[Epidemiological description of long-term oral glucocorticoid use: Results from the French health insurance database]. / Description épidémiologique de la corticothérapie orale prolongée : résultats issus de la base de données de l'assurance maladie.

BACKGROUND: There is very little epidemiologic data available in the literature concerning long-term corticosteroid prescriptions in France. METHODS: The information was collected from a national public health-insurance database in our geographic area of Provence-Alpes-Côte-d'Azur and Corsica. We included in the analysis, patients using a daily glucocorticoid above 7,5 milligrams for a period exceeding 90 days. RESULTS: Among the patients, 4,1 million were included in the analysis. The prevalence of glucocorticoids was around 0.8% and the incidence was 2.3/1000 inhabitants/year. The mean age of the patients was 57.6±18.8 years old. The median prednisone-equivalent dose was 11.9mg/day (Interquartile range: 8.6-20.0). The average treatment duration was 206 days (CI 95% 202-210). Most prescriptions (72,0%) were started by general practitioners. CONCLUSION: Long-term corticosteroid therapy is frequent in France. Its description is close to what is already known in Europe.

Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: a prospective randomized clinical trial using magnetic resonance imaging and spectroscopy.

AIM: To conduct a prospective randomized trial to investigate the effect of glucagon-like peptide-1 (GLP-1) analogues on ectopic fat stores. METHODS: A total of 44 obese subjects with type 2 diabetes uncontrolled on oral antidiabetic drugs were randomly assigned to receive exenatide or reference treatment according to French guidelines. Epicardial adipose tissue (EAT), myocardial triglyceride content (MTGC), hepatic triglyceride content (HTGC) and pancreatic triglyceride content (PTGC) were assessed 45 min after a standardized meal with 3T magnetic resonance imaging and proton magnetic resonance spectroscopy before and after 26 weeks of treatment. RESULTS: The study population had a mean glycated haemoglobin (HbA1c) level of 7.5 ± 0.2% and a mean body mass index of 36.1 ± 1.1 kg/m(2) . Ninety five percent had hepatic steatosis at baseline (HTGC ≥ 5.6%). Exenatide and reference treatment led to a similar improvement in HbA1c (-0.7 ± 0.3% vs. -0.7 ± 0.4%; p = 0.29), whereas significant weight loss was observed only in the exenatide group (-5.5 ± 1.2 kg vs. -0.2 ± 0.8 kg; p = 0.001 for the difference between groups). Exenatide induced a significant reduction in EAT (-8.8 ± 2.1%) and HTGC (-23.8 ± 9.5%), compared with the reference treatment (EAT: -1.2 ± 1.6%, p = 0.003; HTGC: +12.5 ± 9.6%, p = 0.007). No significant difference was observed in other ectopic fat stores, PTGC or MTGC. In the group treated with exenatide, reductions in liver fat and EAT were not associated with homeostatic model assessment of insulin resistance index, adiponectin, HbA1c or fructosamin change, but were significantly related to weight loss (r = 0.47, p = 0.03, and r = 0.50, p = 0.018, respectively). CONCLUSION: Our data indicate that exenatide is an effective treatment to reduce liver fat content and epicardial fat in obese patients with type 2 diabetes, and these effects are mainly weight loss dependent.

Ergot Use and Overuse: A Pharmacoepidemiology Retrospective Cohort Study.

OBJECTIVE: The objective of this study was to estimate and to characterize the actual patterns of ergot use and overuse in France using a drug reimbursement database. METHODS: We included all people covered by the French General Health Insurance System (GHIS) from the Provence-Alpes-Côte-d'Azur (PACA) and Corsica administrative areas who had at least one prescription of ergot between May 2010 and December 2011. All prescriptions of ergots, migraine prophylactic treatment, and psychotropic medications were extracted from the GHIS database. We defined occasional ergot users (<3 months of prescription) and regular ergot users (>3 months of prescription). Among regular ergot users, we identified overusers and nonoverusers. RESULTS: We included 4358 patients who had at least one prescription of ergots (oral ergotamine tartrate, dihydroergotamine mesilate nasal spray, intravenous dihydroergotamine mesilate). Among ergot overusers, a large majority of patients had ergotamine tartrate overuse. The proportion of ergotamine tartrate overusers is maximum after 55 years. Compared with regular users, overusers use more frequently a prophylactic treatment (93/165 [56.4%] versus 398/1057, OR = 2.15, P < .001), antidepressants (72/165 [43.6%] versus 326/1057 [30.8%] OR = 1.79, P < .001), benzodiazepines (111/165 [67.3%] versus 613/1057 [58.0%], OR = 1.50, P < .001), weak opioids (95/165 [57.6%] versus 463/1057 [43.8], OR = 1.77, P < .001) and strong opioids (13/165 [7.9%] versus 24/1057 [2.3%], OR = 3.86, P < .001). The coexistence of ergot consumption and triptan overuse, and the possibility of both triptan and ergot overuse was described; triptan overusers were more described in ergotamine overusers than in nonoverusers. CONCLUSIONS: This work outlines a high prevalence of ergotamine tartrate overuse (11.1%). As ergotamine tartrate users are mostly aged more than 55 years, an evaluation of ergotamine cardiovascular risk profile is necessary in the elderly population.

Anterolateral ligament of the knee: myth or reality?

PURPOSE: A ligament of the knee has recently drawn the attention: the rediscovered anterolateral ligament (ALL) of the knee. The tibial insertion of the ALL is torn off in the Segond fracture, pathognomonic of the anterior cruciate ligament tear. The ALL originates from the lateral femoral epicondyle and has fibers inserting on the lateral meniscus. It attaches distally to the tibial plateau, midway between the tip of the fibular head and Gerdy's tubercle. The purpose of this study was to evaluate the visibility of the ALL using routine MRI (1.5T) protocol. MATERIALS AND METHODS: In the first part of our study 10 cadaveric knee joints were examined using MR imaging to evaluate the visibility of the ALL. These cadaveric knees have been dissected to assess the presence of the ALL and to evaluate the accordance between MRI and anatomic dissection. In the second part of the study, 61 knee MRI of patients were examined to evaluate the visibility of the ALL using axial and coronal DP-FS weighted sequences. RESULTS: In all cadaveric knee MRI, the ALL was visualized (full visualization in 75 % and partial visualization in 25 % of the cases), with 100 % accordance between MRI and anatomic dissection. Two cadaveric knees where the ALL was not viewed were excluded of the radio-anatomic analysis. The ALL was visualized in 93.4 % (95 % CI = 84.1-98.2) of the knee MRI studies of the 61 patients included. The whole ligament was visualized in 82 % (95 % CI = 70-90.6) examinations and it was partially visualized in 11.5 % (95 % CI = 4.7-22.2). CONCLUSION: Our results show that the ALL of the knee can be identified using routine 1.5T MR imaging, which suggest that better radiological description of this underestimated anatomical structure may be beneficial in the preoperative planning of ACL tears.

[Incidence and clinical impact of seizures after surgery for chronic subdural haematoma]. / Incidence et impact clinique des crises comitiales périopératoires pour les hématomes sous-duraux chroniques.

BACKGROUND AND PURPOSE: Seizures can occur in patients who have surgery for a chronic subdural hematoma. However, the incidence of seizures and their impact on the clinical course of patients in the perioperative period is not well known. METHODS: In this retrospective study, we reviewed 161 cases of patients treated for chronic subdural hematoma in our institution. The surgical procedures consisted in trephine craniotomy in 156 cases, burr-hole craniotomy in three cases, and bone flap craniotomy in two cases. All the patients had systematic antiepileptic drug prophylaxis. RESULTS: In our patients' population, the incidence of seizures was 10.6% before surgery and 14.9% after surgery. Low initial score on the Glasgow Coma Scale (P<0.001) and preoperative cognitive impairment (P=0.005) were associated with a higher rate of postoperative seizures. In our study, the mortality rate was 14.9%. Low initial score on the Glasgow Coma Scale (P=0.068) and postoperative seizures (P=0.002) were associated with a higher mortality rate. CONCLUSIONS: We have shown that patients suffering from seizures may have worse outcome. The benefit of a systematic perioperative prophylaxis using antiepileptic drugs has to be evaluated.

Estimated magnitude of diversion and abuse of opioids relative to benzodiazepines in France.

INTRODUCTION: Prescription drug abuse is a major concern in several countries. France appears to be particularly prone to the abuse of opiate maintenance treatment (OMT) opioids and benzodiazepines (BZD), whereas the abuse of opioid analgesics (OA) is less commonly reported. To estimate the extent of psychoactive drug abuse, the French drug agency relies on different methods measuring various diversion indicators used as proxies for the detection of abuse/misuse: suspicion of abuse/dependence, illegal acquisition by patients seen in specialized care centers, prescription forgery and doctor shopping. The main objectives of the present study are to analyse the abuse and diversion of opioids (both OA and OMT), in comparison with those of BZDs, through the concurrent use of three different data sources. METHODS: Diversion and abuse of opioids were analysed using indicators of abuse and diversion derived from three data sources over the period 2006-2008. Then, opioids were compared to BZDs for the year 2008 using the same indicators. RESULTS: The analysis suggests that BZDs are more commonly dispensed than OAs and OMTs but that abuse and diversion are related mainly to OMT (particularly to buprenorphine), morphine and BZDs and less to OAs (except for morphine). CONCLUSION: This study presents an original approach, based on the use of multiple data sources, to evaluate and compare the estimated abuse and diversion of opioids and benzodiazepines. It provides health authorities with a global, comparative and summarized overall view of the importance of different patterns of diversion and abuse for different prescription drugs.

Ramadan fasting with diabetes: an interview study of inpatients' and general practitioners' attitudes in the South of France.

AIM: The aim of this study was to evaluate attitudes in hospital inpatients and physicians towards Ramadan fasting and diabetes in Marseille. METHODOLOGY: This cross-sectional study was conducted during the three months prior to the month of Ramadan. A total of 101 patients (age: 57±17 years) and 101 general practitioners (GPs) were recruited into the study. RESULTS: The patients had low levels of education (52% illiteracy). Of the 101 patients, 52 continued to fast during Ramadan, and only 65 patients had discussed the matter with their GP. Of these, 36 were told that fasting was forbidden, but more than half (n=19) fasted despite the medical advice. Six patients thus experienced daily hypoglycaemia because they had continued to take their hypoglycaemic agent or insulin analogue at noon. Both inadequate education and religious attitudes were found to endanger patients during the fast: 15 patients skipped the meal scheduled before dawn, five of whom persisted in taking their sulphonylurea. Also, 27% of patients refused, in spite of daytime hypoglycaemia, to ingest anything orally to avoid breaking their fast. Among the GP population, medical knowledge of Ramadan fasting with diabetes was low, leading to medically unjustified negative advice for fasting and a lack of patient education on adjusting treatments. This particular situation weakened the patient-physician relationship. CONCLUSION: This study confirms the importance of Ramadan fasting for Muslim patients, and reveals a wide cross-cultural gap between GPs and their patients. Systematic advice on treatment adjustment needs to be given. For this reason, we encourage more sensitive care of these patients and more medical training for physicians.

Efficacy of etifoxine compared to lorazepam monotherapy in the treatment of patients with adjustment disorders with anxiety: a double-blind controlled study in general practice.

Adjustment Disorders With Anxiety (ADWA) account for almost 10% of psychologically motivated consultations in primary care. The aim of this double-blind randomised parallel group study was to compare (non-inferiority test) the efficacies of etifoxine, a non-benzodiazepine anxiolytic drug, and lorazepam, a benzodiazepine, for ADWA outpatients followed by general practitioners. 191 outpatients (mean age: 43, female: 66%) were assigned to receive etifoxine (50 mg tid) or lorazepam (0.5-0.5-1 mg /day) for 28 days. Efficacy was evaluated on days 7 and 28 of the treatment. The main efficacy assessment criterion was the Hamilton Rating Scale for Anxiety score (HAM-A) on Day 28 adjusted to Day 0. The anxiolytic effect of etifoxine was found not inferior to that of lorazepam (HAM-A score decrease: 54.6% vs 52.3%, respectively, p=0.0006). The two drugs were equivalent on Day 28. However, more etifoxine recipients responded to the treatment (HAM-A score decreased by >or=50%, p=0.03). Clinical improvement (based on Clinical Global Impression scale CGI, Social Adjustment Scale Self-Report SAS-SR, and Sheehan scores) was observed in both treatment arms, but more etifoxine patients improved markedly (p=0.03) and had a marked therapeutic effect without side effects as assessed by CGI, p=0.04. Moreover, 1 week after stopping treatment, fewer patients taking etifoxine experienced a rebound of anxiety, compared to lorazepam (1 and 8, respectively, p=0.034).

A randomized clinical trial comparing doses and efficacy of lormetazepam tablets or oral solution for insomnia in a general practice setting.

Lormetazepam is a short-acting benzodiazepine hypnotic which is beneficial in shortening the time to onset of sleep. The aim of the study was to assess a new formulation of lormetazepam (oral solution) in comparison with lormetazepam tablets in out-patients with insomnia. This trial was an open randomized parallel group study conducted by 30 general practitioners. One hundred and eight patients took 0.5 mg on the first night and were allowed to increase their dosage by 0.25 mg (for oral solution) and 0.5 mg (for tablets), respectively, each day and every 2 days. The patients assessed the efficacy, acceptability and tolerance of lormetazepam using a diary card and a set of visual analogue scales assessing their sleep. Over 14 days of treatment, the mean daily dose of lormetazepam was lower in the oral solution group than in the tablets group (0.78 mg versus 0.97 mg). The cumulated dose of lormetazepam was lower with the oral solution (18% reduction). No significant difference between the two groups was found in the assessment of sleep characteristics. The occurrence of side effects did not differ between the two groups. These results suggest that a unitary dose as achieved by an oral solution of lormetazepam allows easier determination of the minimal individual effective dose.

Standardization and quality control studies of 'real-time' quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia - a Europe Against Cancer program.

Detection of minimal residual disease (MRD) has proven to provide independent prognostic information for treatment stratification in several types of leukemias such as childhood acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and acute promyelocytic leukemia. This report focuses on the accurate quantitative measurement of fusion gene (FG) transcripts as can be applied in 35-45% of ALL and acute myeloid leukemia, and in more than 90% of CML. A total of 26 European university laboratories from 10 countries have collaborated to establish a standardized protocol for TaqMan-based real-time quantitative PCR (RQ-PCR) analysis of the main leukemia-associated FGs within the Europe Against Cancer (EAC) program. Four phases were scheduled: (1) training, (2) optimization, (3) sensitivity testing and (4) patient sample testing. During our program, three quality control rounds on a large series of coded RNA samples were performed including a balanced randomized assay, which enabled final validation of the EAC primer and probe sets. The expression level of the nine major FG transcripts in a large series of stored diagnostic leukemia samples (n=278) was evaluated. After normalization, no statistically significant difference in expression level was observed between bone marrow and peripheral blood on paired samples at diagnosis. However, RQ-PCR revealed marked differences in FG expression between transcripts in leukemic samples at diagnosis that could account for differential assay sensitivity. The development of standardized protocols for RQ-PCR analysis of FG transcripts provides a milestone for molecular determination of MRD levels. This is likely to prove invaluable to the management of patients entered into multicenter therapeutic trials.

Analysis of donor NK and T cells infused in patients undergoing MHC-matched allogeneic hematopoietic transplantation.

We retrospectively analyzed the percentages and absolute numbers of T cells, natural killer (NK) cells and NK cell subsets in cryopreserved samples of either bone marrow or blood non-T cell-depleted allogeneic MHC-matched hematopoietic grafts. Using flow cytometry, we found higher numbers of NK cells in aphereses than in bone marrow collections. We further investigated the distribution of NK cell subsets, defined by the cell surface expression of MHC class I-specific receptors, in these allogeneic grafts. The distribution of NK cell subsets from the two different origins were similar, with the exception of the CD158a/h(+) NK cell subset, whose size appeared to be smaller in bone marrow. The search for relations between the numbers of infused cells and post-transplantation events demonstrated that increasing numbers of infused T cells but not NK cells are related with decreased overall survival. Our study highlights the toxicity of infused T cells but not NK cells in allogeneic MHC-matched hematopoietic grafts. These data pave the way for further trials to investigate the effect of NK cell infusion in MHC-matched allogeneic transplantation, and in particular whether ex vivo NK cell expansion and activation may enhance the anti-tumoral effect of the procedure and decrease its morbidity.

Buprenorphine prescription by general practitioners in a French region.

Since 1996 French general practitioners (GPs) may prescribe sublingual buprenorphine tablets as maintenance treatment for opiate dependence. The computerised data management of the main French health reimbursement system now allows surveillance of the use of this drug, and how it is prescribed. The purpose of this study is to determine the profile of maintained patients, prescribed doses, associated psychotropic treatments and how practitioners prescribe these treatments. This study analyses the 11186 buprenorphine prescriptions electronically transmitted for reimbursement between September and December 1999 in a specific French region. It was found that the 2078 treated patients consumed a mean of 11.5 mg of buprenorphine per day and 12% of them procured prescriptions from more than two prescribers. 43% of maintained patients had an associated benzodiazepine prescription, mainly flunitrazepam, often on the same prescription form. 61% of patients had regular follow-up, others had occasional consultations (21%) and another 18% had deviant maintenance treatment (more than two prescribers or more than 20 mg per day of daily buprenorphine dose). Benzodiazepine consumption was much higher in the 'deviant group' (71.4%). 85% of buprenorphine prescriptions were made by GPs. 21% of GPs prescribed buprenorphine and 61% of those had only one or two maintained patients. Buprenorphine prescription by French GPs is a procedure with no particular requirements, allowing many patients to easily access maintenance treatments. However, a high risk of abuse exists, which demands extensive investigation and evaluation of these practices.

Can fructosamine be a surrogate for HbA(1c) in evaluating the achievement of therapeutic goals in diabetes?

OBJECTIVE: To determine if fructosamine can be used as a surrogate for HbA(1c) to monitor whether therapeutic goals in diabetes mellitus are achieved when HbA(1c) cannot be used for this purpose (hemoglobinopathies, anemia...). MATERIAL AND METHODS: Blood samples of 76 diabetic patients and 30 healthy subjects characterized by the absence of any risk of interference in the interpretations of HbA(1c) and fructosamine were studied in order to, first, deduce from the correlation a prediction of HbA(1c) from the fructosamine values, second, to evaluate the predictive value of such predicted HbA(1c) in the determination of poor metabolic control as defined by UKPDS and DCCT studies. RESULTS: The correlation between predicted HbA(1c) and actual fructosamine was fair (r=0.88) in diabetic patients but not in control subjects (r=0.01). It was therefore only possible to estimate HbA(1c) from fructosamine in diabetic patients. Nevertheless, the range of positive and negative predictive values of estimated HbA(1c) to detect a poor metabolic control defined by two thresholds of HbA(1c) (7%, 7.5%) was 91-93% and 86-87%, respectively. Then, even in this highly selected population, the risk of misclassification was around 10% when fructosamine was used to estimate HbA(1c). These results were unchanged when fructosamine was corrected by plasma protein level. CONCLUSIONS: This study shows the limitations to use fructosamine in place of HbA(1c) to evaluate the efficacy of antidiabetic treatments, even in a selected population.

Correlation between apoptosis microarray gene expression profiling and histopathological lymph node lesions.

AIMS: Microarray technology has recently led to the identification of molecular prognostic subgroups in non-Hodgkin's lymphomas. To determine the usefulness of ready made macroarrays as routine diagnostic tools in haematopathology, lymph node biopsies were analysed using a cDNA macroarray containing genes involved in apoptosis, including caspases. METHODS: Nine biopsy specimens were analysed using total frozen tissues: four samples of B cell follicular lymphoma, two of B cell diffuse large cell lymphoma, and three of non-neoplastic lymph nodes from benign lymphadenitis. Nine cell populations were sorted from fresh tissues: malignant B cells from two patients with follicular lymphoma and two with diffuse large cell lymphoma, reactive B cells from two benign lymph nodes, reactive T cells from one benign lymph node, and virgin (mantle zone) B cells and germinal centre B cells from benign tonsils. Immunohistochemistry (IHC) on paraffin wax sections was performed for the localisation of caspases 2, 3, 4, 7, 8, and 9. RESULTS: In the clustered array data, sorted cells from samples sharing common histological lesions were grouped together, whereas the array/histology correlation was less satisfactory for tissues. The expression profiles of both the array and IHC methods correlated for most caspases and samples. CONCLUSIONS: Variations in array profiles of sorted cell populations can be associated with specific histological features, suggesting a possible diagnostic application of ready made apoptosis macroarrays in haematopathology.