Glutamic Acid Decarboxylase 65: A Link Between GABAergic Synaptic Plasticity in the Lateral Amygdala and Conditioned Fear Generalization

An imbalance of the gamma-aminobutyric acid (GABA) system is considered a major neurobiological pathomechanism of anxiety, and the amygdala is a key brain region involved. Reduced GABA levels have been found in anxiety patients, and genetic variations of glutamic acid decarboxylase (GAD), the rate-limiting enzyme of GABA synthesis, have been associated with anxiety phenotypes in both humans and mice. These findings prompted us to hypothesize that a deficiency of GAD65, the GAD isoform controlling the availability of GABA as a transmitter, affects synaptic transmission and plasticity in the lateral amygdala (LA), and thereby interferes with fear responsiveness. Results indicate that genetically determined GAD65 deficiency in mice is associated with (1) increased synaptic length and release at GABAergic connections, (2) impaired efficacy of GABAergic synaptic transmission and plasticity, and (3) reduced spillover of GABA to presynaptic GABA_B receptors, resulting in a loss of the associative nature of long-term synaptic plasticity at cortical inputs to LA principal neurons. (4) In addition, training with high shock intensities in wild-type mice mimicked the phenotype of GAD65 deficiency at both the behavioral and synaptic level, indicated by generalization of conditioned fear and a loss of the associative nature of synaptic plasticity in the LA. In conclusion, GAD65 is required for efficient GABAergic synaptic transmission and plasticity, and for maintaining extracellular GABA at a level needed for associative plasticity at cortical inputs in the LA, which, if disturbed, results in an impairment of the cue specificity of conditioned fear responses typifying anxiety disorders.     

Intravenous drug preparation practices: a survey in a French university hospital

OBJECTIVE: To describe current practices for i.v. drug admixture preparation, to identify potential improvements for the enhancement of patient safety. DESIGN: A survey was conducted in a University hospital in Paris. Nurse practices were explored through the evaluation of five i.v. drug delivery systems: reconstituted freeze-dried drugs administered by syringe or i.v. bags, reconstituted drugs from vials administered by syringe or i.v. bags Ready to Use (RtU). PARTICIPANTS: i.v. drug preparation practices were documented by a representative sample of nurses in the following departments: intensive care, emergency, abdominal surgery, cardiology, infectious diseases, hepatology. MAIN OUTCOME MEASURES: Data were collected regarding: existence of written procedures for preparations, sources of information, labelling, methods of preparation and calculation of doses, nurse satisfaction regarding safety and ease of use of the different i.v. systems. RESULTS: A total of 299 questionnaires were completed and 100 nurses from the chosen wards were surveyed. The study highlighted a lack of procedure (71-85%) and a lack of labelling (37%). CONCLUSION: This survey highlighted areas for improvement in the preparation of i.v. drugs. It may contribute to raising awareness among nurses and physicians about the risks of medication errors. This survey also helped the pharmacy department in supporting the development of pharmaceutical procedures, the development of satellite pharmacy, the set up of training sessions for i.v. preparation and the switch toward ready to use packages when these are available.     

Imported Dengue in French University Hospitals: a 6-year survey

Dengue fever (DF) is a mosquito-transmitted acute disease caused by any of four dengue flavivirus serotypes (DEN-1, DEN-2, DEN-3, and DEN-4) which is becoming a major public health problem in intertropical areas.1 DF is increasingly observed in febrile travelers returning from tropical areas,2 especially those returning from the Caribbean islands and Southeast Asia, but it is rarely diagnosed in travelers returning from Africa.3-8 Diagnosis is often serologic, and in most cases is not confirmed; virus isolation remains exceptional. In a retrospective study of 44 cases of imported DF diagnosed in France, we found that the epidemiologic, clinical and diagnostic characteristics of these cases were similar to those reported in other previous published studies; diagnosis was carried out with serology, and no virus isolation was reported. To draw the attention of physicians from nonendemic areas to the possible occurrence of dengue infection in febrile travelers from all tropical countries, including those in Africa, and to reinforce recommendations required to establish diagnosis with certainty, we report herein a prospective study from 1998-1999 which we compiled with our previously published data.     

Cannabis and road crashes: a survey of recent French studies

The clarification of the mechanisms of action of cannabis and its effects on motor and cognitive functions, the results of previous studies performed on driving simulators and closed or open-road driving trials, are important criteria for highlighting the increased risk of road crashes for drivers after a recent use of cannabis. In addition epidemiological studies allow to measure the magnitude of the problem. A survey of French epidemiological studies performed from 1999 to 2004, as well as the data of THC distribution in tissues studies performed on man and animal allowed us to draw a number of conclusions. The risk of road crash after a recent use of cannabis is increased by more than 2.4 in all studies. The prevalence of cannabis use in drivers involved in a road crash has dramatically increased during the last years. For methodological reasons (a too high threshold for THC positivity, a too long time delay between accident and blood sampling), the annual number of fatal cases induced by a cannabis use was likely underestimated. This assessment is consistent with recent data which indicate that THC could be still present in brain while absent in blood. A positivity threshold for THC in blood of 0.5 ng/mL would be more appropriated. So, all recent French studies highlighted that a recent use of cannabis impairs driving ability and that it would be advisable to intensify roadside testing for drugs of abuse.     

Carriage of genes for various extended-spectrum β-lactamases: a novel resistance strategy of Klebsiella pneumoniae in Poland

Among 110 randomly sampled strains from a collection of 247 extended-spectrum β-lactamase (ESBL)-producing clinical isolates of Klebsiella pneumoniae collected from hospitalised children in three paediatric hospitals in Poland, 64 strains (58.2%) with multiple ESBLs were found, including five non-clonal strains (4.5%) harbouring bla genes for ESBLs of three families (CTX-M, SHV and TEM). This is the first report of the emergence of triple ESBL-producing K. pneumoniae in Poland. In addition, K. pneumoniae strains harbouring bla genes for TEM-130 and TEM-132 ESBLs were detected in Poland for the first time. Epidemiological analysis of the multiple ESBL-producing K. pneumoniae isolates by pulsed-field gel electrophoresis (PFGE) revealed a relatively high genetic diversity between isolates producing the same combination of enzymes. Clonally related strains were uncommon.     

Drug-Related Nephrotoxic and Ototoxic Reactions : A Link through a Predictive Mechanistic Commonality

BACKGROUND: Drug-induced ototoxicity is a subject of interest because many diseases are treated with drugs that have potential toxic effects on the ear. There is evidence that both inner ear and kidney tissue are immunologically, biochemically and functionally related. It has been suggested that drugs that influence the transport of sodium and/or potassium change ionic homeostasis in the inner ear and, hence, induce functional disturbances such as hearing loss, tinnitus and vertigo. OBJECTIVES: To assess whether renal suspected adverse drug reactions (sADRs) have predictive value for ear and labyrinth adverse drug reactions (ADRs) and whether drug classes involved have influence ion transport systems. STUDY DESIGN: Data were obtained from the Netherlands Pharmacovigilance Centre Lareb. The study base comprised all reports of sADRs up until 1 January 2007. Cases were all sADRs for relevant renal disorders and all sADRs for relevant ear disorders. All other reported sADRs were selected as 'non-cases'. The relationship between drug classes and renal, ear and labyrinth sADRs was evaluated by calculating reporting odds ratios (RORs). An ROR >/=1.50 was regarded as a cut-off value for an association. Drug classes were classified into four groups: (A) ROR kidney <1.50 and ROR ear <1.50 or no reports on ear sADRs (reference group); (B) ROR kidney <1.50 and ROR ear >/=1.50; (C) ROR kidney >/=1.50 and ROR ear <1.50 or no reports on ear sADRs; and (D) ROR kidney >/=1.50 and ROR ear >/=1.50. For each group, we calculated odds ratios (ORs) for the association between the group classification and the effect on ion channels/ion transport systems in kidney and ear tissues. RESULTS: Of 193 drug classes with relevant ADRs for renal disorders, 120 drug classes also had reports on ototoxic reactions. Fourteen out of 120 drug classes had an ROR >/=1.50 for the association between the drug class and both renal and ear sADRs. Among these drug classes were several with a well known ability to induce renal (adverse) effects and ear and labyrinth disorders, such as loop diuretics, aminoglycosides and quinine. We found that one mechanistic commonality of the drug classes mentioned in the reports was the ability to affect ion transport systems. The percentage of drugs having this property differed between the four groups. The ORs for groups D and B were significantly higher compared with the reference group (OR 12.2, 95% CI 3.0, 30.5 and OR 8.7, 95% CI 2.4, 18.7, respectively), whereas there was no association for group C. CONCLUSION: Our data suggest that renal sADRs as such are not a marker for drug-induced ear and labyrinth disorders. However, the ability of drugs to act on ion channels or ion transport systems and, therefore, have an influence on ionic homeostasis in the kidney and ear might be a predictor for the possible occurrence of drug-related ototoxicity.     

Potentially inappropriate medications in the elderly: a French consensus panel list

OBJECTIVE: To evaluate drug-related problems in the elderly, various lists of potentially inappropriate medications have been published in North America. Unfortunately, these lists are hardly applicable in France. The purpose of this study was to establish a list of inappropriate medications for French elderly using the Delphi method. METHOD: A two-round Delphi method was used to converge to an agreement between a pool of 15 experts from various parts of France and from different backgrounds (five geriatricians, five pharmacologists, two pharmacists, two general practitioners, one pharmacoepidemiologist). In round one, they were sent a questionnaire based on a literature review listing medications and clinical situations. They were asked to comment on the potential inappropriateness of the criteria proposed using a 5-point Likert scale (from strong agreement to strong disagreement) and to suggest therapeutic alternatives and new criteria. In round two, the experts confirmed or cancelled their previous answers from the synthesis of the responses of round one. After round two, a final list of potentially inappropriate drugs was established. RESULTS: The final list proposed 36 criteria applicable to people >/=75 years of age. Twenty-nine medications or medication classes applied to all patients, and five criteria involved medications that should be avoided in specific medical conditions. Twenty-five medications or medication classes were considered with an unfavourable benefit/risk ratio, one with a questionable efficacy and eight with both unfavourable benefit/risk ratio and questionable efficacy. CONCLUSION: This expert consensus should provide prescribers with an epidemiological tool, a guideline and a list of alternative therapies.     

Coeliac disease in chronic hepatitis C: a French multicentre prospective study

BACKGROUND: A prevalence of 1.2% of coeliac disease (CD) in patients with chronic hepatitis C was recently reported, suggesting a possible epidemiological link between these two diseases. However, other studies have not found this relationship. AIM: To conduct a French multicentre prospective study to assess the prevalence of CD in hepatitis C virus (HCV)-infected patients. METHODS: Between June 2003 and November 2005, 624 consecutive HCV-positive out-patients were tested for antiendomysial IgA antibodies (AEA), antigliadin IgA and IgG antibodies (AGA). Patients with positive AEA or IgA AGA and positive IgG AGA in a context of a high suspicion of CD were asked to undergo gastroscopy with duodenal biopsies. RESULTS: Isolated IgA AEA, IgA AGA and IgG AGA were 0.16%, 5.7% and 4.4%, respectively. Gastroscopy was required for 39 patients, 31 were performed (eight refusals), but only 25 duodenal biopsies were performed as six patients had cirrhosis. CD was never detected. CONCLUSIONS: The prevalence of CD in HCV-positive patients was 0% (95% confidence interval: 0-0.59%), but there is a low prevalence of CD in the whole French population.     

G-CSF (Granulocyte Colony-Stimulating Factor): follow-up and use in a French University hospital

Granulocyte Colony-Stimulating Factor or G-CSF (NEUPOGEN) was approved for use in France in November 1991 for prevention of chemotherapy-induced neutropenia. This retrospective study was conducted at Saint-Louis Hospital, Paris, France, from November 1991 to March 1993 with a more detailed analysis of patient profiles for courses ordered between November 1991 and December 1992. Data were collected on standardized G-CSF-treatment summary forms. The purpose of the study was to define, in clinical terms, the patients treated by G-CSF to determine the average cost per course of therapy and its impact on the hospital pharmacy budget. From November 1991 to December 1992 data from 307 patient profiles were collected and analyzed. The subcutaneous route was the preferred route and only 16.6% of courses were administered intravenously. 45.6% of patients received a single course, 24.3% received two courses, and 30.1% received more than two courses. Each patient completed an average of 2.3 courses at an average cost per course of $2,000.00 (Canadian dollars). During March 1993, 50% of vials dispensed were administered to outpatients. During the 14-month period, an average of 613.8 vials were dispensed per month corresponding to an average monthly expenditure of $104,000.00 (Canadian dollars). In the first 12 months following the commercial availability of G-CSF, G-CSF expenditures accounted for 8% of the pharmacy budget.     

Experiences and perspectives of implementing antimicrobial stewardship in five French hospitals: a qualitative study

The aim of this study was to describe current antimicrobial stewardship programmes (ASPs) in France, both at policy level and at local implementation level, and to assess how ASP leaders (ASPL) worked and prioritised their activities. A qualitative study based on face-to-face semi-structured interviews with healthcare professionals responsible for ASPs across five French hospitals was conducted. Five infectious diseases specialists and one microbiologist were interviewed between April–June 2016. Stewards had dedicated time to perform ASP activities in two university-affiliated hospitals, whilst in the other hospitals (one university, one general and one semi-private), ASPLs had to balance these activities with clinical practice. Consequently, they had to adapt interventions according to their resources (IT or human). Responding to colleagues' consultation requests formed baseline work. Systematic and pro-active measures allowed for provision of unsolicited counselling, whilst direct counselling on wards required appropriate staffing. ASPLs aimed at increasing clinicians' ability to prescribe adequately and awareness of the unintended consequences of inappropriate use of antibiotics. Thus, persuasive, e.g. education, measures were preferred to coercive ones. ASPLs faced several challenges in implementing the ASP: overcoming physicians' or units' reluctance; and balancing the influence of medical hierarchy and professional boundaries. Beyond resources constraints, ASPLs' conceptions of their work, as well as contextual and cultural aspects, led them to adopt a persuasive and collaborative approach of counselling. This is the first qualitative study regarding ASPs in France exploring stewards' experiences and points of view.     

Prescribed drugs and violence: a case/noncase study in the French PharmacoVigilance Database

Aim  

Our aim was to identify prescribed drugs associated with violent behaviours using the French PharmacoVigilance Database (FPVD).     

Establishing a pharmacy presence in the emergency department: opportunities and challenges in the French setting

Overview of clinical pharmacy practice around the world shows that pharmaceutical services in emergency departments (EDs) are far less common in Europe than in North America. Reported experiences have shown the impact of a clinical pharmacy service on drug utilisation and safety issues. This commentary presents the implementation of a pharmacy presence in the ED of a French tertiary care hospital. Our experience helps to define the role of the clinical pharmacist in the ED, including patient interviewing, providing medication reconciliation, promoting drug safety, and supporting specific interventions to improve quality of care and patient safety. The role of ED pharmacists in the improvement of quality of care is not necessarily limited to drug therapy, e.g. by helping outpatients to access care and treatment facilities as best suits their needs. Challenges of implementing ED pharmacy services have been identified well, but still require developing strategies to be overcome.     

Drugs and dilated cardiomyopathies: a case/noncase study in the French PharmacoVigilance Database

AIMS

To evaluate putative associations between drugs and dilated cardiomyopathy.

METHODS

We used the case/noncase method in the French PharmacoVigilance Database (FPVD). Cases were all the observations with dilated cardiomyopathy registered into the FPVD between 1 January 1990 and 30 June 2007. Noncases were all other reports other than those studied. Anthracyclines were used as positive controls. Data were expressed as reporting odds ratio (ROR) with their 95% confidence intervals.

RESULTS

Out of the 258 729 adverse drug reaction (ADR) reports recorded in the FPVD between 1 January 1990 and 30 June 2007, 47 (22 men, mean age 49 years) were defined as dilated cardiomyopathy. In these 47 patients, 67 drugs were ‘suspect’. A significant ROR was found with cytotoxic (epirubicin, mitoxantrone, cyclophosphamide, gemcitabine, fluorouracil) and antiretroviral (lamividune, zidovudine, abacavir) but also with isotretinoin, prednisone, appetite suppressant (clobenzorex) and psychotropic [antipsychotic (clozapine, olanzapine), lithium, antidepressant (clomipramine, amitriptyline, fluvoxamine)] drugs.

CONCLUSIONS

The present study describes an association between some drugs and reports of dilated cardiomyopathies. This relationship involves not only some already suspected drugs (anthracyclines, antiretrovirals), but also other drugs (antipsychotics, lithium, antidepressants, retinoids) less known to induce such an ADR. Despite the mandatory limits of this kind of study (underreporting, confounding factors …), these data represent a pharmacovigilance signal and could contribute to establish further prospective studies in order to confirm such signals.