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Studies the effects of repeated ethanol intake over a 24-hour period which is a pattern of consumption closer to the clinical condition of chronic alcoholism. Comparison of body temperature during alcohol session at night and at daytime; Percent reduction in the amplitude of the circadian temperature rhythm between the control and alcohol session; Number of volunteers who experienced a hyperthermic effect at night.

Explores the effect of alcohol consumption on the circadian control of human core body temperature. Induction of significant hyperthermic effect; Reduction of circadian amplitude; Impact of jet lag, shift work and aging.

Examines the inhibition of amiodarone metabolism induced by grapefruit juice. Identification of the drug kinetics of grapefruit juice; Evaluation of the pharmacokinetics on the adult volunteers; Prescription recommendation on the antiarrhythmic drug indication.

In the present subanalysis of a cross-sectional study showing the favorable effect of prior transient ischemia, leisure-time physical activity, and lipid-lowering drug therapy on stroke severity, we aimed to evaluate whether previous physical activity was dose dependently associated to minor stroke (NIHSS 0-3) and to identify possible underlying factors. Among 362 consecutive patients, less severe stroke was related to weekly exercise duration prior to stroke (no exercise: 36.1%; <2 hours: 49.3%; 2-5 hours: 58.8%; >5 hours: 64.0%; P = 0.003). Only weak and moderate exercise practices were protective (weak: 50.0%; moderate: 79.3%; heavy: 22.2%;P < 0.0001). Such a beneficial effect was observed independently of age and was associated with a trend to a lower frequency of arterial hypertension, alcohol abuse, and a better metabolic profile. Besides other therapeutic approaches, physical activity may be a simple way to decrease cerebral ischemia severity. [ABSTRACT FROM AUTHOR]

Unlabelled: Increased carotid intima-media thickness (cIMT) in adults may be caused by a childhood exposure to cardiovascular risk factors. We systematically reviewed observational studies to determine whether obesity, insulin-dependent diabetes mellitus (IDDM), dyslipidemia (DL), hypertension (HT), and chronic renal failure (CRF) are associated with increased cIMT in children and adolescent patients compared with control subjects. We performed a PubMed literature search from January 1986 to February 2010. Two reviewers separately verified the inclusion criteria of relevant studies for the objective of the review. The data extracted in the patient and control groups were sample size, age, gender, cIMT measurement methods, cIMT values, and statistical analysis results. From 348 citations, 65 cross-sectional studies (2 cited twice) with case-control design met the inclusion criteria: 26 in obesity, 14 in IDDM, 11 in DL, 8 in HT, and 8 in CRF. cIMT measurement protocols varied according to the studies, with measurements being performed on the common carotid artery in 65/67 cases and on the far wall in 57/67 cases. From the 67 studies cited, 22/26 reported a significantly increased cIMT in obese children and adolescents compared with the control group, 8/14 in IDDM patients, 10/11 in DL patients, 7/8 in HT patients, and 8/8 in CRF patients.Conclusion: Despite the heterogeneity of ultrasound measurement methods, cIMT was significantly increased in 55 out of the 67 cited studies, confirming early vascular damages in pediatric populations with an increased future risk for vascular diseases. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To measure the carotid intima-media-thickness (cIMT) and to assess its determinant factors in healthy adolescents. Methods: 319 adolescents aged 12.5–17.5 years (135 boys, 184 girls) were enrolled in this cross-sectional study. cIMT and carotid diameter were measured by high-resolution B-mode ultrasound. Anthropometric parameters, blood pressure, physical activity (PA), aerobic fitness and dietary intakes were assessed. Socioeconomic status was determined with the family affluence scale (FAS 4). Serum biological markers (lipids, glucose, high-sensitivity C-reactive protein, soluble adhesion molecules) were measured in a subsample of 96 adolescents. Results: Multiple regression analysis showed that cIMT was positively associated with truncal fat (p = 0.021) and negatively with FAS 4 (p = 0.002) independently of age and blood pressure. There were no significant associations between cIMT and PA, fitness and dietary intakes. In the subsample soluble intercellular adhesion molecule 1 was positively correlated with cIMT (p = 0.017), independently of truncal fat, age and blood pressure. Conclusions: Low socioeconomic conditions and increased truncal fat are associated with greater carotid intima-media-thickness in adolescents. [Copyright &y& Elsevier]

Background & Aims: Recent studies reported a role for more than 70 genes or loci in the susceptibility to Crohn's disease (CD). However, the impact of these associations in clinical practice remains to be defined. The aim of the study was to analyse the relationship between genotypes and phenotypes for the main 53 CD-associated polymorphisms. Method: A cohort of 798 CD patients with a median follow up of 7 years was recruited by tertiary adult and paediatric gastroenterological centres. A detailed phenotypic description of the disease was recorded, including clinical presentation, response to treatments and complications. The participants were genotyped for 53 CD-associated variants previously reported in the literature and correlations with clinical sub-phenotypes were searched for. A replication cohort consisting of 722 CD patients was used to further explore the putative associations. Results: The NOD2 rare variants were associated with an earlier age at diagnosis (p = 0.0001) and an ileal involvement (OR = 2.25[1.49-3.41] and 2.77 [1.71-4.50] for rs2066844 and rs2066847, respectively). Colonic lesions were positively associated with the risk alleles of IL23R rs11209026 (OR = 2.25 [1.13-4.51]) and 6q21 rs7746082 (OR = 1.60 [1.10-2.34] and negatively associated with the risk alleles of IRGM rs13361189 (OR = 0.29 [0.11-0.74]) and DEFB1 rs11362 (OR = 0.50 [0.30- 0.80]). The ATG16L1 and IRGM variants were associated with a non-inflammatory behaviour (OR = 1.75 [1.22-2.53] and OR = 1.50 [1.04-2.16] respectively). However, these associations lost significance after multiple testing corrections. The protective effect of the IRGM risk allele on colonic lesions was the only association replicated in the second cohort (p = 0.03). Conclusions: It is not recommended to genotype the studied polymorphisms in routine practice. [ABSTRACT FROM AUTHOR]

Background: Treatment of urinary schistosomiasis by chemotherapy remains challenging due to rapid re-infection and possibly to limited susceptibility to praziquantel treatment. Therefore, therapeutic vaccines represent an attractive alternative control strategy. The objectives of this study were to assess the safety and tolerability profile of the recombinant 28 kDa glutathione S-transferase of Schistosoma haematobium (rSh28GST) in healthy volunteers, and to determine its immunogenicity. Methodology: Volunteers randomly received 100 µg rSh28GST together with aluminium hydroxide (Alum) as adjuvant (n = 8), or Alum alone as a comparator (n = 8), twice with a 28-day interval between doses. A third dose of rSh28GST or Alum alone was administered to this group at day 150. In view of the results obtained, another group of healthy volunteers (n = 8) received two doses of 300 µg of rSh28GST, again with a 28-day interval. A six-month follow-up was performed with both clinical and biological evaluations. Immunogenicity of the vaccine candidate was evaluated in terms of specific antibody production, the capacity of sera to inhibit enzymatic activity of the antigen, and in vitro cytokine production. Principal Findings: Among the 24 healthy male participants no serious adverse events were reported in the days or weeks after administration. Four subjects under rSh28GST reported mild reactions at the injection site while a clinically insignificant increase in bilirubin was observed in 8/24 subjects. No hematological nor biochemical evidence of toxicity was detected. Immunological analysis showed that rSh28GST was immunogenic. The induced Th2-type response was characterized by antibodies capable of inhibiting the enzymatic activity of rSh28GST. Conclusions: rSh28GST in Alum did not induce any significant toxicity in healthy adults and generated a Th2-type immune response. Together with previous preclinical results, the data of safety, tolerability and quality of the specific immune response provide evidence that clinical trials with rSh28GST could be continued in humans as a potential vaccine candidate against urinary schistosomiasis. Author Summary: Therapeutic vaccines represent an attractive tool in the fight against schistosomiasis. Pre-clinical immunization studies with the schistosome enzyme 28 kDa glutathione S-transferase (28GST) has been shown to significantly reduce schistosome egg production and subsequent pathology. The objective of this study was to assess the safety and immunogenicity of the recombinant 28GST of Schistosoma haematobium (rSh28GST) in healthy adult volunteers. After three administrations of 100 µg or two of 300 µg, no serious adverse events were reported in the days or weeks after each administration. Some mild adverse events were noted, including minor reactions at the injection site reported for four subjects receiving rSh28GST, but there was no hematological or biochemical evidence of toxicity. Immunological analysis showed that rSh28GST induced a consistent immune response characterized by antibodies endowed with the capacity to inhibit 28GST enzymatic activity. Present data provide evidence that clinical trials with rSh28GST could be continued in humans as a potential vaccine candidate against urinary schistosomiasis. [ABSTRACT FROM AUTHOR]

Background: Treatment of urinary schistosomiasis by chemotherapy remains challenging due to rapid re-infection and possibly to limited susceptibility to praziquantel treatment. Therefore, therapeutic vaccines represent an attractive alternative control strategy. The objectives of this study were to assess the safety and tolerability profile of the recombinant 28 kDa glutathione S-transferase of Schistosoma haematobium (rSh28GST) in healthy volunteers, and to determine its immunogenicity. Methodology: Volunteers randomly received 100 μg rSh28GST together with aluminium hydroxide (Alum) as adjuvant (n = 8), or Alum alone as a comparator (n = 8), twice with a 28-day interval between doses. A third dose of rSh28GST or Alum alone was administered to this group at day 150. In view of the results obtained, another group of healthy volunteers (n = 8) received two doses of 300 mg of rSh28GST, again with a 28-day interval. A six-month follow-up was performed with both clinical and biological evaluations. Immunogenicity of the vaccine candidate was evaluated in terms of specific antibody production, the capacity of sera to inhibit enzymatic activity of the antigen, and in vitro cytokine production. Principal Findings: Among the 24 healthy male participants no serious adverse events were reported in the days or weeks after administration. Four subjects under rSh28GST reported mild reactions at the injection site while a clinically insignificant increase in bilirubin was observed in 8/24 subjects. No hematological nor biochemical evidence of toxicity was detected. Immunological analysis showed that rSh28GST was immunogenic. The induced Th2-type response was characterized by antibodies capable of inhibiting the enzymatic activity of rSh28GST. Conclusions: rSh28GST in Alum did not induce any significant toxicity in healthy adults and generated a Th2-type immune response. Together with previous preclinical results, the data of safety, tolerability and quality of the specific immune response provide evidence that clinical trials with rSh28GST could be continued in humans as a potential vaccine candidate against urinary schistosomiasis. [ABSTRACT FROM AUTHOR]

Abstract: Background: Road Traffic Accidents (RTA) are most probably the leading cause of post traumatic stress disorder (PTSD) in developed countries. The autonomic nervous system (ANS) disturbances, due to psychological trauma, are part of the pathophysiology of PTSD. The aim of the present study was to determine whether early heart rate variability (HRV) measurement, a biomarker of the ANS function, could act as a predictor of PTSD development after a RTA. Methods: We prospectively investigated 35 survivors of RTA with both physical injury and psychological trauma. HRV data were obtained from 24-h Holter ECG monitoring, which was performed on the second day after the accident. Time domain analysis was applied to the inter-beat (RR) interval time series to calculate the various parameters of HRV. PTSD status was assessed 2 and 6 months after RTA. Results: There was a global diminution of HRV measurements in the PTSD group at both 2 and 6 months. The variability index was the best predictor of PTSD with the area under the receiveroperating curve for discriminating PTSD at 6 months at 0.92 (95% CI: 0.785; 1.046). A cut-off at 2.19% yielded a sensitivity of 85.7% and a specificity of 81.8% for PTSD. Positive and negative predictive values were respectively 75% and 90%. However, initial heart rate (HR) data were relevant at 2 months but not at 6 months. Conclusion: RTA survivors exhibiting lower parasympathetic modulation of HR, indexed by temporal analysis of HRV, are more susceptible to developing PTSD as a short and long-term outcome. [Copyright &y& Elsevier]

Background: Suicide attempts (SA) constitute a serious clinical problem. People who attempt suicide are at high risk of further repetition. However, no interventions have been shown to be effective in reducing repetition in this group of patients. Methods/Design: Multicentre randomized controlled trial. We examine the effectiveness of «ALGOS algorithm»: an intervention based in a decisional tree of contact type which aims at reducing the incidence of repeated suicide attempt during 6 months. This algorithm of case management comprises the two strategies of intervention that showed a significant reduction in the number of SA repeaters: systematic telephone contact (ineffective in first-attempters) and «Crisis card» (effective only in firstattempters). Participants who are lost from contact and those refusing healthcare, can then benefit from «short letters» or «postcards». Discussion: ALGOS algorithm is easily reproducible and inexpensive intervention that will supply the guidelines for assessment and management of a population sometimes in difficulties with healthcare compliance. Furthermore, it will target some of these subgroups of patients by providing specific interventions for optimizing the benefits of case management strategy. Trial Registration: The study was registered with the ClinicalTrials.gov Registry; number: NCT01123174. [ABSTRACT FROM AUTHOR]

Oral hormone therapy is associated with an increased risk of venous thrombosis. Drug agencies recommend the use of the lowest efficient dose to treat menopausal symptoms for a better risk/ratio profile, although this profile has not been totally investigated yet. The aim of the study was to compare the effect of the standard dose of 17β-estradiol to a lower one on thrombin generation (TG). In a 2-month study, healthy menopausal women were randomized to receive daily 1mg or 2 mg of 17β-estradiol (E1, n = 24 and E2, n = 26; respectively) with 10 mg dydrogesterone or placebo (PL, n = 22). Plasma levels factors VII, X, VIII and II were assessed before and after treatment as well as Tissue factor triggered TG, which allows the investigation of the different phases of coagulation process. The peak of thrombin was higher in hormone therapy groups (E1: 42.39 ± 50.23 nm, E2: 31.08 ± 85.86 nm vs. 10.52 ± 40.63 nm in PL, P = 0.002 and P = 0.01). Time to reach the peak was also shortened (PL: 0.26 ± 0.69 min vs. E1: –0.26 ± 0.80 min, E2: –0.55 ± 0.79 min, P <10−3 for both comparisons) and mean rate index of the propagation phase of TG was significantly increased. Among the studied clotting factors, only the levels of FVII were significantly increased after treatment administration. The two doses of 17β-estradiol induced in a similar degree an acceleration of the initiation and propagation phase of tissue factor triggered thrombin generation and a significant increase of FVII coagulant activity. [ABSTRACT FROM AUTHOR]

Background: 'Compassionate use' programmes allow medicinal products that are not authorised, but are in the development process, to be made available to patients with a severe disease who have no other satisfactory treatment available to them. We sought to understand how such programmes are regulated in ten European Union countries. Methods: The European Clinical Research Infrastructures Network (ECRIN) conducted a comprehensive survey on clinical research regulatory requirements, including questions on regulations of 'compassionate use' programmes. Ten European countries, covering approximately 70% of the EU population, were included in the survey (Austria, Denmark, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, and the UK). Results: European Regulation 726/2004/EC is clear on the intentions of 'compassionate use' programmes and aimed to harmonise them in the European Union. The survey reveals that different countries have adopted different requirements and that 'compassionate use' is not interpreted in the same way across Europe. Four of the ten countries surveyed have no formal regulatory system for the programmes. We discuss the need for 'compassionate use' programmes and their regulation where protection of patients is paramount. Conclusions: 'Compassionate use' is a misleading term and should be replaced with 'expanded access'. There is a need for expanded access programmes in order to serve the interests of seriously ill patients who have no other treatment options. To protect these patients, European legislation needs to be more explicit and informative with regard to the regulatory requirements, restrictions, and responsibilities in expanded access programmes. [ABSTRACT FROM AUTHOR]

Abstract: Some host-related factors may predict the risk of metastasis after surgery of colorectal cancer (CRC). The endothelial adhesion molecule E-selectin is implicated in the metastatic spread of CRC. We postulated that some polymorphisms within the E-selectin gene, especially the S128R polymorphism, may increase the risk of metastases by facilitating adhesion of tumour cells to the endothelium. We collected blood samples for DNA extraction from 264 patients treated for stage II or III CRC and from 310 healthy controls in order to assess three polymorphisms within the E-selectin gene (S128R, G98T and L554F) and one within the P-selectin gene (V640L). Genotypes were analysed by the allelic discrimination TaqMan real-time PCR assay. The S128R polymorphism was detected in 59 patients (22.3%) and was strictly correlated with the G98T polymorphism. In multivariate analysis, the S128R polymorphism was associated with shorter event-free survival (EFS) and overall survival (OS) in the whole population (EFS: P =.003, HR 1.82, 95% CI 1.23–2.70; OS: P <10–4, HR 4.31, 95% CI 2.46–10.99), in patients with stage II CRC(EFS: P =.04, HR 1.92, 95% CI 1.02–3.60; OS: P =.02, HR 4.44, 95% CI 1.16–17.03), and in patients with stage III CRC (EFS: P =.04, HR 1.68, 95% CI 1.01–2.80; OS: P =.001, HR 4.04, 95% CI 1.73–9.46). L554F and V640L polymorphisms had no prognostic value. The S128R polymorphism is a constitutional factor associated with a higher risk of relapse and death in patients treated for CRC. This polymorphism detection may permit better selection of patients suitable for adjuvant therapy, especially among those with stage II disease. [Copyright &y& Elsevier]

OBJECTIVES:Anti-Saccharomyces cerevisiae antibodies (ASCAs) are present in 50–60% of patients with Crohn's disease (CD) and in 20–25% of their healthy relatives (HRs). The yeast, Candida albicans, has been shown to generate ASCAs, but the presence of C. albicans in the digestive tract of CD patients and their HRs has never been investigated. Therefore, we studied C. albicans carriage in familial CD and its correlation with ASCAs.METHODS:Study groups consisted of 41 CD families composed of 129 patients and 113 HRs, and 14 control families composed of 76 individuals. Mouth swabs and stool specimens were collected for isolation, identification, and quantification of yeasts. Serum samples were collected for detection of ASCAs and anti-C. albicans mannan antibodies (ACMAs).RESULTS:C. albicans was isolated significantly more frequently from stool samples from CD patients (44%) and their HRs (38%) than from controls (22%) (P<0.05). The prevalence of ACMAs was similar between CD patients, their HRs, and controls (22, 19, and 21%, respectively, P=0.845), whereas the prevalence of ASCAs was significantly increased in CD families (72 and 34% in CD and HRs, respectively, in contrast to 4% in controls, P<0.0001). AMCA levels correlated with C. albicans colonization in all populations. ASCA levels correlated with C. albicans colonization in HRs but not in CD patients.CONCLUSIONS:CD patients and their first-degree HRs are more frequently and more heavily colonized by C. albicans than are controls. ASCAs correlate with C. albicans colonization in HRs but not in CD. In HRs, ASCAs could result from an altered immune response to C. albicans. In CD, a subsequent alteration in sensing C. albicans colonization could occur with disease onset.Am J Gastroenterol 2009; 104:1745–1753; doi:10.1038/ajg.2009.225; published online 26 May 2009 [ABSTRACT FROM AUTHOR]

The article describes a randomized controlled trial to determine the effect of contacting patients by telephone over one year, either one month or three months after discharge from an emergency department for deliberate self poisoning, as compared with the usual treatment. The study was carried out in with patients from 13 emergency departments in the north of France. The study measured deaths by suicide, reattempts, and losses at follow up after 13 months.

The human cytochrome CYP2A13, which is mainly expressed in the respiratory tract, has been shown to be highly efficient in vitro in the metabolism of tobacco-smoke carcinogens and procarcinogens such as 4-methylnitroso-1-(3-pyridyl)-1-butanone (NNK). In order to investigate the extent of CYP2A13 genetic polymorphism in a French Caucasian population of 102 individuals, a screening for sequence variations in the 5′-untranslated and protein encoding regions of its gene was performed using a polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) strategy. Six polymorphisms in the coding region were identified, including two rare missense mutations (C474G or Asp158Glu, G967T or Val323Leu) and one nonsense mutation (Arg101Stop). This deleterious mutation, the most frequent (5%) in our population, presumably encodes a severely truncated protein. The influence of the nonsense mutation in lung cancer susceptibility was examined by PCR-SSCP using peripheral blood DNA from 204 cases of lung cancer and 201 controls. The CYP2A13*7 allele, which harbours the C301T mutation, was present in 2.0% of controls and 3.4% of cases. However, multivariate analysis showed an elevated risk for small cell lung cancer in subjects heterozygous for the null allele (odds ratio OR=9.9; 95% confidence interval CI=1.9–52.2). This increased risk was not linked to other histological types of lung cancer. [Copyright &y& Elsevier]

Human thiopurine S-methyltransferase (TPMT) is an enzyme responsible for the detoxification of widely used thiopurine drugs such as azathioprine (Aza). Its activity is inversely related to the risk of developing severe hematopoietic toxicity in certain patients treated with standard doses of thiopurines. DNA samples from four leucopenic patients treated with Aza were screened by PCR-SSCP analysis for mutations in the 10 exons of the TPMT gene. Four missense mutations comprising two novel mutations, A83T (TPMT*13, Glu28Val) and C374T (TPMT*12, Ser125Leu), and two previously described mutations, G430C (TPMT*10, Gly144Arg) and T681G (TPMT*7, His227Gln) were identified. Using a recombinant yeast expression system, kinetic parameters (Km and Vmax) of 6-thioguanine S-methylation of the four TPMT variants were determined and compared to those obtained with wild-type TPMT. This functional analysis suggests that these rare allelic variants are defective TPMT alleles. The His227Gln variant retained only 10% of the intrinsic clearance value (Vmax/Km ratio) of the wild-type enzyme. The Ser125Leu and Gly144Arg variants were associated with a significant decrease in intrinsic clearance values, retaining about 30% of the wild-type enzyme, whereas the Glu28Val variant produced a more modest decrease (57% of the wild-type enzyme). The data suggest that the sporadic contribution of the rare Glu28Val, Ser125Leu, Gly144Arg, and His227Gln variants may account for the occurrence of altered metabolism of TPMT substrates. These findings improve our knowledge of the genetic basis of interindividual variability in TPMT activity and would enhance the efficiency of genotyping methods to predict patients at risk of inadequate responses to thiopurine therapy. [Copyright &y& Elsevier]

A drastic change in a human's way of life is known to lead to dramatic modifications in intestinal microbial balance. The effects of mild stress of everyday life have, however, been poorly investigated. In this study, we have attempted to assess whether final written examination stress modifies the faecal microbiota in healthy young adults. Diet was standardised and faecal samples collected during two periods of 48 h each, the first 6 weeks before and the second during the final written examination. Faecal hydration as well as counts in total aerobes, anaerobes, enterobacteria, enterococci, Clostridium perfringens and bifidobacteria were determined. Bifidobacteria, enterococci and enterobacteria did not show any significant variation. A significant rise in C. perfringens counts was observed throughout this examination period. It preceded the increase in faecal hydration only observed after a change in diet. Since psychological stress is known to increase intestinal mucin release, C. perfringens overgrowth might reflect a better adaptation to substrates provided by the stressed host. [ABSTRACT FROM AUTHOR]