The costs of disorders of the brain in Switzerland: an update from the European Brain Council Study for 2010.

BACKGROUND: In 2005, findings of the first "cost of disorders of the brain in Europe" study of the European Brain Council (EBC) showed that these costs cause a substantial economic burden to the Swiss society. In 2010 an improved update with a broader range of disorders has been analysed. This report shows the new findings for Switzerland and discusses changes. METHODS: Data are derived from the EBC 2010 census study that estimates 12-month prevalence of 12 groups of disorders of the brain and calculates costs (direct health-care costs, direct non-medical costs and indirect costs) by combining top-down and bottom up cost approaches using existing data. RESULTS: The most frequent disorder was headache (2.3 million). Anxiety disorders were found in 1 million persons and sleep disorders in 700,000 persons. Annual costs for all assessed disorders total to 14.5 billion Euro corresponding to about 1,900 EUR per inhabitant per year. Mood, psychotic disorders and dementias (appr. 2 billion EUR each) were most costly. Costs per person were highest for neurological/neurosurgery-relevant disorders, e.g. neuromuscular disorders, brain tumour and multiple sclerosis (38,000 to 24,000 EUR). CONCLUSION: The estimates of the EBC 2010 study for Switzerland provide a basis for health care planning. Increase in size and costs compared to 2005 are mostly due to the inclusion of new disorders (e.g., sleep disorders), or the re-definition of others (e.g., headache) and to an increase in younger cohorts. We suggest coordinated research and preventive measures coordinated between governmental bodies, private health-care and pharmaceutical companies.

Nouveau spectre des troubles cognitifs liés à l'infection par le VIH à l'ère des trithérapies [New spectrum of HIV-associated cognitive disorders in the HAART era]

Highly active anti-retroviral therapy (HAART) has almost abolished HIV-related mortality and serious opportunistic diseases; among them, AIDS-related dementia. However, minor forms of cognitive dysfunction, have not disappeared, and even increased in frequency. Ageing of HIV+ patients, insufficient penetration of anti-viral drugs into the brain with continuous low-grade viral production and inflammation may play a role. Minor cognitive dysfunction in HIV infection shares some clinical and pathophysiological features with neuro-degenerative diseases, in particular Alzheimers disease. It can thus be postulated that, such in Alzheimer disease, anti-cholinesterase drugs might also be efficacious in AIDS-related minor cognitive dysfunction. This hypothesis has not been tested yet however A clinical trial using ravistigmine is starting this spring in patients with HIV-associated cognitive dysfunction in Geneva and Lausanne.

Mouvements anormaux et accident vasculaire cérébral [Movement disorders in stroke]

Dyskinesias are infrequent presentations in acute stroke (1%). They can be found more frequently as delayed presentations after a stroke, but the prevalence is not available from the literature. The full spectrum of hyper- and hypo-akinetic syndromes has been described, but three main pictures are rather specific of an acute stroke: limb shaking, hemichorea-hemiballism and unilateral asterixis. Besides limb shaking, that seems to reflect a transient diffuse ischemia of the frontosubcortical motor pathway, lesions are described at all levels of the frontosubcortical motor circuit including the sensorimotor frontoparietal cortex, the striatum, the pallidum, the thalamic nuclei, the subthalamic nucleus, the substantia nigra, the cerebellum, the brainstem and their interconnecting pathways, as ischemic or hemorrhagic strokes. The preferentially late development of dyskinesia could reflect the return to a more ancestral motor control level, the most functional possible with the remaining configuration of structures, elaborated by brain plasticity after stroke.

Diabète de type 2: n'oubliez pas les troubles du comportement alimentaire [Patient with type 2 diabetes: don't forget eating disorders!]

The coexistence of diabetes and eating disorder (ED) is more prevalent than we think; indeed it seems to occur in 10 to 20% of cases. Therefore ED deserve attention to be detected and treated in order to permit a decreased in morbidity and better outcomes in body weight loss. The association of type 2 diabetes and ED is frequently seen in younger, overweighed or obese patients suffering of at least one psychiatric co-morbidities and frequently in a difficult psychosocial setting. To succeed in ED treatment, a multidisciplinary and specialised team in eating disorder is requested, however these patients are highly fragile and complex and therapeutic failure has to be feared.

L'entretien motivationnel, une nouvelle "panacée" dans la prise en charge de patients toxicodépendants ? Une revue de littérature [Motivational interviewing, the new "panacea" for treatment of substance use disorders ? A review of literature]

Cet article aborde l'entretien motivationnel (EM), considéré comme un style thérapeutique centré sur le client et directif, visant à développer la motivation au changement par l'exploration et la résolution de l'ambivalence (Miller, W.R., Rollnick, S., 2002. Motivational interviewing: preparing people for change. The Guilford Press, New York, p. 25). Après une brève présentation théorique de ce style thérapeutique, nous présentons un survol des principaux résultats empiriques relatifs à la question de son efficacité dans la prise en charge des troubles liés à l'utilisation de substances psychoactives. Malgré un corpus important de travaux qui mettent en évidence les effets de l'EM, la question des « ingrédients actifs » reste encore relativement peu explorée. Quelques hypothèses permettant de mieux comprendre le succès de l'EM sont évoquées.

Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations.

The cause of many autoimmune and inflammatory diseases is unresolved, although dysregulated production of tumor necrosis factor (TNF) family members appears to be important in many cases. BAFF, a new member of the TNF family, binds to B cells and costimulates their growth in vitro. Mice transgenic for BAFF have vastly increased numbers of mature B and effector T cells, and develop autoimmune-like manifestations such as the presence of high levels of rheumatoid factors, circulating immune complexes, anti-DNA autoantibodies, and immunoglobulin deposition in the kidneys. This phenotype is reminiscent of certain human autoimmune disorders and suggests that dysregulation of BAFF expression may be a critical element in the chain of events leading to autoimmunity.

Effect of religion on suicide attempts in outpatients with schizophrenia or schizo-affective disorders compared with inpatients with non-psychotic disorders

Little is known of the relations between psychosis, religion and suicide. One hundred and fifteen outpatients with schizophrenia or schizo-affective disorder and 30 inpatients without psychotic symptoms were studied using a semi-structured interview assessing religiousness/spirituality. Their past suicide attempts were examined. Additionally, they were asked about the role (protective or incentive) of religion in their decision to commit suicide. Forty-three percent of the patients with psychosis had previously attempted suicide. Religiousness was not associated with the rate of patients who attempted suicide. Twenty-five percent of all subjects acknowledged a protective role of religion, mostly through ethical condemnation of suicide and religious coping. One out of ten patients reported an incentive role of religion, not only due to negatively connotated issues but also to the hope for something better after death. There were no differences between groups (i.e. psychotic vs. non-psychotic patients). Religion may play a specific role in the decisions patients make about suicide, both in psychotic and non-psychotic patients. This role may be protective, a finding particularly important for patients with psychosis who are known to be at high risk of severe suicide attempts. Interventions aiming to lower the number of suicide attempts in patients with schizophrenia should take these data into account.

Infection of B cells with hepatitis C virus for the development of lymphoproliferative disorders in patients with chronic hepatitis C.

Infection with hepatitis C virus (HCV) is associated with lymphoproliferative disorders, represented by essential mixed cryoglobulinemia and B-cell non-Hodgkin's lymphoma, but the pathogenic mechanism remains obscure. HCV may infect B cells or interact with their cell surface receptors, and induce lymphoproliferation. The influence of HCV infection of B cells on the development of lymphoproliferative disorders was evaluated in 75 patients with persistent HCV infection. HCV infection was more prevalent (63% vs. 16%, 14%, or 17% P < 0.05 for each), and HCV RNA levels were higher (3.35 +/- 3.85 vs. 1.75 +/- 2.52, 2.15 +/- 2.94 or 2.10 +/- 2.90 log copies/100 ng, P < 0.01 for each) in B cells than CD4(+), CD8(+) T cells or other cells. Negative-strand HCV RNA, as a marker of viral replication, was detected in B cells from four of the 75 (5%) patients. Markers for lymphoproliferative disorders were more frequent in the 50 patients with chronic hepatitis C than the 32 with chronic hepatitis B, including cryoglobulinemia (26% vs. 0%, P < 0.001), low CH(50) levels (48% vs. 3%, P = 0.012), and the clonality of B cells (12% vs. 0%, P < 0.01). By multivariate analysis, HCV RNA in B cells was an independent factor associated with the presence of at least one marker for lymphoproliferation (odds ratio: 1.98 [95% confidence interval: 1.36-7.24], P = 0.027). Based on the results obtained, the infection of B cells with HCV would play an important role in the development of lymphoproliferative disorders.

Implication of chromosome 13 on hypertension and associated disorders in Lyon hypertensive rats.

BACKGROUND: Hypertension and associated disorders are major risk factors for cardiovascular disease. The Lyon hypertensive rat (LH) is a genetically hypertensive strain that exhibits spontaneous and salt-sensitive hypertension, exaggerated proteinuria, high body weight, hyperlipidemia, and elevated insulin-to-glucose ratio. Previous genetic mapping identified quantitative trait loci (QTLs) influencing blood pressure (BP) on rat chromosome 13 (RNO13) in several models of hypertension. METHODS: To study the effects of a single chromosome on the mapped traits, we generated consomic strains by substituting LH RNO13 with that of the normotensive Brown Norway (BN) strain (LH-13BN) and reciprocal consomics by substituting a BN RNO13 with that of LH (BN-13LH). These reciprocal consomic strains, as well as the two parental strains were characterized for BP, metabolic and morphological parameters. RESULTS: Compared with LH parents, LH-13BN rats showed decreased mean BP (up to -24 mmHg on 2% NaCl in the drinking water), urine proteins and lipids, and increased body weight. Differences between BN-13LH and BN rats were much smaller than those observed between LH-13BN and LH rats, demonstrating the effects of the highly resistant BN genome background. Plasma renin activity was not affected by the substitution of RNO13, despite the significant BP differences. CONCLUSION: The present work demonstrates that RNO13 is a determinant of BP, proteinuria, and plasma lipids in the LH rat. The distinct phenotypic differences between the consomic LH-13BN and the LH make it a powerful model to determine genes and pathways leading to these risk factors for cardiovascular and renal disease.

Genetic factors of obesity and eating disorders: Copy number variations (CNV) involving SH2B1

Context : It is now clearly shown that genetic factors in association with environment play a key role in obesity and eating disorders. This project studies the clinical symptoms and molecular abnormalities in patients carrying a strong hereditary predisposition to obesity and eating behavior disorders. We have previously published the association between the 16:29.5-30.1 deletion and a very penetrant form of morbid obesity and macrocephaly. We have also demonstrated the association between the reciprocal 16:29.5-30.1 duplication and underweight and small head circumference. These 2 studies demonstrate that gene dosage of one or several genes in this region regulates BMI as well as brain growth. At present, there are no data pointing towards particular candidate genes. We are currently investigating a second non-overlapping recurrent CNV encompassing SH2B1, upstream of the aforementioned rearrangement. SNPs in this gene have been associated with BMI in GWAS studies and mice models confirmed this association. Bokuchova et al have reported an association between deletions encompassing this gene and severe early onset obesity, as well as insulin resistance. We are currently collecting and analyzing data to fully characterize the phenotype and the transcriptional patterns associated with this rearrangement. Aims : 1. Identify carriers of any CNVs in the greater 16p11.2 region (between 16:28MB and 32MB) in the EGG consortium. 2. Perform association studies between SNPs in the greater 16p11.2 region (16:28-32MB) and anthropometric measures with adjusted "locus-wide significance", to identify or prioritize candidate genes potentially driving the association observed in patients with the CNVs (and thus worthy of further validation and sequencing). 3. Explore associations between GSV genome-wide and brain volume. 4. Explore relationship between brain volumes (whole brain and regional for those who underwent brain MRI), head circumference and BMI. 5. Extrapolate this procedure to other regions covered by the Metabochip. Methods : - Examine and collect clinical informations, as well as molecular informations in these patients. - Analysis of MRI data in children and adults with BMI > 2SD. Compare changes to MRI data obtained in patients with monogenic forms of obesity (data from Lausanne study) and to underweight (BMI<-2SD) individuals from EGG. - Test whether opposite extremes of the phenotypic distribution may be highly informative Expected results : This is a highly focused study, pertaining to approximately 1 0/00 of the human genome. Yet it is clear that if successful, the lessons learned from this study could be extrapolated to other segments of the genome and would need validation and replication by additional studies. Altogether they will contribute to further explore the missing heritability and point to etiologic genes and pathways underlying these important health burdens.

The prolyl-aminodipeptidases and their inhibitors as therapeutic targets for fibrogenic disorders

Many biologically active peptides are protected from general proteolytic degradation by evolutionary conserved prolines (Pro), due to conformational constraints imposed by the Pro residue. Thus the biological importance of prolyl-specific peptidases points to a high potential for drug discovery for this family of enzymes. Panels of inhibitors have been synthesized and their effects, determined in biological models, suggest the inhibition of families of enzymes with similar activities. Prolyl-specific aminodipeptidases include dipeptidyl-aminodipeptidase IV (DPP IV)/CD26, DPP8, DPP9 and fibroblast activation protease-alpha (FAP-alpha)/seprase, able to release X-Pro dipeptides from the N-terminus of peptides. DPP IV inhibitors are in clinical use for type 2 diabetes. In this review, the expression and the potential functions of prolyl-aminodipeptidases are reviewed in diseases, and the inhibitors developed for these enzymes are discussed, with a specific focus on inhibitors able to discriminate between DPP IV and fibroblast activation protease-alpha (FAPalpha)/seprase as potential leads for the treatment of fibrogenic diseases.