125,317 research outputs found
Ryhiner-Kartensammlung / 40 Nova mappa generalis totius orbis amplissimae Russorum monarchiae : = Nouvelle carte generale d'empire de Russie et de Tartarie grande et petite en Europe et Asie
No full textopera et sumptibus Iohan[n]: Michael Probst geogr ; Iohann Georg Probst filius sculp. 1783. 7.brNullmeridian: Ferr
SERPINA1 PiZ and PiS heterozygotes and lung function decline in the SAPALDIA cohort
No full textBACKGROUND: Severe alpha1-antitrypsin (AAT) deficiency is a strong risk factor for COPD. But the impact of gene variants resulting in mild or intermediate AAT deficiency on the longitudinal course of respiratory health remains controversial. There is indication from experimental studies that pro-inflammatory agents like cigarette smoke can interact with these variants and thus increase the risk of adverse respiratory health effects. Therefore, we tested the effect of the presence of a protease inhibitor (Pi) S or Z allele (PiMS and PiMZ) on the change in lung function in different inflammation-exposed subgroups of a large, population-based cohort study.METHODOLOGY AND PRINCIPAL FINDINGS: The SAPALDIA population includes over 4600 subjects from whom SERPINA1 genotypes for S and Z alleles, spirometry and respiratory symptoms at baseline and after 11 years follow-up, as well as proxies for inflammatory conditions, such as detailed smoking history, obesity and high sensitivity C-reactive protein (hs-CRP), were available. All analyses were performed by applying multivariate regression models. There was no overall unfavourable effect of PiMS or PiMZ genotype on lung function change. We found indication that PiZ heterozygosity interacted with inflammatory stimuli leading to an accelerated decline in measures in use as indices for assessing mild airway obstruction. Obese individuals with genotype PiMM had an average annual decline in the forced mid expiratory flow (?FEF25-75%) of 58.4 ml whereas in obese individuals with PiMZ it amounted to 92.2 ml (p?=?0.03). Corresponding numbers for persistent smokers differed even more strongly (66.8 ml (PiMM) vs. 108.2 ml (PiMZ), p?=?0.005). Equivalent, but less strong associations were observed for the change in the FEV1/FVC ratio. CONCLUSIONS: We suggest that, in addition to the well established impact of the rare PiZZ genotype, one Z allele may be sufficient to accelerate lung function decline in population subgroups characterized by elevated levels of low grade inflammation
Biobanking across the phenome - at the center of chronic disease research
No full textRecognized public health relevant risk factors such as obesity, physical inactivity, smoking or air pollution are common to many non-communicable diseases (NCDs). NCDs cluster and co-morbidities increase in parallel to age. Pleiotropic genes and genetic variants have been identified by genome-wide association studies (GWAS) linking NCD entities hitherto thought to be distant in etiology. These different lines of evidence suggest that NCD disease mechanisms are in part shared. Identification of common exogenous and endogenous risk patterns may promote efficient prevention, an urgent need in the light of the global NCD epidemic. The prerequisite to investigate causal risk patterns including biologic, genetic and environmental factors across different NCDs are well characterized cohorts with associated biobanks. Prospectively collected data and biospecimen from subjects of various age, sociodemographic, and cultural groups, both healthy and affected by one or more NCD, are essential for exploring biologic mechanisms and susceptibilities interlinking different environmental and lifestyle exposures, co-morbidities, as well as cellular senescence and aging. A paradigm shift in the research activities can currently be observed, moving from focused investigations on the effect of a single risk factor on an isolated health outcome to a more comprehensive assessment of risk patterns and a broader phenome approach. Though important methodological and analytical challenges need to be resolved, the ongoing international efforts to establish large-scale population-based biobank cohorts are a critical basis for moving NCD disease etiology forward. Future epidemiologic and public health research should aim at sustaining a comprehensive systems view on health and disease. The political and public discussions about the utilitarian aspect of investing in and contributing to cohort and biobank research are essential and are indirectly linked to the achievement of public health programs effectively addressing the global NCD epidemic
The role of air pollution in the aetiology of type 2 diabetes
No full textBackground. The public health burden of type 2 diabetes cannot be overestimated. Prevalence of type 2 diabetes is continuously increasing and has caused a great number of deaths and economic losses. Optimal prevention measures for type 2 diabetes entail that more risk factors need to be identified. Air pollution is one of the modifiable environmental risk factors causing health problems, most notably respiratory diseases. Recently there have been indications for a spill-over of its effects into the cardio-metabolic systems. Short-term exposure to air pollution may exert acute or sub-acute inflammatory cardio-metabolic responses which on long-term, sustained exposure could lead to overt cardiovascular diseases and type 2 diabetes. However, it is unclear if long-term exposure to pollutants in the air contributes to the development of type 2 diabetes. This work generates evidence to fill knowledge gaps on the impact of air pollutants on the development of type 2 diabetes and on how different susceptibilities in the general population could contribute to the understanding of the mechanisms involved in this relationship.
Methods. First, this work summarized the existing evidence on the possible relationship between long-term exposure to air pollutants and type 2 diabetes. Furthermore, in the framework of the first follow-up of SAPALDIA- the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults, this work used indices for long-term exposure air pollution – 10-year mean particulate matter <10μm in diameter [PM10] and nitrogen dioxide [NO2] - assigned to participants’ residences using a combination of Gaussian dispersion and Land-use regression models, participants residential histories and pollutant trends at monitoring stations. It identified diabetes and metabolic syndrome cases in a comprehensive way considering self-reports, blood tests and other physical measures. It additionally identified genetic variants through genotyping on two different arrays – the Human Illumina610quad Bead Chip and the Taqman PCR assay - for 63 type 2 diabetes genetic polymorphisms [towards a diabetes gene score] and a functional polymorphism on the IL6 gene respectively. Based on the above and detailed health socio-demographic and lifestyle characteristics including smoking habits, occupational exposures, alcohol, nutrition, physical activity, body measurements and additional data collected in SAPALDIA, it was ideal to investigate the cross-sectional relationships between air pollutants and diabetes and to explore interactions [based on various susceptibilities] to understand mechanisms involved in the relationship between long-term exposure to air pollutants and type 2 diabetes.
Results. In this work, we found a positive relationship between PM2.5 and NO2 and the risk of T2D in the pooled evidence synthesized from electronic databases. In the frame of SAPALDIA biobank, we found a moderate positive association between long-term exposure to PM10 [and NO2] and prevalent diabetes, and demonstrated a sustained effect of PM10 independent of NO2, while NO2 lost its association on accounting for PM10 in multi-pollutant models. Among the measures of cardio-metabolic function, PM10 impacted most on impairment of glucose homeostasis and least on blood lipoproteins and triglycerides. The relationship between PM10 and impaired fasting glycaemia was more apparent among the physically active. Age also appeared to influence the relationship between PM10 and impaired fasting glycaemia. People at higher polygenic risk for type 2 diabetes were more susceptible to PM10. Genetic risk for insulin resistance and obesity appeared to be more relevant than those for beta-cell function in modifying the effects of PM10, especially among those with some background inflammatory conditions. Carriers of the pro-inflammatory major ‘G’ allele of IL6-572GC, with allele frequency of 93%, were also more susceptible to PM10 in relation to diabetes.
Conclusions. This work has greatly contributed to evidence suggesting the possible role of air pollutants in diabetes aetiology. The reported associations were observed at mean concentrations below current air quality guidelines. PM10 may be a good marker for aspects of air pollution [rather than NO2] relevant for the development of diabetes. In particular, PM10 might act through sub-clinical inflammation and resultant impaired insulin sensitivity. Impairment of insulin secretion may be a less relevant pathway for PM10 action. Physical activity, though beneficial, presented another likely pathway for PM10 effects. These findings, if confirmed, call for the strengthening of air quality policies and adaptation of physical activity promotion to environmental contrasts. Future studies should explore the totality of environmental exposures – exposomics –in a life-course fashion. The mediating role of DNA methylation influencing genetic expression should be further explored. For global generalizability, there is a strong need for evidence replication in developing countries where outdoor and indoor air pollution is quite high and mostly unregulated, and the burden of non-communicable diseases is rapidly growing
Comorbidity between counnunicable and non-communicable diseases : the example of the dual burden of tuberculosis and diabetes in Dar es Salaam, Tanzania
No full textBackground
Although recognized for centuries, the association between tuberculosis (TB) and diabetes mellitus (DM) was forgotten with the discovery of efficient treatments. In the last decade, the prevalence of DM has dramatically increased, particularly in low- and middle-income countries experiencing a high burden of TB, leading to a new interest in this association. DM increases TB risk while TB, as an infectious disease, leads to hyperglycemia. The relationship between TB and DM has been poorly studied in Sub-Saharan Africa, where the high incidence of TB is associated with HIV infection. Concentration of vitamin D is inversely associated with TB and DM, and it has been suggested that low vitamin D could mediate some of the association between TB and DM. DM affects the immune response to TB, but the precise mechanisms underlying this association are not clear.
To address this issue of high public health relevance, we undertook a project on the association between TB, DM and HIV in Tanzania. The project had three major components:
(1) Assessing the association of TB and its outcome with the presence and persistence of hyperglycemia in Tanzania, using three different DM screening tests.
(2) Describing the association between vitamin D, TB and DM.
(3) Studying the immunological features underlying TB and DM comorbidity in sub-Saharan Africa and testing the hypothesis of delayed adaptive immune response with increasing glycemia.
The overall aim of the project was to improve knowledge on the dynamic interaction between TB and DM in an African setting with high HIV prevalence by integrating a longitudinal component into the case-control study.
Methods
A case-control study with longitudinal follow-up of cases was conducted in Dar es Salaam. Consecutive adults with new active TB were included and followed up for five months after the start of anti-TB treatment. Healthy controls, matched by age and sex to TB cases, were recruited among volunteering adults accompanying patients to the outpatient departments of the same hospitals. Exclusion criteria were a biological relationship to TB case, TB history, symptoms or signs of TB, other acute infection or major trauma within the last three months. All underwent 25-hydroxyvitamin D (25(OH)D) measurement and DM screening tests (fasting glucose (FCG), 2-hour capillary glucose after standard oral glucose tolerance test (2h-CG) and glycated hemoglobin (HbA1c)) at enrolment and TB patients were again tested after five months of TB treatment. Data on the outcome of TB (treatment failure, death, lost to follow-up) were collected.
For the nested immunological study, four groups of HIV negative patients were included: i) active TB without DM, ii) active TB with DM, iii) latent TB patients without DM and iv) latent TB patients with DM. Latent TB patients were selected among the healthy volunteering adults, as well as among diabetic patients attending the DM clinic in the participating hospitals. Exclusion criteria for groups iii and iv were past TB history and symptoms or signs of active TB. Peripheral blood mononuclear cells were stimulated with Mycobacterium tuberculosis (Mtb)-specific peptide pools and live Mycobacterium bovis BCG and then analysed by polychromatic flow cytometry for Th1, Th2, Th9 and Th17 cytokine production. Cell culture supernatants were analysed by Luminex® for 34 cytokines and chemokines.
Findings
At enrolement, DM prevalence was significantly higher among TB patients (N=539; FCG>7mmol/L: 4.5%, 2-hCG>11mmol/L: 6.8% and HbA1c>6.5%: 9.3%) compared to controls (N=496; 1.2%, 3.1% and 2.2%). However, the association between hyperglycemia and TB disappeared after TB treatment (aOR(95% CI) at enrolment vs follow-up: FCG 9.6(3.7-24.7) vs 2.4(0.7-8.7); 2-hCG 6.6(4.0-11.1) vs 1.6(0.8-2.9); HbA1c 4.2(2.9-6.0) vs 1.4(0.9-2.0)). FCG hyperglycemia at enrolment was associated with TB treatment failure or death (aOR(95%CI) 3.3(1.2-9.3).
The prevalence of 25(OH)D insufficiency (25(OH)D<75nmol/l) was not statistically different between TB patients and controls (25.8% versus 31.0%; p=0.22). But the association between 25(OH)D insufficiency and TB was modified by hyperglycemia (pinteraction=0.01). Patient with vitamin D insufficiency were only at higher risk for TB in the presence of underlying hyperglycemia. The OR (95%CI) for TB risk in patients with vitamin D insufficiency and hyperglycemia was 4.94(1.16-21.0) versus 0.68(0.39-1.17) for patients with vitamin D insufficiency and normoglycemia where normoglycemia and normal vitamin D were the reference category.
Patients with active TB and DM had a lower frequency of INF-γ CD4+ T cells and a lower proportion of CD4+ T cells producing both TNF-α and IFN-γ after live M. bovis BCG but not after Mtb-specific peptide pool stimulation, compared to normoglycemic TB patients. A negative correlation between INF-γ or TNF-α CD4+ T cell frequency and increasing glycemia was observed in the context of live M. bovis BCG stimulation only.
Conclusions
Transient hyperglycemia is frequent during TB, and DM needs confirmation after TB treatment. However, DM screening at TB diagnosis gives the opportunity to detect patients at risk of adverse outcome.
25(OH)D insufficiency seams to increase the risk of TB only if associated with hyperglycemia. DM patients living in high TB burden settings might benefit from preventive vitamin D supplementation.
The immunological findings suggest that DM might affect Mtb-specific CD4+ T cell immune responses at the level of reduced antigen processing and presentation, a defect that could be compensated by metformin.
The results of the study are of public health and clinical utility. First, they lend support to the integration of care between TB and DM programs. Second, they imply that, at the time of TB diagnosis, patients should be screened for hyperglycemia using cost-effective fasting glucose tests. Treatment of hyperglycemia should be initiated to improve TB outcome. Third, before initiation of long-term DM treatment, DM diagnosis must be confirmed after the resolution of TB. Finally, in the absence of evidence for a strong contribution of DM to TB risk in this African setting with high HIV prevalence, DM patients should not be screened for TB with expensive test. DM physicians and patients should rather be trained for recognizing TB symptoms and signs as a cost-effective way to recognize TB early
Lung function in the general population : the complex interplay of variants in "Serpina1" and other genes with the environment
No full textBackground. One of the globally most frequent health problems are obstructive lung
diseases such as asthma and chronic obstructive pulmonary disease. Both of them
show heterogeneous phenotypes and are most commonly diagnosed by lung function
measurements. Apart from several well-established environmental risk factors,
there are also genetic factors which play an important role in determining lung
function. Notably, SERPINA1 gene variants which severely reduce the
alpha1-antitrypsin (AAT) concentration in the blood and consequently lead to a
protease-antiprotease disequilibrium in the lung have been known as risk factors
for several years. Intermediate deficiency of AAT serum level is however assumed
to be a risk factor in only part of the population, but neither is it entirely
clear how to define this range of protein concentration for the general population,
nor do we know which co-factors are health-relevant in intermediately deficient individuals.
Methods. In this work, SAPALDIA, the Swiss cohort study on air pollution and lung disease
in adults, was used to find the essential genetic polymorphisms which determine AAT serum
level. Deficiency ranges for AAT were defined in the general population, and the association
between SERPINA1 deficiency genotypes and age-related lung function decline was investigated
in a comprehensive way. The assessment of gene-environment interactions in terms of pulmonary
health was a central part of this work and embraced also genes beyond SERPINA1. The
environment-related focus was set on factors associated with inflammatory stress, namely smoking,
air pollution, high occupational exposure to vapours, gas, dusts and fumes as well as obesity.
The availability of serum inflammatory markers including AAT, genome-wide data including
additional genotype and sequence information of the SERPINA1 gene as well as very comprehensive
and detailed environmental and respiratory health data made SAPALDIA, unlike any other study,
ideally suited to investigate the aforementioned associations and interactions.
Results. This work found a smaller range of AAT serum level in subjects with intermediate AAT
deficiency than reported in the literature and clarified the role of elevated inflammatory
conditions on AAT serum level. It confirmed uncommon variants in the SERPINA1 locus as the
major genetic determinants of AAT blood level and pointed to some of the inherent weaknesses
of genome-wide association studies. A high burden of inflammatory stress was suggested to
modify the association between intermediate AAT deficiency and lung function decline. Further
genetic interaction with obesity in terms of asthma and with air pollution in terms of lung
function decline was suggested, pointing on the one hand to a still proliferative research
area of gene-environment interactions which has not yet been systematically assessed, but
revealing on the other hand the complexity of drawing firm conclusions from such analyses.
Discussion and Conclusion. In summary, this work may potentially facilitate the diagnostic
procedure for subjects with an assumed AAT deficiency. Although generally not regarded
as a risk group for adverse pulmonary health, individuals with an intermediate AAT
deficiency seem more susceptible to elevated inflammatory conditions compared to the
general population. They would potentially more strongly benefit from measures like
counselling against the uptake of smoking, for healthy diet programmes or improvements
of occupational safety
Ryhiner-Kartensammlung / 11 Mappa nova principatus Moldaviæ & Bucovinæ cum finitimis regionibus : = Neue Landkarte von dem jezigen Fürstenthum Moldau mit der Bukowina und benachbarten Landschaften = Carte nouvelle et exacte de la principaute Moldavie et Bukovine avec des confins
No full textgezeichnet von I.F. Carl J.A.P. ; Johan[n] Georg Probst sculp
alpha1-antitrypsin level and pheno/genotypes
No full textThe authors comment on a few aspects regarding the interpretation of the reference values given in a previously pubblished paper
1. (Bornhorst JA, Greene DN, Ashwood ER, Grenache DG. A1-antitrypsin phrnotypes and associated serum protein concentration in a large clinical population. Chest 2013; 143:1000-1008.
Ryhiner-Kartensammlung / 46 Belgivm, catholicvm seu decem, provinciae Germaniae inferioris : cum, confiniis, Germaniae, svp. et Franciae = Carte des Pais Bas catoliqves ou des X provinces de l'Allemagne inferieure
No full textrecentissime et curatissime in lucem edita per Iohan[n] Mich: Probst geogr. ; Joh: Michael Probst, feci
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