Discrimination.

Survival critically depends on selecting appropriate defensive or exploratory behaviors and is strongly influenced by the surrounding environment. Contextual discrimination is a fundamental process that is thought to depend on the prefrontal cortex to integrate sensory information from the environment and regulate adaptive responses to threat during uncertainty. However, the precise prefrontal circuits necessary for discriminating a previously threatening context from a neutral context remain unknown. Using a combination of single-unit recordings and optogenetic manipulations, we identified a neuronal subpopulation in the dorsal medial prefrontal cortex (dmPFC) that projects to the lateral and ventrolateral periaqueductal gray (l/vlPAG) and is selectively activated during contextual fear discrimination. Moreover, optogenetic activation and inhibition of this neuronal population promoted contextual fear discrimination and generalization, respectively. Our results identify a subpopulation of dmPFC-l/vlPAG-projecting neurons that control switching between different emotional states during contextual discrimination.

Species-specific diversity in the anatomical and physiological organisation of the BNST-VTA pathway.

The anteromedial part of the bed nucleus of the stria terminalis (amBNST) is a limbic structure innervating the ventral tegmental area (VTA) that is remarkably constant across species. The amBNST modulates fear and anxiety, and activation of VTA dopamine (DA) neurons by amBNST afferents seems to be the way by which stress controls motivational states associated with reward or aversion. Because fear learning and anxiety states can be expressed differently between rats and mice, we compared the functional connectivity between amBNST and the VTA-DA neurons in both species using consistent methodological approaches. Using a combination of in vivo electrophysiological, neuroanatomical tracing and laser capture approaches we explored the BNST influences on VTA-DA neuron activity. First, we characterised in rats the molecular phenotype of the amBNST neurons projecting to the VTA. We found that this projection is complex, including both GABAergic and glutamatergic neurons. Then, VTA injections of a conventional retrograde tracer, the ß-sub-unit of the cholera toxin (CTB), revealed a stronger BNST-VTA projection in mice than in rats. Finally, electrical stimulations of the BNST during VTA-DA neuron recording demonstrated a more potent excitatory influence of the amBNST on VTA-DA neuron activity in rats than in mice. These data illustrate anatomically, but also functionally, a significant difference between rats and mice in the amBNST-VTA pathway. More generally, together with previous findings, our research highlights the importance of species differences for the interpretation and the generalisation of research data.

NMDA-receptor-dependent plasticity in the bed nucleus of the stria terminalis triggers long-term anxiolysis.

Anxiety is controlled by multiple neuronal circuits that share robust and reciprocal connections with the bed nucleus of the stria terminalis (BNST), a key structure controlling negative emotional states. However, it remains unknown how the BNST integrates diverse inputs to modulate anxiety. In this study, we evaluated the contribution of infralimbic cortex (ILCx) and ventral subiculum/CA1 (vSUB/CA1) inputs in regulating BNST activity at the single-cell level. Using trans-synaptic tracing from single-electroporated neurons and in vivo recordings, we show that vSUB/CA1 stimulation promotes opposite forms of in vivo plasticity at the single-cell level in the anteromedial part of the BNST (amBNST). We find that an NMDA-receptor-dependent homosynaptic long-term potentiation is instrumental for anxiolysis. These findings suggest that the vSUB/CA1-driven LTP in the amBNST is involved in eliciting an appropriate response to anxiogenic context and dysfunction of this compensatory mechanism may underlie pathologic anxiety states.

Physiological phenotyping of pediatric chronic obstructive airway diseases.

Inert tracer gas washout (IGW) measurements detect increased ventilation inhomogeneity (VI) in chronic lung diseases. Their suitability for different diseases, such as cystic fibrosis (CF) and primary ciliary dyskinesia (PCD), has already been shown. However, it is still unclear if physiological phenotypes based on different IGW variables can be defined independently of underlying disease. Eighty school-age children, 20 with CF, 20 with PCD, 20 former preterm children, and 20 healthy children, performed nitrogen multiple-breath washout, double-tracer gas (DTG) single-breath washout, and spirometry. Our primary outcome was the definition of physiological phenotypes based on IGW variables. We applied principal component analysis, hierarchical Ward's clustering, and enrichment analysis to compare clinical characteristics between the clusters. IGW variables used for clustering were lung clearance index (LCI) and convection-dependent [conductive ventilation heterogeneity index (Scond)] and diffusion-convection-dependent variables [acinar ventilation heterogeneity index (Sacin) and carbon dioxide and DTG phase III slopes]. Three main phenotypes were identified. Phenotype I (n = 38) showed normal values in all IGW outcome variables. Phenotype II (n = 21) was characterized by pronounced global and convection-dependent VI while diffusion-dependent VI was normal. Phenotype III (n = 21) was characterized by increased global and diffusion- and convection-dependent VI. Enrichment analysis revealed an overrepresentation of healthy children and former preterm children in phenotype I and of CF and PCD in phenotypes II and III. Patients in phenotype III showed the highest proportion and frequency of exacerbations and hospitalization in the year prior to the measurement. IGW techniques allow identification of clinically meaningful, disease-independent physiological clusters. Their predictive value of future disease outcomes remains to be determined.

Improvement of medical care in a cohort of newborns with sickle-cell disease in North Paris: impact of national guidelines.

We conducted a retrospective study on newborns with sickle-cell disease (SCD), born 1995-2009, followed in a multicentre hospital-based network. We assessed patient outcomes, medical care and compliance with the national guidelines published in December 2005. Data from 1033 patients (742 SS/Sß°-thalassaemia) with 6776 patient-years of follow-up were analysed (mean age 7·1 ± 3·9 years). SCD-related deaths (n = 13) occurred only in SS-genotype patients at a median age of 23·1 months, mainly due to acute anaemia (n = 5, including 2 acute splenic sequestrations) and infection (n = 3). Treatment non-compliance was associated with a 10-fold higher risk of SCD-related death (P = 0·01). Therapeutic intensification was provided for all stroke patients (n = 12), almost all patients with abnormal transcranial Doppler (TCD) (n = 76) or with >1 acute chest syndrome/lifetime (n = 64) and/or ≥3 severe vaso-occlusive crises/year (n = 100). Only 2/3 of patients with baseline haemoglobin <70 g/l received intensification, mainly for other severity criteria. Overall, hydroxycarbamide was under-prescribed, given to 2/3 of severe vaso-occlusive patients and 1/3 of severely anaemic patients. Nevertheless, introduction of the on-line guidelines was concomitant with an improvement in medical care in the 2006-2009 cohort with a trend towards increased survival at 5 years, from 98·3% to 99·2%, significantly increased TCD coverage (P = 0·004) and earlier initiation of intensification of therapy (P ≤ 0·01).

Academic pediatric clinical research: factors associated with study implementation duration.

BACKGROUND: The ethical, methodological, and technical aspects of pediatric research, often results in complications and delays in implementation. Our objective was to identify factors associated with the implementation duration of hospital-based pediatric studies. METHODS: All hospital-based pediatric studies sponsored by AP-HP between 2002 and 2008 were retrospectively identified. Association of the funding mechanism and methodological factors with the implementation duration was assessed using a multivariable mixed linear model. Pharmaceutical factors were explored as part of a subgroup analysis restricted to the studies involving drug therapy. Given that we took an exploratory approach, factors associated with implementation duration with p < 0.10 were kept in the final models. RESULTS: A total of 139 studies were evaluated. The median implementation duration was 17.1 months (range: 0.9-55.3 months), and tended to increase over time (from 14.9 [25(th) percentile-75(th) percentile: 11.5-19.9] months in 2002 to 23.7 [15.2-31.0] months in 2008, p = 0.01). External (coefficient [95 % confidence interval]: -7.7 [-11.9;-3.5] months, p < 0.001) and internal funding (-5.3 95 % CI [-9.8;-0.8], p = 0.02) compared to governmental funding and number of centers (-0.1 95 % CI[-0.2;0.02] months for 1 center increase, p = 0.07) were associated with reduced duration, whereas interventional study (either involving drug therapy (6.0 95 % CI[0.7;11.3] months, p = 0.03 or not (3.5 95 % CI[-0.3;7.3] months, p = 0.06) was associated with increased duration compared to observational study. Regarding the 35 studies involving drug therapy, external funding decreased duration (-6.7 95 % CI[-13.2;-0.2] months, p = 0.05), whereas studies involving solely a pediatric population (7.8 95 % CI[1.1;14.5] months, p = 0.01) (compared to mixed adult-pediatric population), a placebo-controlled design (6.6 95 % CI[0.9;12.3] months, p = 0.01), and inappropriate drug formulation for at least one drug used in the study (6.9 95 % CI[-0.2;14.0] months, p = 0.06) were associated with increased duration. CONCLUSION: Implementation of hospital-based pediatric studies primarily faced delays when they were interventional and, in particular, when they involved drug therapy. Regarding the latter, difficulties that resulted in delayed studies arose with respect to the supply of drugs and placebo in age-appropriate dosages and route of administration. Therefore, difficulties related to the use of pharmaceuticals need to be anticipated earlier in order to avoid implementation delays.

Weaning Off Prognosis Factors of Home Parenteral Nutrition for Children With Primary Digestive Disease.

OBJECTIVES: The aim of the present study was to describe the indications for home parenteral nutrition (HPN) in children with primary digestive diseases and to identify factors associated with weaning off. METHODS: All the children initially discharged on HPN between January 1, 2000, and December 31, 2009, for chronic intestinal failure (IF) were included. The associations between clinical factors and weaning off of HPN were assessed using a multivariable Cox regression model. RESULTS: Among the 151 children (boys = 58%) included in this study, 98 (65%) presented with short bowel syndrome (SBS), 17 (11%) with digestive neuromuscular disorders, 14 (9%) with mucosal diseases, 13 (9%) with inflammatory bowel disease, and 9 (6%) with other primary digestive diseases. The probability of survival was ∼100%. At the end of the follow-up, the probability for weaning off of HPN was 0.73 (95% confidence interval 0.54-0.84) but varied according to the underlying cause of IF (for example, SBS and inflammatory bowel disease had a better prognosis). The median time until weaning off was 21 months (95% confidence interval 18-38 months). Unfavourable prognostic factors for weaning off of HPN included a bowel remnant of <40 cm, the presence of <50% of the colon, and daily lipid intakes >1.5 g · kg · day. Underlying disease was also associated with weaning off. CONCLUSIONS: HPN is a safe therapeutic option for children with chronic IF requiring long-term nutritional management. Prognostic factors for weaning off of HPN were identified, and they highlight the relevance of SBS anatomy and parenteral nutrition caloric intake. The outcome of children on HPN was primarily dependent on the underlying disease.

Long-term smoking cessation and heart rate dynamics in an aging healthy cohort: Is it possible to fully recover?

AIM: To evaluate the long-term influence of smoking cessation on the regulation of the autonomic cardiovascular system in an aging general population, using the subpopulation of lifelong non-smokers as control group. METHODS: We analyzed 1481 participants aged ≥50 years from the SAPALDIA cohort. In each participant, heart rate variability and heart rate dynamics were characterized by means of various quantitative analyzes of the inter-beat interval time series generated from 24-hour electrocardiogram recordings. Each parameter obtained was then used as the outcome variable in multivariable linear regression models in order to evaluate the association with smoking status and time elapsed since smoking cessation. The models were adjusted for known confounding factors and stratified by the time elapsed since smoking cessation. RESULTS: Our findings indicate that smoking triggers adverse changes in the regulation of the cardiovascular system, even at low levels of exposure since current light smokers exhibited significant changes as compared to lifelong non-smokers. Moreover, there was evidence for a dose-response effect. Indeed, the changes observed in current heavy smokers were more marked as compared to current light smokers. Furthermore, full recovery was achieved in former smokers (i.e., normalization to the level of lifelong non-smokers). However, while light smokers fully recovered within the 15 first years of cessation, heavy former smokers might need up to 15-25 years to fully recover. CONCLUSION: This study supports the substantial benefits of smoking cessation, but also warns of important long-term alterations caused by heavy smoking.

Prevalence and predictors of early cardiovascular events after kidney transplantation: evaluation of pre-transplant cardiovascular work-up.

INTRODUCTION: Cardiovascular disease is the leading cause of mortality after renal transplantation. The purpose of this study was to analyze cardiovascular risk factors at transplantation, occurrence of cardiovascular events in the first year after transplantation and evaluate pre-transplant work-up. MATERIAL AND METHOD: In total, 244 renal transplant recipients older than 50 years were included. The results of pre-transplant work-up, including clinical evaluation, electrocardiogram, echocardiography, myocardial perfusion testing and coronary angiography were analyzed. RESULTS: Patients had multiple risk factors at inclusion on renal transplantation waiting list as high blood pressure (94.7%), dyslipidemia (81.1%), smoking (45.3%), diabetes (23.6%), past history of cardiovascular disease (21.3%) and obesity (12.7%). Following transplantation, 15.5% (n = 38) of patients experienced a cardiovascular event, including 2.8% (n = 7) acute coronary syndrome, 5.8% (n = 14) isolated increase in troponin level and 5.3% (n = 13) new onset atrial fibrillation. The pre-transplant parameters associated with a cardiovascular event were a past medical history of cardiovascular disease (HR = 2.06 [1.06-4.03], p = 0.03), echocardiographic left ventricular hypertrophy (HR = 2.04 [1.04-3.98], p = 0.037) and abnormal myocardial perfusion testing (HR = 2.25 [1.09 -5.96], p = 0.03). Pre-transplantation evaluation allowed the diagnosis of unknown coronary artery lesions in 8.9% of patients.

Stress switches cannabinoid type-1 (CB1) receptor-dependent plasticity from LTD to LTP in the bed nucleus of the stria terminalis.

The bed nucleus of the stria terminalis (BNST) exerts a coordinated modulation of the psychoneuroendocrine responses to stress. However, how acute stress impacts on BNST in vivo plasticity is a crucial question that still remains unanswered. Here, neurons from the anterior portion of the BNST (aBNST) were recorded in vivo during and after stimulation of their medial prefrontal cortical (mPFC) afferents. In C57BL/6N mice, a 1 h restraint stress induced a switch from long-term depression (LTD) to long-term potentiation (LTP) in the aBNST after a 10 Hz mPFC stimulation. This switch was independent from glucocorticoid receptor stimulation. Because the endocannabinoid system regulates aBNST activity, we next examined the role of cannabinoid type-1 receptors (CB1-Rs) in these changes. Mutant mice lacking CB1-Rs (CB1(-/-) mice) displayed a marked deficit in the ability to develop plasticity under control and stress conditions, compared with their wild-type littermates (CB1(+/+) mice). This difference was not accounted for by genetic differences in stress sensitivity, as revealed by Fos immunohistochemistry analyses. Local blockade of CB1-Rs in the aBNST and the use of mutant mice bearing a selective deletion of CB1-Rs in cortical glutamatergic neurons indicated that stress-elicited LTP involved CB1-Rs located on aBNST excitatory terminals. These results show that acute stress reverts LTD into LTP in the aBNST and that the endocannabinoid system plays a key role therein.

How to improve the implementation of academic clinical pediatric trials involving drug therapy? A qualitative study of multiple stakeholders.

OBJECTIVE: The need for encouraging pediatric drug research is widely recognized. However, hospital-based clinical trials of drug treatments are extremely time-consuming, and delays in trial implementation are common. The objective of this qualitative study was to collect information on the perceptions and experience of health professionals involved in hospital-based pediatric drug trials. METHODS: Two independent researchers conducted in-depth semi-structured interviews with principal investigators (n = 17), pharmacists (n = 7), sponsor representatives (n = 4), and drug regulatory agency representatives (n = 3) who participated in institutionally sponsored clinical trials of experimental drugs in pediatric patients between 2002 and 2008. RESULTS: Dissatisfaction was reported by 67% (16/24) of principal investigators and pharmacists: all 7 pharmacists felt they were involved too late in the trial implementation process, whereas 11 (65%) principal investigators complained of an excessive regulatory burden and felt they were insufficiently involved in the basic research questions. Both groups perceived clinical trial implementation as burdensome and time-consuming. The sponsor and regulatory agency representatives reported a number of difficulties but were not dissatisfied. CONCLUSIONS: The heavy burden related to regulatory requirements, and suboptimal communication across disciplines involved, seem to be the main reasons for the major delays in pediatric drug trial implementation. The pharmaceutical aspects are intrinsically tied to trial methodology and implementation and must therefore be examined, in particular by involving Clinical Research Pharmacists at early stages of study conception.

Vitamin D status and outcomes after renal transplantation.

Kidney transplant recipients usually have low vitamin D levels, especially in the early posttransplantation period, but the association between vitamin D status with renal outcomes is not well described in this population. Here, we studied a prospective cohort of 634 kidney recipients who underwent transplantation at a single institution between January 2005 and June 2010. In this cohort, low 25-hydroxyvitamin D concentrations 3 months after transplantation did not predict early death or graft loss but were independently associated with lower measured GFR at 12 months (P=0.001) and higher risk for interstitial fibrosis and tubular atrophy (P=0.01). In contrast, levels of calcium, phosphorus, calcitriol, parathyroid hormone, or fibroblast growth factor-23 were not consistently associated with any of the studied outcomes. In conclusion, low 25-hydroxyvitamin D concentration measured 3 months after transplantation is an independent risk factor for interstitial fibrosis progression and is associated with a lower GFR 1 year after transplantation.

Alcohol as a risk factor for injury: lessons from French data.

The relationship between alcohol and injury is complex and the evidence level varies depending on the type of injury. The role of alcohol as a causal factor of traffic accidents is clear. There is less evidence concerning home and leisure injuries which include a wide range of accident causes and mechanisms. However, several studies dealing with specific injuries, such as drowning and fracture injuries in seniors, suggest a correlation between alcohol and the occurrence of injuries. Intentional injuries (violence, suicide) are complex and multifactorial phenomena. It is therefore more complicated to find the link between alcohol consumption and these kind of injuries. However, several physiological, psychological and social mechanisms are suggested to clarify this relationship. In conclusion, further data are needed to improve knowledge regarding the link between alcohol and injuries and, consequently, to implement preventive interventions. The collection of data on alcohol consumption at the moment of admission in emergency wards should be particularly promoted.

Transport, deglycosylation, and metabolism of trans-piceid by small intestinal epithelial cells.

BACKGROUND: Numerous epidemiological and animal studies have shown that consumption of red wine is related to reduced incidence of cardiovascular diseases and cancer. Trans-resveratrol (3, 5, 4'-trihydroxystilbene), a phenolic compound present in wine, has been reported to have a potential cancer chemopreventive activity. Moreover, it may exert a protective effect against atherogenesis through its antioxidant properties. Trans-piceid (3-ss glucoside of trans-resveratrol) is present to a greater extent than its aglycone in red wine, but hydrolysis of this glycosylated derivative can occur in small intestine and liver, which would enhance the amount of the biological active trans-resveratrol. AIMS: The present study aimed to investigate the rate of transepithelial transport of trans-piceid using human intestinal Caco-2 cell monolayers and metabolism of this compound during its absorption across the small intestine. METHODS: The transport of trans-piceid was evaluated in the human epithelial cell line Caco-2, which possesses enterocyte-like properties in vitro. For transepithelial experiments, confluent monolayers of Caco-2 cells were grown on Transwell inserts. For metabolic studies, we used both Caco-2 cells seeded on 6-well plates and rat small intestine cell-free extracts. RESULTS: The time course of apical (AP) to basolateral (BL) transport of trans-piceid showed that the favorable apparent permeability coefficient (Papp) declined rapidly during the 6 h of the experiment. This observation could be correlated with the appearance of metabolites. After incubation of Caco-2 cells with trans-piceid, trans-resveratrol was detected on both AP and BL sides. By using protein extracts obtained from rat, we conclude that the Lactase Phlorizin Hydrolase (LPH) and Cytosolic-ss-Glucosidase (CBG) are involved in the hydrolysis of trans-piceid. Furthermore, we show that after deglycosylation, the resulting aglycone is metabolized in trans-resveratrol-3-O-ss-glucuronide and to a lesser extent in trans-resveratrol-4'-O-ss-glucuronide, and that UGT1A1 is mainly involved in this metabolism. CONCLUSIONS: This study demonstrates that the transepithelial transport of trans-piceid occurs at a high rate and that the compound is deglycosylated in trans-resveratrol. There are two possible pathways by which trans-piceid is hydrolyzed in the intestine. The first is a cleavage by the CBG, after passing the brush-border membrane by SGLT1. The second is deglycosylation on the luminal side of the epithelium by the membrane-bound enzyme LPH, followed by passive diffusion of the released aglycone, which is further metabolized inside the cells into two glucuronoconjugates.