Microglia, Calcification and Neurodegenerative Diseases

Neurodegeneration is a complex process involving different cell types andneurotransmitters. A common characteristic of neurodegenerative disorders such asAlzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis, Huntington’s disease (HD) and Amyotrophic Lateral Sclerosis (ALS) is the occurrence of a neuroinflammatoryreaction in which cellular processes involving glial cells (mainly microglia and astrocytes) and T cells are activated in response to neuronal death. This inflammatory reaction has recently received attention as an unexpected potential target for the treatment of these diseases.Microglial cells have a mesenchymal origin, invade the central nervous system (CNS)prenatally (Chan et al., 2007b) and are the resident macrophages in the CNS (Ransohoff &Perry, 2009). They comprise approximately 10-20% of adult glia and serve as the CNS innateimmune system. In neurodegenerative diseases, microglia is activated by misfoldedproteins. In the case of AD, amyloid- (A ) peptides accumulate extracellularly and activate the microglia locally. In the case of PD, ALS and HD, the misfolded proteins accumulate intracellularly but are still associated with activation of the microglia (Perry et al., 2010). Reactive microglia in the substantia nigra and striatum of PD brains have been described, and increased levels of proinflammatory cytokines and inducible nitric oxide synthase havebeen detected in these brain regions, providing evidence of a local inflammatory reaction (Hirsch & Hunot, 2009). The injection of lipopolysaccharide (a potent microglia activator) into the substantia nigra produces microglial activation and the death of dopaminergic cells. These findings support the hypothesis that microglial activation and neuroinflammationcontribute to PD pathogenesis (Herrera et al., 2000)...

Evaluation des technologies médicales : travaux présentés pendant le Congrès TEKMED 87 = Assessment of medical technologies : the papers presented during the TEKMED 87 Congress

[Table des matières] Technology assessment in health care in the United States: an historical review / S. Perry. - The aims and methods of technology assessment / JH Glasser. - Evaluation des technologies de la santé / A. Griffiths. - Les données nécessaires pour l'évaluation des technologies médicales / R. Chrzanowski, F. Gutzwiller, F. Paccaud. - Economic issues in technology assessment/DR Lairson, JM Swint. - Two decades of experience in technology assessment: evaluating the safety, performance, and cost effectiveness of medical equipment / JJ Nobel. - Demography and technology assessment / H. Hansluwka. - Méthodes expérimentale et non expérimentale pour l'évaluation des innovations technologiques / R. Chrzanowski, F. Paccaud. - Skull radiography in head trauma: a successful case of technology assessment / NT Racoveanu. - Complications associées à l'anesthésie: une étude prospective en France / L. Tiret et al. - Impact de l'information publique sur les taux opératoires: le cas de l'hystérectomie / G. Domenighetti, P. Luraschi, A. Casabianca. - The clinical effectiveness of acupuncture for the relief of chronic pain / MS Patel, F. Gutzwiller, F. Paccaud, A. Marazzi. - Soins à domicile et hébergement à long terme: à la recherche d'un développement optimum / G. Tinturier. - Economic evaluation of six scenarios for the treatment of stones in the kidney and ureter by surgery or ESWL / MS Patel et al. - Technology assessment and medical practice / F. Gutzwiller. - Technology assessment and health policy / SJ Reiser. - Global programme on appropriate technology for health, its role and place within WHO / K. Staehr Johansen.

New horizons for black holes and branes

We initiate a systematic scan of the landscape of black holes in any spacetime dimension using the recently proposed blackfold effective worldvolume theory. We focus primarily on asymptotically flat stationary vacuum solutions, where we uncover large classes of new black holes. These include helical black strings and black rings, black odd-spheres, for which the horizon is a product of a large and a small sphere, and non-uniform black cylinders. More exotic possibilities are also outlined. The blackfold description recovers correctly the ultraspinning Myers-Perry black holes as ellipsoidal even-ball configurations where the velocity field approaches the speed of light at the boundary of the ball. Helical black ring solutions provide the first instance of asymptotically flat black holes in more than four dimensions with a single spatial U(1) isometry. They also imply infinite rational non-uniqueness in ultraspinning regimes, where they maximize the entropy among all stationary single-horizon solutions. Moreover, static blackfolds are possible with the geometry of minimal surfaces. The absence of compact embedded minimal surfaces in Euclidean space is consistent with the uniqueness theorem of static black holes

Depression, migraine with aura and migraine without aura: their familiality and interrelatedness.

Migraine is frequently comorbid with depression. There appear to be common aetiological factors for both disorders, but the aetiology of migraine within depressed patients, in particular the significance of aura, has been little studied. A large sample of concordantly depressed sibling pairs [the Depression-Network (DeNT) sample] was assessed as having migraine with aura (MA), migraine without aura (MoA), probable migraine or no migraine according to International Headache Society guidelines. Correlations between siblings' migraine status were used to assess the nature of familial liability to migraine. A multiple threshold isocorrelational model fit best, in which different syndromes are conceptualized as different severities of one underlying dimension rather than as having separate aetiologies. Thus, MA and MoA were found to be different forms of the same disorder, with MA occupying the more extreme end of the spectrum of liability. Implications for our understanding of the relationship between migraine and depression are discussed.

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Genome-wide association study of recurrent major depressive disorder in two European case-control cohorts.

Major depressive disorder (MDD) is a highly prevalent disorder with substantial heritability. Heritability has been shown to be substantial and higher in the variant of MDD characterized by recurrent episodes of depression. Genetic studies have thus far failed to identify clear and consistent evidence of genetic risk factors for MDD. We conducted a genome-wide association study (GWAS) in two independent datasets. The first GWAS was performed on 1022 recurrent MDD patients and 1000 controls genotyped on the Illumina 550 platform. The second was conducted on 492 recurrent MDD patients and 1052 controls selected from a population-based collection, genotyped on the Affymetrix 5.0 platform. Neither GWAS identified any SNP that achieved GWAS significance. We obtained imputed genotypes at the Illumina loci for the individuals genotyped on the Affymetrix platform, and performed a meta-analysis of the two GWASs for this common set of approximately half a million SNPs. The meta-analysis did not yield genome-wide significant results either. The results from our study suggest that SNPs with substantial odds ratio are unlikely to exist for MDD, at least in our datasets and among the relatively common SNPs genotyped or tagged by the half-million-loci arrays. Meta-analysis of larger datasets is warranted to identify SNPs with smaller effects or with rarer allele frequencies that contribute to the risk of MDD.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

Specificities of defense mechanisms in bipolar affective disorder: relations with symptoms and therapeutic alliance.

Defense mechanisms as a central notion of psychoanalysis have inspired various levels of interest in research in psychotherapy and psychopathology. Defense specificities have only recently been investigated systematically with regard to several clinical diagnoses, such as affective and personality disorders. For the present study, 30 inpatients diagnosed with Bipolar Affective Disorder I (BD) were interviewed. An observer-rater method, the Defense Mechanisms Rating Scales (DMRS), applied to session-transcripts, of assessment of defenses was used. A matched, nonclinical control group was introduced. Defense specificities in BD encompass a set of 5 immature defenses, of which omnipotence is linked with symptom level. The level of the therapeutic alliance is predicted by mature defenses. These results are discussed with regard to the psychological vulnerability of BD, and treatment implications for psychodynamic psychotherapy with such challenging patients are evoked.

Aspectos morfológicos e influência do tamanho da semente na germinação do jambo-vermelho

O jambo-vermelho (Syzygium malaccense (L.) Merryl et Perry), espécie pertencente à família Myrtaceae, possui frutos ricos em vitaminas, ferro e fósforo. Este trabalho teve por objetivos fornecer informações sobre aspectos morfológicos do fruto, semente e plântula e avaliar a influência do tamanho da semente na germinação dessa espécie. O fruto é uma baga piriforme, carnoso e indeiscente. O epicarpo é delgado, liso e avermelhado; o mesocarpo e o endocarpo são esbranquiçados e suculentos. Os frutos pesam, em média, 35,57g e medem 7,16cm de comprimento e 5,15cm de largura. As sementes são poliembriônicas e exalbuminosas, pesando, em média, 7,62g. Os cotilédones são maciços e esverdeados. A germinação é hipógea, e a emergência das plântulas inicia-se aos 36 dias após a semeadura. A raiz primária é longa e esbranquiçada. As raízes secundárias são curtas e filiformes. As sementes de maior tamanho são as mais vigorosas, não havendo diferença entre as de tamanho médio e pequeno. O estudo morfológico do jambo-vermelho pode ser utilizado para a identificação da espécie ou em relações ecológicas interespecíficas.

Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study.

BACKGROUND: Survival outcomes for patients with glioblastoma remain poor, particularly for patients with unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter. This phase II, randomized, open-label, multicenter trial investigated the efficacy and safety of 2 dose regimens of the selective integrin inhibitor cilengitide combined with standard chemoradiotherapy in patients with newly diagnosed glioblastoma and an unmethylated MGMT promoter. METHODS: Overall, 265 patients were randomized (1:1:1) to standard cilengitide (2000 mg 2×/wk; n = 88), intensive cilengitide (2000 mg 5×/wk during wk 1-6, thereafter 2×/wk; n = 88), or a control arm (chemoradiotherapy alone; n = 89). Cilengitide was administered intravenously in combination with daily temozolomide (TMZ) and concomitant radiotherapy (RT; wk 1-6), followed by TMZ maintenance therapy (TMZ/RT→TMZ). The primary endpoint was overall survival; secondary endpoints included progression-free survival, pharmacokinetics, and safety and tolerability. RESULTS: Median overall survival was 16.3 months in the standard cilengitide arm (hazard ratio [HR], 0.686; 95% CI: 0.484, 0.972; P = .032) and 14.5 months in the intensive cilengitide arm (HR, 0.858; 95% CI: 0.612, 1.204; P = .3771) versus 13.4 months in the control arm. Median progression-free survival assessed per independent review committee was 5.6 months (HR, 0.822; 95% CI: 0.595, 1.134) and 5.9 months (HR, 0.794; 95% CI: 0.575, 1.096) in the standard and intensive cilengitide arms, respectively, versus 4.1 months in the control arm. Cilengitide was well tolerated. CONCLUSIONS: Standard and intensive cilengitide dose regimens were well tolerated in combination with TMZ/RT→TMZ. Inconsistent overall survival and progression-free survival outcomes and a limited sample size did not allow firm conclusions regarding clinical efficacy in this exploratory phase II study.

Polychlorinated and polybrominated biphenyls

This volume of the IARC Monographs provides evaluations of the carcinogenicity of polychlorinated biphenyls and polybrominated biphenyls. Polychlorinated biphenyls are a class of aromatic compounds comprising 209 congeners, each containing 1 to 10 chlorine atoms attached to a biphenyl nucleus. Technical products, which were manufactured to obtain a certain degree of chlorination, are mixtures of numerous congeners. These products were widely used as dielectric fluid in capacitors and transformers, and to a lesser extent in building materials. Although their production and use has been banned in most countries, these compounds are ubiquitous environmental pollutants, including in polar regions and the deep ocean, because they are persistent and bioaccumulate. Worldwide monitoring programmes have shown that polychlorinated biphenyls are present in most samples of human milk. An IARC Monographs Working Group reviewed epidemiological evidence, animal bioassays, and mechanistic and other relevant data to reach conclusions as to the carcinogenic hazard to humans of polychlorinated biphenyls, of the subclass of dioxinlike polychlorinated biphenyls, and of polybrominated biphenyls.