Novel pathomechanisms and disease associations of the voltage-gated sodium channel NaV1.4

Voltage-gated sodium channels initiate and shape the upstroke of the action potential, allowing fast electrical signaling between cells. Mutations in the genes encoding these channels are associated with a group of disorders known as channelopathies. This project aimed to characterize mutations in SCN4A encoding NaV1.4 associated with traditional skeletal muscle channelopathies as well as novel conditions using functional expression in Xenopus oocytes or HEK293T cells. Mutations of gating charges in the voltage sensor domain in the fourth transmembrane segment (S4), such as p.R222W or p.R222G, were found in patients with hypokalemic periodic paralysis. Another mutation, p.R222Q, was found in an individual with myotonia. I found that unlike hypoPP S4 arginine mutations causing gating pore currents, p.R222Q results in gain of function typically associated with sodium-channel myotonia. In another project, novel homozygous or compound heterozygous SCN4A mutations were found in eleven families with congenital myopathy. Each affected individual carried at least one mutation causing full loss of function. In all but one case the mutation in the opposite allele caused full or partial loss of function. The genetic and functional data are consistent with heteroallelic loss of function mutations—one of which confers full loss of function—underlying the clinical presentation by reducing the action potential amplitude in the muscle to a level insufficient to sustain normal muscle function. Some SCN4A mutations are lethal in infants when affecting muscle regulating respiration. Whole-exome sequencing of 434 cases of sudden infant death syndrome (SIDS) identified in six novel and five very rare SCN4A variants. Channel defects were found in four variants, two of which were gain of function and the other two loss of function. Dysfunctional SCN4A variants were also overrepresented in the SIDS cohort compared to controls. These results suggest pathogenic variations in SCN4A may be a genetic risk factor for SIDS

Regulatory Trust in EU Free Movement Law: Adopting the Level of Protection of the Other?

The principles of mutual trust and mutual recognition are well established features of EU law. On a technical level, it is clear that the principles may require adoption of foreign levels of protection in individual cases as well as in legislation. At a closer look, however, the principles through “the rule of reason” also may imply quite the opposite: the imposing of domestic requirements on foreign goods, services etc. The CJEU case law following the Cassis judgement may be seen as striking a balance between cooperation and Member State self-determination, or between trust and distrust, in different fields. This contribution aims at looking into the regulatory function of the legal principle of trust in EU law. Taking this wider regulatory perspective, the mutual recognition regimes of EU must be seen from a holistic perspective. Rather than dwelling upon harmonized and non-harmonized fields separately, we will approach mutual trust as one, albeit multi-faceted, concept, where harmonization, proportionality assessments and Member State actions in various fields of law form part of the same wider picture. In this regulatory perspective, the law on mutual trust and mutual recognition may be seen as a balancing between the regulatory interests of the EU (promoting free movement and cooperation) and the various Member States (promoting their interests of – alleged – protection of safety of various kinds). Through this perspective, we will be able to address the tension between regulation and deregulation, between integration and disintegration, and between unity and diversity present in EU law on a very general level. The first section of this contribution will look at the constitutional life of mutual trust within the CJEU case law: looking at its origins and main logic. The second section will attempt to clarify why the principle of mutual trust is mostly invisible in the free movement jurisprudence. This section also argues for understanding mutual recognition in terms of Regulatory Trust. The last section focuses on the thorny issue of the levels of protection and attempts to understand which are the key factors used by the CJEU in reviewing the (host) States measures that restrict free movement law and thus may constitute a break to the application of the principles of mutual trust and mutual recognition

The health risk associated with smoking has been seriously underestimated. The Reykjavik Study

Hægt er að lesa greinina í heild sinni með því að smella á hlekkinn View/OpenOBJECTIVE: To assess the risk for coronary heart disease, myocardial infarction, cancer deaths, and all deaths associated with different smoking categories as determined by smoking status at a baseline examination only and at a baseline with reexamination 15-19 years later (persistent smokers). MATERIAL AND METHODS: The participants were a random sample of 2930 men and 3084 women aged 34-61 years (when selected in 1967) invited for various standardized examinations under two periods, 1967-1972 and 1979-1991 and followed-up until the end of year 2001. The main outcome measures were clinical coronary heart disease, myocardial infarction, cancer deaths, and all deaths. Risk was calculated for each smoking category as determined by two assessments of smoking habits and also compared with the risk as determined by one baseline examination only. RESULTS: Mean follow-up for men was 26 years (SD 9 years). For women the mean follow-up was 28 years (SD 7 years). There were substantial differences in hazard ratios (HR) and median lifetime in smoking groups as determined by one or two examinations. In men the greatest difference in hazard ratios was for cancer deaths (one examination: 2.80, two: 3.83) in women for total deaths (3.02 vs. 3.7). Loss of median lifetime was greatest in "heavy" cigarette smoking men (one examination: eight years; two examinations: 13 years), in women the corresponding figures were nine and 10 years, in "light" cigarette smokers, the figures for men were four and nine years, and for women four and six years. CONCLUSIONS: Middle-aged men smoking one or more packets of cigarettes per day shorten their life expectancy by 13 years and middle-aged women by 10 years. Only one baseline determination of smoking status with subsequent follow-up underestimates the health risk associated with smoking by 15-40% at least in populations where smoking prevalence is declining.Tilgangur: Í Hóprannsókn Hjartaverndar sem stóð yfir í um 30 ár voru reykingavenjur kannaðar með stöðluðum spurningalista. Í þessari grein er metin áhætta sem fylgir mismunandi reykingavenjum, annars vegar ef þær eru ákvarðaðar með einni grunnrannsókn og hins vegar ef þær eru ákvarðaðar með tveimur athugunum með 15-19 ára millibili, til að staðfesta hverjir reykja að staðaldri. Efniviður og aðferðir: Þátttakendur voru tilviljunarúrtak 2930 karla og 3084 kvenna sem voru á aldrinum 34-61 árs í upphafi rannsóknarinnar og voru boðaðir til rannsóknar í Rannsóknarstöð Hjartaverndar, fyrst á tímabilinu 1967-1972 og aftur 1979-1991 og síðan fylgt eftir til ársloka 2001. Endapunktar voru klínískur kransæðasjúkdómur, kransæðastífla, krabbameinsdauði og heildardauði. Áhætta var reiknuð fyrir sérhvern reykingaflokk þegar hann var ákvarðaður með báðum heimsóknunum en einnig ef flokkunin byggðist eingöngu á fyrri heimsókninni. Niðurstöður: Meðaleftirfylgnitími hjá körlum var 26 ár (staðalfrávik 9 ár). Meðal kvenna var eftirfylgnitími 28 ár (staðalfrávik 7 ár). Það var verulegur munur á áhættuhlutfalli (hazard ratio) með tilliti til framangreindra sjúkdóma eftir því hvort reykingaflokkur var ákvarðaður með einni eða tveimur skoðunum. Meðal karla var þessi munur mestur í sambandi við krabbameinsdauða (ein skoðun: 2,80, tvær: 3,83) en meðal kvenna vegna heildardauða (3,02 og 3,7). Stytting á meðalævi samfara slíkum innbyrðis samanburði var mest meðal karla er reyktu ?15 sígarettur á dag (við eina skoðun átta ár en við tvær 13 ár), meðal kvenna voru samsvarandi tölur níu og 10 ár. Hjá þeim sem reyktu <15 sígarettur á dag voru tölurnar hjá körlum fjögur og níu ár en hjá konum fjögur ár og sex ár. Ályktun: Miðaldra karlar sem að staðaldri reykja pakka eða meira af sígarettum á dag stytta meðalævina um 13 ár en miðaldra konur um 10 ár. Þegar reykingavenjur eru kannaðar eingöngu í upphafi rannsóknar leiðir það til verulegs vanmats á skaðsemi reykinga um 15-40% eftir endapunktum

Latent autoimmune diabetes in adults in Iceland: prevalence, phenotype and relatedness

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/OpenINTRODUCTION: Ninety percent of diabetic individuals in Iceland suffer from type 2 diabetes mellitus. Antibodies against ss-cell components characterise type 1 diabetes, but these antibodies are also found in type 2 diabetic individuals, defined as latent autoimmune diabetes in adults or LADA. The purpose of this investigation was to estimate the prevalence of LADA in Iceland and to describe the phenotype and relatedness of these individuals. MATERIAL AND METHODS: A list of individuals diagnosed with type 2 diabetes was generated from outpatient clinic lists and the Reykjavik Study of the Icelandic Heart Association. A genealogy database (Book of Icelanders; deCODE Genetics) was used to identify all individuals related to these index cases within six meioses. This method identified 950 type 2 diabetic individuals during the years 1998-2000. We analyzed their phenotype and measured glutamic acid decarboxylase antibody (GAD). Kinship coefficient was used to compare the relatedness of those with antibodies to GAD to the relatedness of all type 2 diabetic individuals in the study. RESULTS: 10.1% of men and 9.3% women had measurable antibodies against GAD (non-significant difference). The mean age of GAD positive and GAD negative individuals was comparable (67.1 +/- 10.7 and 68.0 +/- 11.3; years +/- SD). Body mass index was significantly lower (p=0,02) for the GAD positive individuals or 28.2 kg/m(2) (27.2-29.2; 95% CI) vs. 29.7 (29.3-30.1). Of the GAD positive individuals, 47% +/- 9% (95% CI) had the metabolic syndrome as defined by WHO compared with 60 +/- 4% of the GAD negative individuals (p=0.02). The kinship coefficient for GAD positive individuals (n=94) was 6.00x10(-4) compared with 3.93x10(-4) +/- 8.3x10(-5) for 500 random samples (each of 94 individuals) of the whole cohort (p=0.008). CONCLUSION: About 10% of Icelandic type 2 diabetic individuals have antibodies against GAD, which is comparable to the results of other investigators. Icelandic GAD positive type 2 diabetic individuals have less frequently the metabolic syndrome than other type 2 diabetic individuals and GAD positive individuals are significantly more related to each other than type 2 diabetic individuals in general.Tilgangur: 90% sykursjúkra á Íslandi eru með tegund 2 sykursýki (SS2). Meirihluti sjúklinga með tegund 1 sykursýki (SS1) hafa ß-frumumótefni en hafi sjúklingur með SS2 slík mótefni er hann sagður hafa mótefnatengda sykursýki af tegund 2 (MTSS2, latent autoimmune diabetes in adults eða LADA). Tilgangur rannsóknarinnar var að ákvarða algengi MTSS2 á Íslandi og jafnframt að lýsa svipgerð og skyldleika þessara sjúklinga. Efniviður og aðferðir: Búinn var til listi yfir SS2 sjúklinga úr sjúkraskrám og Reykjavíkurrannsókn Hjartaverndar. Ættfræðigagnagrunnur Íslenskrar erfðagreiningar „Íslendingabók“ var notuð til að finna alla sem skyldir voru þessum sjúklingum í sex ættliði. Á árunum 1998-2000 fundust 950 sjúklingar sem greindir voru með SS2. Svipgerð sjúklinganna var ákvörðuð og ELISA notuð til að mæla mótefni gegn Glutamic Acid Decarboxylase (GAD). Skyldleikastuðull var notaður til að bera saman innbyrðis skyldleika GAD-jákvæðra (GADAb+) og skyldleika allra SS2 sjúklinga. Niðurstöður: 10,1% karla og 9,3% kvenna voru GADAb+ (ómarktækur munur). Meðalaldur GADAb+ og GADAb- sjúklinga var sambærilegur (67,1 ± 10,7 og 68,0 ± 11,3; ár ± staðalfrávik). Holdastuðull var marktækt lægri (p=0,02) hjá GADAb+ sjúklingum eða 28,2 kg/m2 (27,2-29,2; 95% öryggismörk) miðað við 29,7 (29,3-30,1) hjá GADAb-. Efnaskiptavilla var til staðar hjá 47 ± 9% (95% öryggismörk) GADAb+ sjúklinganna saman­borið við 60 ± 4% GADAb- sjúklinganna (p=0,02). Skyldleikastuðullinn fyrir GADAb+ sjúk­lingana (n=94) var 6,00×10-4 samanborið við 3,93×10-4 ± 8,3×10-5 fyrir fimm hundruð 94 manna slembi­úr­tök úr öllum SS2 sjúklingahópnum (p=0,008). Ályktun: Um 10% íslenskra SS2 sjúklinga eru GADAb+ sem er sambærilegt við niðurstöður annarra. Íslenskir GADAb+ SS2 sjúklingar eru sjaldnar með efnaskiptavillu og eru marktækt skyldari innbyrðis en SS2 sjúklingahópurinn í heild

The Montana Kaimin, January 17, 1922

Student newspaper of the University of Montana, Missoula.https://scholarworks.umt.edu/studentnewspaper/1675/thumbnail.jp

Verdien av en robust vannforsyning - Hvordan verdsette konsekvenser av brudd i drikkevannsforsyningen?

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Samfunnsøkonomisk optimale investeringer i robust drikkevannsinfrastruktur

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The association between glucose abnormalities and heart failure in the population-based Reykjavik study

To access publisher full text version of this article. Please click on the hyperlink in Additional Link fieldOBJECTIVE: Diabetes is an independent risk factor for heart failure, whereas the relation between heart failure and abnormal glucose regulation (AGR) needs further evaluation. We studied this combination in the Reykjavik Study. RESEARCH DESIGN AND METHODS: The Reykjavik Study, a population-based cohort study during 1967-1997, recruited 19,381 participants aged 33-84 years who were followed until 2002. Oral glucose tolerance tests and chest X-rays were obtained from all participants. Cases were defined in accordance with World Health Organization criteria for type 2 diabetes or AGR (impaired glucose tolerance or impaired fasting glucose) and European Society of Cardiology guidelines for heart failure. RESULTS: The overall prevalence of type 2 diabetes and heart failure was 0.5% in men and 0.4% in women, while AGR and heart failure were found in 0.7% of men and 0.6% of women. Among participants with normal glucose regulation, heart failure was diagnosed in 3.2% compared with 6.0 and 11.8% among those with AGR and type 2 diabetes, respectively. The prevalence of type 2 diabetes in the age-group 45-65 years increased in both sexes during the period (P for trend = 0.007). The odds ratio was 2.8 (95% CI 2.2-3.6) for the association between type 2 diabetes and heart failure and 1.7 (1.4-2.1) between AGR and heart failure. CONCLUSIONS: There is a strong association between any form of glucometabolic perturbation and heart failure. Future studies in this field should focus on all types of glucose abnormalities rather than previously diagnosed diabetes only

Effect of vertebral fractures on function, quality of life and hospitalisation the AGES-Reykjavik study.

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.Understanding the determinants of health burden after a fracture in ageing populations is important. Assess the effect of clinical vertebral and other osteoporotic fractures on function and the subsequent risk of hospitalisation. Individuals from the prospective population-based cohort study Age, Gene/Environment Susceptibility (AGES)-Reykjavik study were examined between 2002 and 2006 and followed up for 5.4 years. A total of 5,764 individuals, 57.7% women, born 1907-35, mean age 77. Method: four groups with a verified fracture status were used; vertebral fractures, other osteoporotic fractures excluding vertebral, non-osteoporotic fractures and not-fractured were compared and analysed for the effect on mobility, strength, QoL, ADL, co-morbidity and hospitalisation. Worst performance on functional tests was in the vertebral fracture group for women (P < 0.0001) and the other osteoporotic fractures group for men (P < 0.05). Both vertebral and other osteoporotic fractures, showed an increased risk of hospitalisation, HR = 1.4 (95% CI: 1.3-1.7) and 1.2 (95% CI: 1.1-1.2) respectively (P < 0.0001). Individuals with vertebral fractures had 50% (P < 0.0001) longer hospitalisation than not-fractured and 33% (P < 0.002) longer than the other osteoporotic fractures group. Individuals with a history of clinical vertebral fracture seem to carry the greatest health burden compared with other fracture groups, emphasising the attention which should be given to those individuals.National Institutes of Health, USA N01-AG-12100 National Institute on Aging Hjartavernd (The Icelandic Heart Association) Althingi (The Icelandic Parliament