Facilitated CA1 hippocampal synaptic plasticity in dystrophin‐deficient mice: Role for GABAA receptors?

Duchenne muscular dystrophy (DMD) is associated with cognitive deficits that may result from a deficiency in the brain isoform of the cytoskeletal membrane-associated protein, dystrophin. CA1 hippocampal short-term potentiation (STP) of synaptic transmission is increased in dystrophin-deficient mdx mice, which has been attributed to a facilitated activation of NMDA receptors. In this study, extracellular recordings in the hippocampal slice preparation were used first to determine the consequences of this alteration on short-term depression (STD). STD induction was facilitated in mdx as compared with wild-type mice in a control medium. Because brain dystrophin deficiency results in a decreased number of gamma-aminobutyric acid A (GABAA)-receptor clusters, we tested the hypothesis that neuronal disinhibition contributes to the enhanced synaptic plasticity in mdx mice. We found that the GABAA receptor antagonist, bicuculline, increased basal neurotransmission in wild-type, but not in mdx mice and prevented the enhanced STP and STD in the CA1 area of slices from mdx mice. The possibility that altered GABA mechanisms underlie the facilitation of NMDA receptor-dependent synaptic plasticity in mdx mice is discussed.     

The effect of moving textures on the responses of cells in the cat's dorsal lateral geniculate nucleus

Neurons in the dorsal lateral geniculate nucleus (dLGN) of the anaesthetized cat were activated with test stimuli (flashing spots, counterphased gratings and moving bars) in the presence of a moving background texture. Moving texture alone produced mild excitation, as a result of stimulation of the receptive field centre. Fast moving coarse textures were more effective than fine slow moving textures. The predominant effect of texture motion, however, was to reduce the response to all test stimuli displayed in the receptive field centre. The effects were similar for X- and Y-like cells. In the case of flashed spots, the sustained response was more strongly suppressed than the transient response. The direction of motion of the texture and differences in the relative motion of bar and texture had no influence on the degree of suppression. These observations are similar to effects seen on cat retinal ganglion cells, and are probably a form of gain control. Such suppressive effects are transmitted to the cortex and are likely to be evoked by large gratings, textures and by natural stimuli, all of which activate extensive regions of the receptive field surround.     

In vitro tests for assessing heparin-induced thrombocytopenia in patients after elective hip replacement. A medico-economical evaluation

OBJECTIVES: Considering the previously published incidences of heparin-induced thrombocytopenia (HIT) in patients receiving a thromboprophylactic therapy, the role of the hemostasis laboratory is essential in making a clinical decision. The purpose of this project was to compare the strategies of diagnosis and associated care of patients with suspected HIT after elective hip replacement using platelet aggregation assay, carbon 14-serotonin release, and "doing nothing." METHODS: The authors used an incremental cost-effectiveness analysis based on data extracted from the literature. The effectiveness of the strategies was represented by the number of deep venous thromboses prevented. Cost data were collected from the observation of biological and medical practice at Edouard Herriot University Hospital, Lyon, France, in 1999. RESULTS: In comparison with the strategies of doing nothing using no biological test for diagnosis, and clinical care of HIT-suspected patients, the strategy using platelet aggregation test was more expensive and less effective. With respect to the strategy using carbon 14-serotonin release assay, the incremental cost-effectiveness ratio, expressed as U.S. dollars per deep venous thrombosis prevented, reached $200,000, with a marginal effectiveness of eight deep venous thromboses prevented for 10,000 HIT-suspected patients. CONCLUSION: This study suggests that clinical hemostasis laboratories might consider replacing the platelet aggregation test with the carbon 14-serotonin release assay or should use another functional assay such as the flow cytometric assay for the diagnosis and care of patients with suspected HIT.     

Cost-benefit analysis of vaccination against tick-borne encephalitis among French troops

BACKGROUND: French troops are exposed to tick-borne encephalitis (TBE) during their tours of duty in the Balkans. This disease, potentially serious because of its lethality and morbidity, has an effective vaccination. The epidemiological characteristics of TBE in the Balkans are not well known. OBJECTIVE: In order to provide the French Department of Defence with arguments on the utility of vaccinating troops on missions in this area of Europe, we conducted a cost-benefit study. DESIGN AND SETTING: Through a decision analysis, we estimated the net benefit of a three-injection vaccination programme for all French military personnel in the Balkans versus no vaccination during a period from 2004 to 2014. We used a review of the literature to estimate the parameters necessary for the present study: the disease's morbidity and death incidence rate; the disease's sequelae; and the adverse effects of the vaccination. The initial hypothesis of the seroconversion rate of TBE in the Balkans was 834 per 100,000 person-years. Human life was valued in Euro (year 2004 values) by calculating the amounts paid by the French Department of Defence to military personnel in case of disabling sequelae and to their heirs in case of death. MAIN RESULTS: The net benefit was negative: -5.68 million Euro. The vaccination programme's cost was 10.05 million Euro. 121 cases of TBE could be prevented by this vaccination; however, the sensitivity analysis showed that the results are closely related to the incidence of the disease. CONCLUSION: Very high incidence rates of TBE were initially hypothesised compared with what has actually been reported. As a result, the vaccination programme against TBE for French military personnel should not be implemented unless the objective of the armed forces is to prevent all cases of TBE and they are willing to assume the cost of doing so.     

Could post-liver transplantation course be helpful for the diagnosis of so called cryptogenic cirrhosis?

Cryptogenic cirrhosis (CC) is diagnosed in 5-30% of cirrhotic patients overall and 7% of patients who undergo liver transplantation for cirrhosis. In our series of patients transplanted for CC, pre-transplant clinical and histological data and the post-transplant course were reexamined in an attempt to identify the aetiology. Among the 881 patients transplanted in our centre between 1987 and 2000, 28 patients with a median age of 46 yr (range: 18-69) at transplantation were initially classified as having CC. Two patients were excluded because of intense ischaemic lesions caused by chemoembolization prevented histological analysis of the native liver (n = 1) and because of cryptic HBV infection (n = 1). Among the remaining 26 patients, four groups were individualized: (i) patients with chronic inflammatory liver disease with autoimmune features (n = 14, 54%); (ii) patients with features suggestive of non-alcoholic fatty liver disease (n = 3, 11.5%); (iii); patients with incomplete septal cirrhosis (ISC) and vascular liver disease (n = 3), and (iv) patients with unresolved CC (n = 6, 23%). In the autoimmune liver disease group, the median International Autoimmune Hepatitis score was 12.5 (range: 11-19) after reevaluation and review of the post-transplantation course was helpful to confirm the diagnosis with the occurrence of active graft hepatitis in nine patients, with autoantibodies in five patients. The vascular group was characterized by lesions of obliterative portal venopathy and ISC in all native livers. Diagnosis of NAFLD was based on the clinical background of obesity and/or type 2 diabetes and the presence of steatosis or steatohepatitis in native livers and graft biopsies. A definite aetiological diagnosis can be achieved in the majority of patients initially diagnosed with CC. Autoimmune liver disease emerged as the main aetiology (14 of 26 patients, 54%) and frequently recurred on the grafted liver (nine cases). In all cases a precise diagnosis is obviously of practical interest for better management of post-transplant survey and treatment.     

The usefulness of 99mTc sulfur colloid bone marrow scintigraphy combined with 111In leucocyte scintigraphy in prosthetic joint infection

AIM: To assess the extent to which bone marrow scintigraphy (BMS) makes the interpretation of leucocyte scintigraphy (LS) easier and improves its diagnostic value. METHODS: Seventy-three 111In LSs, 99mTc hydroxymethylene diphosphonate bone scintigraphies (BSs) and 99mTc sulfur colloid BMSs were performed in 60 patients with suspected infection related to a hip prosthesis or knee prosthesis, either in situ (+group, n = 43) or after removal for septic loosening (-group, n = 30). Bacteriological samples were obtained from all patients. LS was interpreted together with BS (LS-BS) or with BMS (LS-BMS) by three independent readers. RESULTS: The concordance among readers, estimated by the kappa test, was average with LS-BS (kappa/kappam coefficients = 0.58, 0.58 and 0.46, respectively, for the three pairs of readers) and excellent with LS-BMS (kappa/kappam coefficients = 1.00 for the three pairs of readers). With LS-BS, 64/219 interpretations were equivocal whereas only one was equivocal with LS-BMS. Sensitivity, specificity and accuracy of LS-BMS were, respectively, 80%, 94% and 91% in the +group, and 33%, 100% and 93% in the -group. CONCLUSION: We conclude that (1) the interpretation of the results for LS-BMS is very easy, in contrast to LS-BS; (2) the diagnostic value of LS-BMS for detecting infected joint prostheses is good; and (3) additional data are needed to assess the accuracy of LS-BMS when the prosthesis has been removed.     

Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1,3-diphenyl-1H- pyrazol-5-yl)benzamides that potentiate receptor function in vivo

This report describes the discovery of the first centrally active allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5). Appropriately substituted N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides (e.g., 8) have been identified as a novel class of potent positive allosteric modulators of mGluR5 that potentiate the response to glutamate. An iterative analogue library synthesis approach provided potentiators with excellent potency and selectivity for mGluR5 (vs mGluRs 1-4, 7, 8). Compound 8q demonstrated in vivo proof of concept in an animal behavior model where known antipsychotics are active, supporting the development of new antipsychotics based on the NMDA hypofunction model for schizophrenia.     

Methodology of economic assessment: example in oncology

The increasing costs of care make it important to identify those strategies of greatest value from both an effectiveness and cost perspective. Economic analysis is characterized by a simultaneous consideration of alternatives costs and outcomes, and can provide useful data for managerial decision making. In this paper, methods of economic evaluations in general and in cancer in particular is reviewed. In cancer treatment, preventive, curative or palliative strategies can be concerned. Economic evaluation have become increasingly important in oncology because of the proliferation of expensive new treatments. Furthermore, considering quality of life effects is particularly important in oncology, where many treatments obtain modest improvements in response or survival. Quality of life measurements are also reviewed.