Insulinoma associated with a case of multiple endocrine neoplasia type I: Functional somatostatin receptors and abnormal glucose-induced insulin secretion.

A sporadic case of multiple endocrine neoplasia type I with coexisting insulinoma and hyperparathyroidism was investigated in vivo and in vitro. The insulinoma was localized by somatostatin receptor scintigraphy and these receptors were functionally active. Octreotide administration decreased the basal insulin and glucagon secretion by 90 and 46%, respectively. Immunocytochemistry of the insulinoma tissue was positive for insulin, chromogranin A and neuropeptide Y. The insulinoma cells were also isolated and cultured in vitro. Incubation experiments revealed that a low glucose concentration (1 mmol/l) was sufficient to increase cytosolic free calcium and to produce a maximal glucose-induced insulin release. Northern blot analysis of RNA obtained from the tumor showed a high abundance of the low Km glucose transporter GLUT1 but no transcript for the high Km glucose transporter GLUT2. The abnormal distribution of glucose transporters probably relates to the abnormal glucose sensing of insulinoma cells, and explains their sustained insulin secretion at low glucose concentrations. Whether these abnormalities share a pathogenetic link with the presence of functionally active somatostatin receptors remains to be elucidated.

Improving appropriateness of antibiotic therapy: randomized trial of an intervention to foster reassessment of prescription after 3 days.

OBJECTIVES: Reassessment of ongoing antibiotic therapy is an important step towards appropriate use of antibiotics. This study was conducted to evaluate the impact of a short questionnaire designed to encourage reassessment of intravenous antibiotic therapy after 3 days. PATIENTS AND METHODS: Patients hospitalized on the surgical and medical wards of a university hospital and treated with an intravenous antibiotic for 3-4 days were randomly allocated to either an intervention or control group. The intervention consisted of mailing to the physician in charge of the patient a three-item questionnaire referring to possible adaptation of the antibiotic therapy. The primary outcome was the time elapsed from randomization until a first modification of the initial intravenous antibiotic therapy. It was compared within both groups using Cox proportional-hazard modelling. RESULTS: One hundred and twenty-six eligible patients were randomized in the intervention group and 125 in the control group. Time to modification of intravenous antibiotic therapy was 14% shorter in the intervention group (adjusted hazard ratio for modification 1.28, 95% CI 0.99-1.67, P = 0.06). It was significantly shorter in the intervention group compared with a similar group of 151 patients observed during a 2 month period preceding the study (adjusted hazard ratio 1.17, 95% CI 1.03-1.32, P = 0.02). CONCLUSION: The results suggest that a short questionnaire, easily adaptable to automatization, has the potential to foster reassessment of antibiotic therapy.

Etude d'administration contrôlée de cannabis et profils cinétiques des cannabinoïdes dans les fluides biologiques

Le cannabis est l'une des drogues illégales les plus consommées au monde. Le delta-9- tétrahydrocannabinol (THC) est le composé psychoactif majeur du cannabis et est fréquemment détecté dans le sang de conducteurs impliqués dans un accident de la route, alors qu'il est actuellement interdit de conduire sous l'influence du THC en Suisse comme dans de nombreux pays européens. La détection de ce composé dans le sang est suivie d'une série de mesures pénales et administratives à l'encontre du conducteur impliqué. Cette thèse intitulée « Etude d'administration contrôlée de cannabis et profils cinétiques dans les fluides biologiques » s'inscrit dans une étude toxicologique menée au Centre Hospitalier Universitaire Vaudois (CHUV). Le but de cette étude est d'évaluer les effets du cannabis sur le fonctionnement du cerveau lorsque le consommateur accompli une tâche fondamentale de la conduite automobile. Pour cela, l'imagerie médicale par résonnance magnétique fonctionnelle (IRMf) est combinée à un test informatisé simulant une tâche psychomotrice requise pour une conduite automobile sûre. Il s'agit d'un test de double tâche de poursuite d'une cible au moyen d'un curseur dirigé par un joystick, combiné à une tâche secondaire de détection de signaux routiers. Parallèlement, les profils cinétiques sanguins et salivaires des volontaires ont été déterminés grâce à des prélèvements effectués tout au long de la journée d'étude. Les objectifs principaux de ce travail de thèse sont les suivants : après une revue de la littérature existante sur les techniques d'analyse des cannabinoïdes dans les fluides biologiques, une méthode a été développée et validée pour ces composés dans la salive puis appliquée aux échantillons de l'étude. En parallèle, les échantillons sanguins et urinaires ont été analysés, en partie avec une méthode adaptée de celle développée pour la salive. Pour montrer la versatilité de cette méthode, celle-ci a été employée pour analyser des échantillons de bile qui a l'avantage de contenir des concentrations élevées de métabolites conjugués. Dans un deuxième temps, les dosages effectués sur le sang et la salive ont permis d'établir les profils cinétiques des cannabinoïdes, de déterminer leurs paramètres pharmacocinétiques et de les comparer. Les données obtenues ont montré que la concentration sanguine en acide 11-nor-9- carboxy-delta-9-tétrahydrocannabinol (THCCOOH) pouvait servir à distinguer les fumeurs occasionnels des fumeurs réguliers de cannabis, car elle est significativement plus élevée chez les consommateurs réguliers. De plus, d'autres cannabinoïdes présents dans la salive pourraient servir de marqueurs de consommation récente dans ce fluide biologique. Enfin, que ce soit dans le sang, la salive ou l'urine, des phytocannabinoïdes peuvent être utilisés comme marqueur de consommation de cannabis illégal car ils sont absents des médicaments à base de cannabis utilisant des préparations synthétiques ou purifiées du THC.

Plasma angiotensin-(1-8) octapeptide measurement to assess acute angiotensin-converting enzyme inhibition with captopril administered parenterally to normal subjects.

The blood pressure (BP), heart rate (HR), and humoral effects of single intravenous (i.v.) doses of the angiotensin-converting enzyme (ACE) inhibitor captopril was investigated in five normotensive healthy volunteers. Each subject received at 1-week intervals a bolus dose of either captopril (1, 5, and 25 mg) or its vehicle. The study was conducted in a single-blind fashion, and the order of treatment phases was randomized. The different doses of captopril had no acute effect on BP and HR. They induced a dose-dependent decrease in plasma ACE activity and plasma angiotensin II levels. The angiotensin-(1-8) octapeptide was isolated by solid-phase extraction and high-performance liquid chromatography (HPLC) prior to radioimmunoassay (RIA). All three doses of captopril reduced circulating angiotensin II levels within 15 min of drug administration. Only with the 25-mg dose was the angiotensin II concentration below the detection limit at 15 min and still significantly reduced 90 min after drug administration. Simultaneous and progressive decreases in plasma aldosterone levels were observed both with ACE inhibition and during vehicle injection, but the relative fall was more pronounced after captopril administration. No adverse reaction was noticed. These results demonstrate that captopril given parenterally blocks the renin-angiotensin system in a dose-dependent manner. Only with the dose of 25 mg was the inhibition of plasma-converting enzyme activity and the reduction of plasma angiotensin II sustained for at least 1 1/2 h.

Sublingual sugar for hypoglycaemia in children with severe malaria: a pilot clinical study.

BACKGROUND: Hypoglycaemia is a poor prognostic indicator in severe malaria. Intravenous infusions are rarely feasible in rural areas. The efficacy of sublingual sugar (SLS) was assessed in a pilot randomized controlled trial among hypoglycaemic children with severe malaria in Mali. METHODS: Of 151 patients with presumed severe malaria, 23 children with blood glucose concentrations < 60 mg/dl (< 3.3 mmol/l) were assigned randomly to receive either intravenous 10% glucose (IVG; n = 9) or sublingual sugar (SLS; n = 14). In SLS, a teaspoon of sugar, moistened with a few drops of water, was gently placed under the tongue every 20 minutes. The child was put in the recovery position. Blood glucose concentration (BGC) was measured every 5-10 minutes for the first hour. All children were treated for malaria with intramuscular artemether. The primary outcome measure was treatment response, defined as reaching a BGC of >or= 3.3 mmol/l (60 mg/dl) within 40 minutes after admission. Secondary outcome measures were early treatment response at 20 minutes, relapse (early and late), maximal BGC gain (CGmax), and treatment delay. RESULTS: There was no significant difference between the groups in the primary outcome measure. Treatment response occurred in 71% and 67% for SLS and IVG, respectively. Among the responders, relapses occurred in 30% on SLS at 40 minutes and in 17% on IVG at 20 minutes. There was one fatality in each group. Treatment failures in the SLS group were related to children with clenched teeth or swallowing the sugar, whereas in the IVG group, they were due to unavoidable delays in beginning an infusion (median time 17.5 min (range 3-40).Among SLS, the BGC increase was rapid among the nine patients who really kept the sugar sublingually. All but one increased their BGC by 10 minutes with a mean gain of 44 mg/dl (95%CI: 20.5-63.4). CONCLUSION: Sublingual sugar appears to be a child-friendly, well-tolerated and effective promising method of raising blood glucose in severely ill children. More frequent repeated doses are needed to prevent relapse. Children should be monitored for early swallowing which leads to delayed absorption, and in this case another dose of sugar should be given. Sublingual sugar could be proposed as an immediate "first aid" measure while awaiting intravenous glucose. In many cases it may avert the need for intravenous glucose.

Oral cancer treatments and adherence: medication event monitoring system assessment for capecitabine

Background: Oncological treatments are traditionally administered via intravenous injection by qualified personnel. Oral formulas which are developing rapidly are preferred by patients and facilitate administration however they may increase non-adherence. In this study 4 common oral chemotherapeutics are given to 50 patients, who are still in the process of inclusion, divided into 4 groups. The aim is to evaluate adherence and offer these patients interdisciplinary support with the joint help of doctors and pharmacists. We present here the results for capecitabine. Materials and Methods: The final goal is to evaluate adhesion in 50 patients split into 4 groups according to oral treatments (letrozole/exemestane, imatinib/sunitinib, capecitabine and temozolomide) using persistence and quality of execution as parameters. These parameters are evaluated using a medication event monitoring system (MEMS®) in addition to routine oncological visits and semi-structured interviews. Patients were monitored for the entire duration of treatment up to a maximum of 1 year. Patient satisfaction was assessed at the end of the monitoring period using a standardized questionary. Results: Capecitabine group included 2 women and 8 men with a median age of 55 years (range: 36−77 years) monitored for an average duration of 100 days (range: 5-210 days). Persistence was 98% and quality of execution 95%. 5 patients underwent cyclic treatment (2 out of 3 weeks) and 5 patients continuous treatment. Toxicities higher than grade 1 were grade 2−3 hand-foot syndrome in 1 patient and grade 3 acute coronary syndrome in 1 patient both without impact on adherence. Patients were satisfied with the interviews undergone during the study (57% useful, 28% very useful, 15% useless) and successfully integrated the MEMS® in their daily lives (57% very easily, 43% easily) according to the results obtained by questionary at the end of the monitoring period. Conclusion: Persistence and quality of execution observed in our Capecitabine group of patients were excellent and better than expected compared to previously published studies. The interdisciplinary approach allowed us to better identify and help patients with toxicities to maintain adherence. Overall patients were satisfied with the global interdisciplinary follow-up. With longer follow up better evaluation of our method and its impact will be possible. Interpretation of the results of patients in the other groups of this ongoing trial will provide us information for a more detailed analysis.

Energy cost of glucose storage in human subjects during glucose-insulin infusions.

The effect of graded levels of hyperinsulinemia on energy expenditure, while euglycemia was maintained by glucose infusion, was examined in 22 healthy young male volunteers by using the euglycemic insulin clamp technique in combination with indirect calorimetry. Insulin was infused at five rates to achieve steady-state hyperinsulinemic plateaus of 62 +/- 4, 103 +/- 5, 170 +/- 10, 423 +/- 16, and 1,132 +/- 47 microU/ml. Total body glucose uptake during each of the five insulin clamp studies was 0.41, 0.50, 0.66, 0.74, and 0.77 g/min, respectively. Glucose storage (calculated from the difference between total body glucose uptake minus total glucose oxidation) was 0.25, 0.29, 0.43, 0.49, and 0.52 g/min for each group, respectively, and represented over 60-70% of total glucose uptake. The net increment in energy expenditure after intravenous glucose was 0.08, 0.10, 0.14, 0.17, and 0.23 kcal/min, respectively. Throughout the physiological and supraphysiological range of insulinemia, there was a significant relationship (r = 0.95, P less than 0.001) between the increment in energy expenditure and glucose storage, indicating an energy cost of 0.45 kcal/g glucose stored. However, at each level of hyperinsulinemia, the theoretical value for the energy cost of glucose storage (assuming that all of the glucose is stored in the form of glycogen) could account for only 45-63% of the actual increase in energy expenditure that was measured by indirect calorimetry. These results indicate that factors in addition to glucose storage as glycogen must be responsible for the increase in energy expenditure that accompanies glucose infusion.

Réduction des risques infectieux chez les usagers de drogues

[Table des matières] 1. Concept de la réduction des risques. 2. Stratégie de réduction des risques en France. 3. Usage des drogues en France et principaux dommages associés. 4. Comorbidités psychiatriques chez les usagers de drogues. 5. Risques infectieux chez les usagers de drogues. 6. Evolution de l'incidence du VHC chez les usagers de drogues en France. 7. Pratiques à risque chez les fumeurs de crack. 8. Prévention de l'initiation à l'injection et transitions vers d'autres modes d'administration. 9. Traitements de substitution aux opiacés. 10. Autres traitements de la dépendance. 11. Programmes d'échange de seringues. 12. Centres d'injection supervisés. 13. Parcours de soins des usagers de drogues. 14. Rapport coût-efficacité des dispositifs de réduction des risques. 15. Dispositifs de réduction des risques en France. 16. Accessibilité et acceptabilité des actions de réduction des risques. 17. Réduction des risques adaptée aux femmes. 18. Réduction des risques en milieu pénitentiaire. Synthèse et recommandations. Communications. Usage de drogue et réduction des risques en Europe. Eléments d'histoire sur la politique de réduction des risques en France. Situation de la politique de réduction des risques en France. Approche judiciaire française. Rôle des associations dans la politique de réduction des risques en France. Prévention de la délinquance et réduction des risques et dommages sociaux au Canada. Complications liées à l'auto-injection des traitements de substitution aux opiacés. Contributions des intervenants et associations. Annexes.

Pharmacokinetic and pharmacodynamic effects of YM087, a combined V1/V2 vasopressin receptor antagonist in normal subjects.

OBJECTIVE: The pharmacokinetic and pharmacodynamic properties of YM087, (4'-[(2-methyl-1,4,5,6- tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)-carbonyl]-2-p henylbenzanilide monohydrochloride), a new orally active, dual V1/V2 receptor antagonist were characterised in healthy normotensive subjects. METHODS: Six subjects were randomly allocated to receive, at 1-week intervals, a single oral dose of 60 mg YM087 and a single i.v. dose of 50 mg YM087 in an open-label, crossover study. RESULTS: YM087 had an oral bioavailability of 44% and a short half-life. Upon oral and i.v. administration of YM087, a significant sevenfold increase in urine flow rate and a fall in urinary osmolality (from 600 mosmol/l to less than 100-mosmol/l) were observed with a peak effect 2 h after drug intake suggesting effective vasopressin V2 receptor blockade. Simultaneously, significant increases in plasma osmolality (from 283 +/- 1.3 mosmol/l to 288 +/- 1.0 mosmol/l after i.v. and from 283 +/- 2.1 mosmol/l to 289 +/- 1.7-mosmol/l after oral administration) and vasopressin levels (from 1.5 +/- 0.3 pg/ml to 3.7 +/- 0.6 pg/ml after i.v. and from 0.9 +/- 0.1 pg/ml to 3.9 +/- 0.7 pg/ml after oral administration) were found. When administered i.v., YM087 inhibited the vasopressin-induced skin vasoconstriction, suggesting a blockade of V1 receptors. However, the YM087-induced antagonism of V1 receptors was less pronounced than V2 receptor blockade. CONCLUSION: These data show that YM087 is an effective dual V1/V2 receptor antagonist in man.

Sédation par propofol administrée par un non-anesthésiste pour l'endoscopie digestive [Administration of propofol by non-anesthesiologists for digestive endoscopy].

Propofol is progressively replacing benzodiazepines for sedation during endoscopy, even when the sedation is administered by non-anesthesiologists. Propofol ensures a more rapid induction of sedation and recovery and, in certain conditions, higher patient satisfaction and improved quality of endoscopic examination. Specific training is required to use this drug. Patients at risk of complications should be identified before the endoscopy to optimize patient management with an anesthesiologist. After sedation, psychomotor recovery is faster with propofol compared to traditional sedation agents but tasks requiring particular attention (eg, driving) should be avoided. It is important to advise patients of these restrictions in advance.

Chemotherapy for advanced gastric cancer.

BACKGROUND: Gastric cancer currently ranks second in global cancer mortality. Most patients are either diagnosed at an advanced stage, or develop a relapse after surgery with curative intent. Apart from supportive care and palliative radiation to localized (e.g. bone) metastasis, systemic chemotherapy is the only treatment option available in this situation. OBJECTIVES: To assess the efficacy of chemotherapy versus best supportive care, combination versus single agent chemotherapy and different combination chemotherapy regimens in advanced gastric cancer. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE up to March 2009, reference lists of studies, and contacted pharmaceutical companies and national and international experts. SELECTION CRITERIA: Randomised controlled trials on systemic intravenous chemotherapy versus best supportive care, combination versus single agent chemotherapy and different combination chemotherapies in advanced gastric cancer. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. A third investigator was consulted in case of disagreements. We contacted study authors to obtain missing information. MAIN RESULTS: Thirty five trials, with a total of 5726 patients, have been included in the meta-analysis of overall survival. The comparison of chemotherapy versus best supportive care consistently demonstrated a significant benefit in overall survival in favour of the group receiving chemotherapy (hazard ratios (HR) 0.37; 95% confidence intervals (CI) 0.24 to 0.55, 184 participants). The comparison of combination versus single-agent chemotherapy provides evidence for a survival benefit in favour of combination chemotherapy (HR 0.82; 95% CI 0.74 to 0.90, 1914 participants). The price of this benefit is increased toxicity as a result of combination chemotherapy. When comparing 5-FU/cisplatin-containing combination therapy regimens with versus without anthracyclines (HR 0.77; 95% CI 0.62 to 0.95, 501 participants) and 5-FU/anthracycline-containing combinations with versus without cisplatin (HR 0.82; 95% CI 0.73 to 0.92, 1147 participants) there was a significant survival benefit for regimens including 5-FU, anthracyclines and cisplatin. Both the comparison of irinotecan versus non-irinotecan (HR 0.86; 95% CI 0.73 to 1.02, 639 participants) and docetaxel versus non-docetaxel containing regimens (HR 0.93; 95% CI 0.75 to 1.15, 805 participants) show non-significant overall survival benefits in favour of the irinotecan and docetaxel-containing regimens. AUTHORS' CONCLUSIONS: Chemotherapy significantly improves survival in comparison to best supportive care. In addition, combination chemotherapy improves survival compared to single-agent 5-FU. All patients should be tested for their HER-2 status and trastuzumab should be added to a standard fluoropyrimidine/cisplatin regimen in patients with HER-2 positive tumours. Two and three-drug regimens including 5-FU, cisplatin, with or without an anthracycline, as well as irinotecan or docetaxel-containing regimens are reasonable treatment options for HER-2 negative patients.