Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations.

High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.

Normalisation informatique et marchés de services : le cas du XML

Extensible Markup Language (XML) is a generic computing language that provides an outstanding case study of commodification of service standards. The development of this language in the late 1990s marked a shift in computer science as its extensibility let store and share any kind of data. Many office suites software rely on it. The chapter highlights how the largest multinational firms pay special attention to gain a recognised international standard for such a major technological innovation. It argues that standardisation processes affects market structures and can lead to market capture. By examining how a strategic use of standardisation arenas can generate profits, it shows that Microsoft succeeded in making its own technical solution a recognised ISO standard in 2008, while the same arena already adopted two years earlier the open source standard set by IBM and Sun Microsystems. Yet XML standardisation also helped to establish a distinct model of information technology services at the expense of Microsoft monopoly on proprietary software

Genetic loci for retinal arteriolar microcirculation.

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.

LKB1 and AMPK differentially regulate pancreatic β-cell identity.

Fully differentiated pancreatic β cells are essential for normal glucose homeostasis in mammals. Dedifferentiation of these cells has been suggested to occur in type 2 diabetes, impairing insulin production. Since chronic fuel excess ("glucotoxicity") is implicated in this process, we sought here to identify the potential roles in β-cell identity of the tumor suppressor liver kinase B1 (LKB1/STK11) and the downstream fuel-sensitive kinase, AMP-activated protein kinase (AMPK). Highly β-cell-restricted deletion of each kinase in mice, using an Ins1-controlled Cre, was therefore followed by physiological, morphometric, and massive parallel sequencing analysis. Loss of LKB1 strikingly (2.0-12-fold, E<0.01) increased the expression of subsets of hepatic (Alb, Iyd, Elovl2) and neuronal (Nptx2, Dlgap2, Cartpt, Pdyn) genes, enhancing glutamate signaling. These changes were partially recapitulated by the loss of AMPK, which also up-regulated β-cell "disallowed" genes (Slc16a1, Ldha, Mgst1, Pdgfra) 1.8- to 3.4-fold (E<0.01). Correspondingly, targeted promoters were enriched for neuronal (Zfp206; P=1.3×10(-33)) and hypoxia-regulated (HIF1; P=2.5×10(-16)) transcription factors. In summary, LKB1 and AMPK, through only partly overlapping mechanisms, maintain β-cell identity by suppressing alternate pathways leading to neuronal, hepatic, and other characteristics. Selective targeting of these enzymes may provide a new approach to maintaining β-cell function in some forms of diabetes.-Kone, M., Pullen, T. J., Sun, G., Ibberson, M., Martinez-Sanchez, A., Sayers, S., Nguyen-Tu, M.-S., Kantor, C., Swisa, A., Dor, Y., Gorman, T., Ferrer, J., Thorens, B., Reimann, F., Gribble, F., McGinty, J. A., Chen, L., French, P. M., Birzele, F., Hildebrandt, T., Uphues, I., Rutter, G. A. LKB1 and AMPK differentially regulate pancreatic β-cell identity.

Hemophilia Registry of the Medical Committee of the Swiss Hemophilia Society: Update and Annual Survey 2008.

The Swiss Haemophilia Registry of the Medical Committee of the Swiss Haemophilia Society was established in 2000. Primarily it bears epidemiological and basic clinical data (incidence, type and severity of the disease, age groups, centres, mortality). Two thirds of the questions of the WFH Global Survey can be answered, especially those concerning use of concentrates (global, per capita) and treatment modalities (on-demand versus prophylactic regimens). Moreover, the registry is an important tool for quality control of the haemophilia treatment centres. There are no informations about infectious diseases like hepatitis or HIV, due to non-anonymisation of the data. We plan to incorporate the results of the mutation analysis in the future.

Population-based registration of phenotypic anatomic and familial data for melanoma: results from a Swiss multicentric study

CONTEXT AND OBJECTIVES: A multicentric study was set up to assess the feasibility for Swiss cancer registries of actively retrieving 3 additional variables of epidemiological and a etiological relevance for melanoma, and of potential use for the evaluation of prevention campaigns. MATERIAL AND METHODS: The skin type, family history of melanoma and precise anatomical site were retrieved for melanoma cases registered in 5 Swiss cantons (Neuchâtel, St-Gall and Appenzell, Vaud and Wallis) over 3 to 6 consecutive years (1995-2002). Data were obtained via a short questionnaire administered by the physicians - mostly dermatologists - who originally excised the lesions. As the detailed body site was routinely collected in Ticino, data from this Cancer Registry were included in the body site analysis. Relative melanoma density (RMD) was computed by the ratio of observed to expected numbers of melanomas allowing for body site surface areas, and further adjusted for site-specific melanocyte density. RESULTS: Of the 1,645 questionnaires sent, 1,420 (86.3%) were returned. The detailed cutaneous site and skin type were reliably obtained for 84.7% and 78.7% of questionnaires, and family history was known in 76% of instances. Prevalence of sun-sensitive subjects and patients with melanoma affected first-degree relatives, two target groups for early detection and surveillance campaigns were 54.1% and 3.4%, respectively. After translation into the 4th digit of the International Classification of Diseases for Oncology, the anatomical site codes from printed (original information) and pictorial support (body chart from the questionnaire) concurred for 94.6% of lesions. Discrepancies occurred mostly for lesions on the upper, outer part of the shoulder for which the clinician's textual description was "shoulder blade". This differential misclassification suggests under-estimation by about 10% of melanomas of the upper limbs and an over-estimation of 5% for truncal melanomas. Sites of highest melanoma risk were the face, the shoulder and the upper arm for sexes, the back for men and the leg for women. Three major features of this series were: (1) an unexpectedly high RMD for the face in women (6.2 vs 4.2 in men), (2) the absence of a male predominance for melanomas on the ears, and (3) for the upper limbs, a steady gradient of increasing melanoma density with increasing proximity to the trunk, regardless of sex. DISCUSSION AND CONCLUSION: The feasibility of retrieving the skin type, the precise anatomical location and family history of melanoma in a reliable manner was demonstrated thanks to the collaboration of Swiss dermatologists. Use of a schematic body drawing improves the quality of the anatomical site data and facilitate the reporting task of doctors. Age and sex patterns of RMD paralleled general indicators of sun exposure and behaviour, except for the hand (RMD=0.2). These Swiss results support some site or sun exposure specificity in the aetiology of melanoma.

Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients.

The paradoxical coexistence of spontaneous tumor antigen-specific immune responses with progressive disease in cancer patients furthers the need to dissect the molecular pathways involved in tumor-induced T cell dysfunction. In patients with advanced melanoma, we have previously shown that the cancer-germline antigen NY-ESO-1 stimulates spontaneous NY-ESO-1-specific CD8(+) T cells that up-regulate PD-1 expression. We also observed that PD-1 regulates NY-ESO-1-specific CD8(+) T cell expansion upon chronic antigen stimulation. In the present study, we show that a fraction of PD-1(+) NY-ESO-1-specific CD8(+) T cells in patients with advanced melanoma up-regulates Tim-3 expression and that Tim-3(+)PD-1(+) NY-ESO-1-specific CD8(+) T cells are more dysfunctional than Tim-3(-)PD-1(+) and Tim-3(-)PD-1(-) NY-ESO-1-specific CD8(+) T cells, producing less IFN-γ, TNF, and IL-2. Tim-3-Tim-3L blockade enhanced cytokine production by NY-ESO-1-specific CD8(+) T cells upon short ex vivo stimulation with cognate peptide, thus enhancing their functional capacity. In addition, Tim-3-Tim-3L blockade enhanced cytokine production and proliferation of NY-ESO-1-specific CD8(+) T cells upon prolonged antigen stimulation and acted in synergy with PD-1-PD-L1 blockade. Collectively, our findings support the use of Tim-3-Tim-3L blockade together with PD-1-PD-L1 blockade to reverse tumor-induced T cell exhaustion/dysfunction in patients with advanced melanoma.

Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis.

Marie Unna hereditary hypotrichosis (MUHH) is an autosomal dominant form of genetic hair loss. In a large Chinese family carrying MUHH, we identified a pathogenic initiation codon mutation in U2HR, an inhibitory upstream ORF in the 5' UTR of the gene encoding the human hairless homolog (HR). U2HR is predicted to encode a 34-amino acid peptide that is highly conserved among mammals. In 18 more families from different ancestral groups, we identified a range of defects in U2HR, including loss of initiation, delayed termination codon and nonsense and missense mutations. Functional analysis showed that these classes of mutations all resulted in increased translation of the main HR physiological ORF. Our results establish the link between MUHH and U2HR, show that fine-tuning of HR protein levels is important in control of hair growth, and identify a potential mechanism for preventing hair loss or promoting hair removal.

Expression of the NH(2)-terminal fragment of RasGAP in pancreatic beta-cells increases their resistance to stresses and protects mice from diabetes.

OBJECTIVE: Our laboratory has previously established in vitro that a caspase-generated RasGAP NH(2)-terminal moiety, called fragment N, potently protects cells, including insulinomas, from apoptotic stress. We aimed to determine whether fragment N can increase the resistance of pancreatic beta-cells in a physiological setting. RESEARCH DESIGN AND METHODS: A mouse line, called rat insulin promoter (RIP)-N, was generated that bears a transgene containing the rat insulin promoter followed by the cDNA-encoding fragment N. The histology, functionality, and resistance to stress of RIP-N islets were then assessed. RESULTS: Pancreatic beta-cells of RIP-N mice express fragment N, activate Akt, and block nuclear factor kappaB activity without affecting islet cell proliferation or the morphology and cellular composition of islets. Intraperitoneal glucose tolerance tests revealed that RIP-N mice control their glycemia similarly as wild-type mice throughout their lifespan. Moreover, islets isolated from RIP-N mice showed normal glucose-induced insulin secretory capacities. They, however, displayed increased resistance to apoptosis induced by a series of stresses including inflammatory cytokines, fatty acids, and hyperglycemia. RIP-N mice were also protected from multiple low-dose streptozotocin-induced diabetes, and this was associated with reduced in vivo beta-cell apoptosis. CONCLUSIONS: Fragment N efficiently increases the overall resistance of beta-cells to noxious stimuli without interfering with the physiological functions of the cells. Fragment N and the pathway it regulates represent, therefore, a potential target for the development of antidiabetes tools.

Timing effects of combined radioimmunotherapy and radiotherapy on a human solid tumor in nude mice.

Timing effects of radioimmunotherapy (RIT) combined with external-beam radiotherapy (RT) were assessed in human colon carcinoma xenografts. Initially, dose effects of fractionated RT and RIT were evaluated separately. Then, 30 Gy RT (10 fractions over 12 days) were combined with three weekly i.v. injections of 200 microCi of 131I-labeled anti-carcinoembryonic antigen monoclonal antibodies in four different treatment schedules. RIT was given either prior to, concurrently, immediately after, or 2 weeks after RT administration. The longest regrowth delay (RD) of 105 days was observed in mice treated by concurrent administration of RT and RIT, whereas the RDs of RT and RIT alone were 34 and 20 days, respectively. The three sequential combination treatments produced significantly shorter RDs ranging from 62 to 70 days. The tumor response represented by the minimal volume (MV) also showed that concurrent administration of RT and RIT gave the best result, with a mean MV of 4.5% as compared to MVs from 26 to 53% for the three sequential treatments. The results were confirmed in a second experiment, in which a RT of 40 Gy was combined with an identical RIT as above (three injections of 200 microCi of 131I-labeled monoclonal antibodies). At comparable toxicity levels, the maximum tolerated RT or RIT alone gave shorter RDs and less tumor shrinkage compared to simultaneous RT+ RIT. These results may be useful for designing clinical protocols of combined RIT and RT.

Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus.

Using immunohistology, electron microscopy, electrophysiology and optogenetics, we found that proliferating adult mouse hippocampal neural precursors received immature GABAergic synaptic inputs from parvalbumin-expressing interneurons. Recently shown to suppress adult quiescent neural stem cell activation, parvalbumin interneuron activation promoted newborn neuronal progeny survival and development. Our results suggest a niche mechanism involving parvalbumin interneurons that couples local circuit activity to the diametric regulation of two critical early phases of adult hippocampal neurogenesis.

Epidemiologie und Prävention des Hautmelanoms in der Schweiz: Update 2010. [Epidemiology and prevention of melanoma in Switzerland: 2010 update]

Zusammenfassung] Die Inzidenz des malignen Melanoms steigt seit über 50 Jahren bei der weißen Bevölkerung stark an. Die Schweiz ist mit ungefähr 1900 neu diagnostizierten Fällen pro Jahr das am stärksten betroffene Land Europas (16/100 000 Welt-standardisierte Rate). In letzter Zeit sind regionale Unterschiede mit höherer Inzidenz in den Westschweizer Kantonen festzustellen. Änderungen in Wissen und Verhalten der Schweizer Bevölkerung gegenüber dem Schutz vor Sonnenexposition bestehen noch zu wenig lange und sind zu bescheiden, als dass sie schon einen Einfluss auf die Inzidenz hätten haben können. Dank der seit 20 Jahren betriebenen Früherfassung sind Überlebensrate und Anteil an dünnen Melanomen gestiegen, allerdings bei gleichbleibender Inzidenz dicker Läsionen. Die Mortalität aufgrund des malignen Melanoms ist neuerdings rückläufig, vor allem bei den Frauen. Werden die gegenwärtigen Präventionsbemühungen weitergeführt, dürften sich bald noch mehr Erfolge zeigen. [Abstract] The incidence of cutaneous malignant melanoma has steadily increased in Caucasian populations over the last decades. With around 1900 new cases each year, Switzerland has one of the highest melanoma rates in Europe (16/100 000 world-standardised rate). Regional differences are emerging within Switzerland, with a higher incidence in the western (French-speaking) region. Observed changes in sun protection attitudes and knowledge in the Swiss population have yet no impact on the incidence trend. Early detection, carried out since the mid 1980s in Switzerland, has led to a substantial increase in survival and rates of thin melanoma, without material change in rates of thick melanoma. Mortality from melanoma has recently decreased, earlier in women than men. The efficacy of prevention campaigns should soon become more blatant if current efforts persist.

Nanotechnology: balancing benefits and risks to public health and the environment : expert paper

Nanotechnology has been heralded as a "revolution" in science, for two reasons: first, because of its revolutionary view of the way in which chemicals and elements, such as gold and silver, behave, compared to traditional scientific understanding of their properties. Second, the impact of these new discoveries, as applied to commerce, can transform the daily life of consumer products ranging from sun tan lotions and cosmetics, food packaging and paints and coatings for cars, housing and fabrics, medicine and thousands of industrial processes.9 Beneficial consumer use of nanotechnologies, already in the stream of commerce, improves coatings on inks and paints in everything from food packaging to cars. Additionally, "Nanomedicine" offers the promise of diagnosis and treatment at the molecular level in order to detect and treat presymptomatic disease,10 or to rebuild neurons in Alzheimer's and Parkinson's disease. There is a possibility that severe complications such as stroke or heart attack may be avoided by means of prophylactic treatment of people at risk, and bone regeneration may keep many people active who never expected rehabilitation. Miniaturisation of diagnostic equipment can also reduce the amount of sampling materials required for testing and medical surveillance. Miraculous developments, that sound like science fiction to those people who eagerly anticipate these medical products, combined with the emerging commercial impact of nanotechnology applications to consumer products will reshape civil society - permanently. Thus, everyone within the jurisdiction of the Council of Europe is an end-user of nanotechnology, even without realising that nanotechnology has touched daily life.

Less Risk, More Effort : Demand Risk Allocation in Incomplete Contracts

This article investigates the allocation of demand risk within an incomplete contract framework. We consider an incomplete contractual relationship between a public authority and a private provider (i.e. a public-private partnership), in which the latter invests in non-verifiable cost-reducing efforts and the former invests in non-verifiable adaptation efforts to respond to changing consumer demand over time. We show that the party that bears the demand risk has fewer hold-up opportunities and that this leads the other contracting party to make more effort. Thus, in our model, bearing less risk can lead to more effort, which we describe as a new example of âeuro~counter-incentivesâeuro?. We further show that when the benefits of adaptation are important, it is socially preferable to design a contract in which the demand risk remains with the private provider, whereas when the benefits of cost-reducing efforts are important, it is socially preferable to place the demand risk on the public authority. We then apply these results to explain two well-known case studies.

Prévention du métanome en Suisse: où en sommes-nous [Melanoma prevention in Switzerland: where do we stand?]

Over the last 50 years, skin cancer rates (particularly melanoma) have markedly increased in Caucasian populations. Switzerland, with some 1,600 cases of, and 220 deaths from, malignant melanoma per year has among the highest rates in Europe. This public health issue, affecting relatively young people, has led to primary and secondary nationwide prevention campaigns being carried out for nearly 20 years. Observed changes in sun protection knowledge and attitudes have yet to impact on incidence trend. Early detection has resulted in a large increase in rates of thin melanoma with little change in rates of thick melanoma. Mortality has levelled off and a recent decrease, especially in women, cannot be ruled out. The efficiency of prevention campaigns should soon become more blatant if current efforts persist.