Chromosomal localization of 15 ion channel genes

Several human Mendelian diseases, including the long-QT syndrome, malignant hyperthermia, and episodic ataxia/myokymia syndrome, have recently been demonstrated to be due to mutations in ion channel genes. Systematic mapping of ion channel genes may therefore reveal candidates for other heritable disorders. In this study, the GenBank and dbEST databases were used to identify members of several ion channel families (voltage-gated calcium and sodium cardiac chloride, and all classes of potassium channels). Genes and ESTs without prior map localization were identified based on GDB and OWL database information and 15 genes and ESTs were selected for mapping. Of these 15, only the serotonin receptor 5HT3R had been previously mapped to a chromosome. A somatic cell hybrid panel (SCH) was screened with an STS from each gene and, if necessary, the results verified by a second SCH panel. For three ESTs, rodent derived PCR products of the same size as the human STS precluded SCH mapping. For these three, human Pl clones were isolated and the genomic location was determined by metaphase FISH. These genes and ESTs can now be further evaluated as candidate genes for inherited cardiac, neuromuscular, and psychiatric disorders mapped to these chromosomes. Furthermore, the ESTs developed in this study can be used to isolate genomic clones, enabling the determination of each transcript's genomic structure and physical map location. This approach may also be applicable to other gene families and may aid in the identification of candidate genes for groups of related heritable disorders.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45548/1/11188_2006_Article_BF02369898.pd

Untangling the effects of overexploration and overexploitation on organizational performance: The moderating role of environmental dynamism

Because a firm's optimal knowledge search behavior is determined by unique firm and industry conditions, organizational performance should be contingent oil the degree to which a firm's actual level of knowledge search deviates from the optimal level. It is thus hypothesized that deviation from the optimal search, in the form of either overexploitation or overexploration, is detrimental to organizational performance. Furthermore, the negative effect of search deviation oil organizational performance varies with environmental dynamism: that is, overexploitation is expected to become more harmful. whereas overexploration becomes less so with all increase in environmental dynamism. The empirical analyses yield results consistent with these arguments. Implications for research and practice are correspondingly discussed

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol—which is a marker of cardiovascular risk—changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million–4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.</p

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol�which is a marker of cardiovascular risk�changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95 credible interval 3.7 million�4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world. © 2020, The Author(s), under exclusive licence to Springer Nature Limited

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities 1,2 . This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity 3�6 . Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55 of the global rise in mean BMI from 1985 to 2017�and more than 80 in some low- and middle-income regions�was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing�and in some countries reversal�of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories. © 2019, The Author(s)

Evidence for the localization of a malignant hyperthermia susceptibility locus (MHS2) to human chromosome 17q

Malignant hyperthermia susceptibility is a lethal autosomal dominant disorder of skeletal muscle metabolism that is triggered by all potent inhalation anesthetic gases. Recent linkage studies suggest a genetic locus for this disorder on 19q13.1. We have previously reported three unrelated families diagnosed with MHS that are unlinked to markers surrounding this locus on 19q13.1. In this report we extend these observations and present linkage studies on 16 MHS families. Four families (25%) were found linked to the region 19q12–q13.2 ( Z max = 2.96 with the ryanodine receptor at θ = 0.0). Five families (31%) were found closely linked to the anonymous marker NME1 (previously designated NM23) on chromosome 17q11.2–q24 ( Z max = 3.26 at θ = 0.0). Two families (13%) were clearly unlinked to either of these chromosomal regions. In five additional families, data were insufficient to determine their linkage status (they were potentially linked to two or more sites). The results of our heterogeneity analyses are consistent with the hypothesis that MHS can be caused in humans by any one of at least three distinct genetic loci. Furthermore, we provide preliminary linkage data suggesting the localization of a gene in human MHS to 17q11.2–q24 (MHS2), with a gene frequency of this putative locus approximately equal to that of the MHS1 locus on 19q

Overexpression of IL-1 Receptor Antagonist Attenuates Obliterative Bronchiolitis in Murine Tracheal Transplant Model

Obliterative bronchiolitis (OB) remains an impediment to long-term survival after lung transplantation. IL-1 beta (IL-1β) has been studied as proinflammatory and profibrotic factor in allograft chronic lung tissue rejection. IL-1 receptor antagonist (IL-1rn) is competitive inhibitor to IL-1β and mediates the anti-inflammatory and antifibrotic effects of mesenchymal stem cells during lung injury. We hypothesized that IL-1rn overexpression prevents the progression of OB in an established heterotopic tracheal transplantation model. Tracheas from BALB/c mice were implanted and wrapped in the omentum of BALB/c (isografts), C57BL/6 (allografts), IL-1rn overexpression (IL-1rn+/+), IL-1rn knock out (IL-1rn-/-) mice. The tracheas explanted after 21 days were evaluated histologically, and real time-PCR for IL-1rn, IL-1β, IL-1 alpha (IL-1α) mRNA levels. Cytokine quantification for these proteins in plasma samples was done by ELISA 21 days after surgery. IL-1rn overexpression mice showed significant reduction of the tracheal luminal occlusion compared to control allograft animals (p<0.0001). The gene expression of IL-1rn in tracheal tissue explanted from IL-1rn overexpression animals was increased (50-150 fold) as compared to tissue from control isograft, allograft and IL-1rn knock out animals (p<0.0001). [figure 1] There was also significant increase in plasma IL-1rn levels in the IL-1rn +/+ animals as compared to other groups (p<0.0001). The results suggest that IL-1rn overexpression protects against experimental OB. These findings provide new insights into the mechanisms of lung chronic rejection and may lead to new strategy for the treatment of OB

Overexpression of IL-1 Receptor Antagonist Attenuates Obliterative Bronchiolitis in Murine Tracheal Transplant Model

Obliterative bronchiolitis (OB) remains an impediment to long-term survival after lung transplantation. IL-1 beta (IL-1β) has been studied as proinflammatory and profibrotic factor in allograft chronic lung tissue rejection. IL-1 receptor antagonist (IL-1rn) is competitive inhibitor to IL-1β and mediates the anti-inflammatory and antifibrotic effects of mesenchymal stem cells during lung injury. We hypothesized that IL-1rn overexpression prevents the progression of OB in an established heterotopic tracheal transplantation model. Tracheas from BALB/c mice were implanted and wrapped in the omentum of BALB/c (isografts), C57BL/6 (allografts), IL-1rn overexpression (IL-1rn+/+), IL-1rn knock out (IL-1rn-/-) mice. The tracheas explanted after 21 days were evaluated histologically, and real time-PCR for IL-1rn, IL-1β, IL-1 alpha (IL-1α) mRNA levels. Cytokine quantification for these proteins in plasma samples was done by ELISA 21 days after surgery. IL-1rn overexpression mice showed significant reduction of the tracheal luminal occlusion compared to control allograft animals (p<0.0001). The gene expression of IL-1rn in tracheal tissue explanted from IL-1rn overexpression animals was increased (50-150 fold) as compared to tissue from control isograft, allograft and IL-1rn knock out animals (p<0.0001). [figure 1] There was also significant increase in plasma IL-1rn levels in the IL-1rn +/+ animals as compared to other groups (p<0.0001). The results suggest that IL-1rn overexpression protects against experimental OB. These findings provide new insights into the mechanisms of lung chronic rejection and may lead to new strategy for the treatment of OB