Cardiac sarcoidosis and coronary artery disease: a two-hit mechanism to left ventricular dysfunction (or is it)?

This report describes a case of cardiac sarcoidosis in a 40-year-old man with minimal risk factors for coronary artery disease who was found to have a critical coronary lesion on angiography performed for declining left ventricular function. The case highlights the diagnostic and therapeutic issues surrounding cardiac sarcoidosis and raises the question of a possible link between sarcoidosis and premature coronary artery disease. It also stresses the importance of ruling out ischemia in any patient with declining left ventricular function.

Increasing overweight in Greenland: social, demographic, dietary and other life-style factors.

OBJECTIVES: In several Arctic countries, weight gain is very evident among the local populations and the percentages of overweight and obese persons are increasing rapidly. Since the development of overweight among the Arctic populations seems to coincide with the westernization of their diet and other life-style factors, it is tempting to hypothesize that the transition to carbohydrate- and fat-rich western food causes the weight gain. The high relative content of (n-3) fatty acids in traditional foods presumably provides some protection against cardiovascular diseases, type 2 diabetes and various other diseases of affluent industrialized societies. In the present study, we have investigated the recent weight gain in Greenland and have tried to relate it to social factors, present dietary habits and other life-styles. STUDY DESIGN: The cross-sectional study, which was part of the Arctic Monitoring and Assess Programme, included 410 men and women (18-49 years) from 5 districts in Greenland. It was based upon questionnaires including a dietary survey, anthropometric measurements and blood lipid analyses. RESULTS: Obesity (Body Mass Index (BMI) > 30 kg/m2, corresponding to about 19% of the participants) increased with age, was most prevalent among higher household economic levels, and correlated with neither local, nor imported food intake. CONCLUSION: Overweight was not found to be correlated with either western, or traditional food composition. Obesity had adverse effects on several health indicators, serum triglyceride, HDL and the cardiovascular risk index, (Chol-HDL)/HDL and TG/HDL, counteracting the positive effects of (n-3) fatty acids and should be considered as a serious health risk for the Greenlandic population.

Circumpolar maternal blood contaminant survey, 1994-1997 organochlorine compounds.

During the past 20 years a number of studies have found neurological and immunological effects in the developing fetus and infants exposed to background or only slightly elevated levels of persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs). To address concerns arising from possible increased human exposure in the Arctic and possible effects of POPs, all circumpolar countries agreed in 1994 to monitoring of specific human tissues for contaminants in the Arctic under the Arctic Monitoring and Assessment Program (AMAP). Mothers in eight circumpolar countries contributed blood samples that were analysed at a single laboratory for 14 PCB congeners (IUPAC No. 28, 52, 99, 105, 118, 128, 138, 153, 156, 170, 180, 183, 187) and 13 organochlorine pesticides (aldrin, beta-hexachlorocyclohexane (beta-HCH), dichlordiphenyltrichloroethane (p,p'-DDT), diphenyldichloroethylene (p,p'-DDE), dieldrin, heptachlorepoxide, hexachlorobenzene (HCB), mirex, and the chlordane derivatives alpha-chlordane, gamma-chlordane, cis-nonachlor, oxychlordane and trans-nonachlor). Inuit mothers from Greenland and Canada have significantly higher levels of oxychlordane, transnonachlor and mirex than mothers from Norway, Sweden, Iceland and Russia. Inuit mothers from Greenland also have significantly higher levels of these contaminants than Inuit mothers from Canada and Alaska. These differences among Inuit groups may represent regional dietary preferences or different contaminant deposition patterns across the Arctic. Levels of PCBs are also elevated among some arctic populations due to their consumption of marine mammals and are in the range where subtle effects on learning and the immune system have been reported. The Russian mothers who consume mainly food imported from southern Russia have elevated levels of DDT, DDE, beta-HCH and a higher proportion of lower chlorinated PCB congeners. This study has allowed an assessment of the variation of contaminants such as PCBs and various organochlorine pesticides (DDT, chlordane, etc.) in human populations around the circumpolar north.

Vitamin D insufficiency in Greenlanders on a westernized fare: ethnic differences in calcitropic hormones between Greenlanders and Danes.

We studied the influence of age, gender, latitude, season, diet and ethnicity on plasma 25-hydroxyvitamin D 25 OHD, PTH, 1,25-dihydroxyvitamin D, vitamin D-binding protein, bone-specific alkaline phosphatase, and osteocalcin levels in 46 Greenlanders living in Nuuk (64 degrees N) on a traditional fare (group A), 45 Greenlanders living in Nuuk on a westernized fare (group B), 54 Greenlanders (group C), and 43 Danes (Group D) living in Denmark (55 degrees N) on a westernized fare. Blood specimens were drawn both summer and winter. Vitamin D insufficiency (plasma 25 OHD <40 nmol/l) was common in all four study groups during summer (23-74%) and winter (42-81%). Compared to groups A and D, vitamin D insufficiency was significantly more frequent in groups B and C. In all groups, summer levels of 25 OHD were above winter levels. Multiple regression analysis revealed a significant effect of ethnicity. Compared to Danes, Greenlanders had higher 1,25-dihydroxyvitamin D levels, but lower 25 OHD and PTH levels despite relatively low plasma calcium concentrations. In addition to ethnicity, 25(OH)D levels were influenced by age, season (summer > winter), and diet (a traditional Inuit diet>westernized diet). Ethnic differences exist between Greenlanders and Danes. Our results suggest that Greenlanders may have an inherent lower "set-point" for calcium-regulated PTH release or an enhanced renal 1,25(OH)(2)D production. In addition to ethnicity, age, season, and diet were important determinants of vitamin D status. Changes from a traditional to a westernized fare are associated with a reduced vitamin D status in Greenlanders. Vitamin D supplementation should be considered.

Ozone exposure decreases the effect of a deep inhalation on forced expiratory flow in normal subjects.

Sixteen healthy nonsmoking subjects (7 women), 21-49 yr old, were exposed in a climate chamber to either clean air or 300 parts/billion ozone on 4 days for 5 h each day. Before each exposure, the subjects had been pretreated with either oxidants (fish oil) or antioxidants (multivitamins). The study design was double-blind crossover with randomized allocation to the exposure regime. Full and partial flow-volume curves were recorded in the morning and before and during a histamine provocation at the end of the day. Nasal cavity volume and inflammatory markers in nasal lavage fluid were also measured. Compared with air, ozone exposure decreased peak expiratory flow, forced expiratory volume in 1 s, and forced vital capacity (FVC), with no significant effect from the pretreatment regimens. Ozone decreased the ratio of maximal to partial flow at 40% FVC by 0.08 +/- 0.03 (mean +/- SE, analysis of variance: P = 0.018) and at 30% FVC by 0.10 +/- 0.05 (P = 0.070). Ozone exposure did not significantly increase bronchial responsiveness, but, after treatment with fish oil, partial flows decreased more than after vitamins during the histamine test, without changing the maximal-to-partial flow ratio. The decreased effect of a deep inhalation after ozone exposure can be explained by changes in airway hysteresis relative to parenchymal hysteresis, due either to ozone-induced airway inflammation or to less deep inspiration after ozone, not significantly influenced by multivitamins or fish oil.

The importance of diet on exposure to and effects of persistent organic pollutants on human health in the Arctic.

AIM: To describe the importance of diet on exposure to and possible health effects of persistent organic pollutants (POPs) in the Arctic. METHODS: The study is based on a literature review. RESULTS: Minor decreases in POPs and minor increases in Hg levels in Arctic populations in Greenland, Eastern Russia, Western Alaska and Eastern Canada are likely to occur by the year 2010 and major decreases in both POPs and Hg levels in these same populations by 2030. Levels of POPs and metals in populations in the Faeroe Islands and the Scandinavian countries are already reasonably low and are only likely to decline marginally by 2030. Estimating the effects on the basis of current knowledge is difficult, but the combination of improved methodology and selection of risk groups will be a progressive step in the process. Any strategies based on traditional food substitution should ensure that the value of the dietary components is sustained. CONCLUSIONS: To improve our understanding of the health effects associated with exposure to contaminants in the Arctic, we recommend that circumpolar epidemiological studies should be implemented on a larger scale. MeHg- and POPs-related effects are still the key issues. However, the role of newly discovered contaminants, such as PBDEs (polybrominated diphenyl ethers) and PCNs (polychlorinated naphthalenes), should be investigated. For exposure assessment, mixtures and nutritional interactions should be considered in epidemiological studies. Epidemiological studies on nutritional benefits of traditional foods should be incorporated in risk-assessment profiles. We need a more nuanced view on human dietary exposure to xenobiotics. Risk should not be evaluated alone, but seen in relation to benefits from specific diets. It is essential that countries ratify and implement multinational environmental agreements.

Twenty-four-hour blood pressure among Greenlanders and Danes: relationship to diet and lifestyle.

BACKGROUND: Greenlanders have a lower rate of cardiovascular mortality and morbidity than Danes, possibly due to lower blood pressure. However, 24-h blood pressure has never been measured in Greenlanders. The aim of this study was to compare the 24-h blood pressure of Greenlanders and Danes, and to analyse the influence of Arctic food and lifestyle on blood pressure. METHODS: Four groups of healthy subjects were recruited for the study. Group I: Danes in Denmark consuming European food; group II: Greenlanders in Denmark consuming European food; group III: Greenlanders in Greenland consuming mainly European food; and group IV: Greenlanders in Greenland consuming mainly traditional Greenlandic food. All subjects underwent a physical examination, laboratory screening of blood and urine samples, and completed a questionnaire on diet, physical activity, smoking status, intake of alcohol, liquorices, vitamins and minerals. Twenty-four-hour blood pressure was measured. RESULTS: It was found that 24-h diastolic blood pressure was lower in Greenlanders than in Danes for the whole 24-h period and during both day and night-time, whereas systolic blood pressure was the same (mean 24-h blood pressure with 95% CI: Danes 123/75 mmHg (120/73-127/77), Greenlanders 122/ 69 (119/68-124/70)). Among Greenlanders, blood pressure increased with age and male gender, and systolic blood pressure increased with body mass index (BMI). No association with diet was found. The difference between the two populations persisted after controlling for age, gender, BMI, outdoor temperature, and lifestyle factors. CONCLUSION: Greenlanders have a lower 24-h diastolic blood pressure than Danes, and it is suggested that genetic factors are mainly responsible for the lower blood pressure level among Greenlanders.

Linker histone function in chromatin: dual mechanisms of action.

Aspects pertaining to linker histone structure and function are discussed, including the extent to which these proteins are essential, their ability to regulate specific gene expression, and recent structural data that provides a potential molecular basis for understanding how linker histones can have both repressive and stimulatory effects on genomic functions in vivo.

Sir3-dependent assembly of supramolecular chromatin structures in vitro.

Baculovirus-expressed recombinant Sir3p (rSir3p) has been purified to near homogeneity, and its binding to naked DNA, mononucleosomes, and nucleosomal arrays has been characterized in vitro. At stoichiometric levels rSir3p interacts with intact nucleosomal arrays, mononucleosomes, and naked DNA, as evidenced by formation of supershifted species on native agarose gels. Proteolytic removal of the core histone tail domains inhibits but does not completely abolish rSir3p binding to nucleosomal arrays. The linker DNA in the supershifted complexes remains freely accessible to restriction endonuclease digestion, suggesting that both the tail domains and nucleosomal DNA contribute to rSir3p--chromatin interactions. Together these data indicate that rSir3p cross-links individual nucleosomal arrays into supramolecular assemblies whose physical properties transcend those of typical 10-nm and 30-nm fibers. Based on these data we hypothesize that Sir3p functions, at least in part, by mediating reorganization of the canonical chromatin fiber into functionally specialized higher order chromosomal domains.

Modulation of atherosclerotic risk factors by seal oil: a preliminary assessment.

We examined whether dietary supplementation with seal oil influenced the risk factors of atherosclerosis in healthy volunteers. Two intervention studies were carried out as preliminary steps in a larger project which aim at elucidating the disease preventive potential of seal oil. In study I ten healthy volunteers added 10 capsules of seal oil to their normal Western diet for six weeks. Blood tests were analysed for total-, HDL-, and LDL-cholesterol and plasma triglyceride, and the ratio of n-6/n-3 fatty acid was determined in plasma and erythrocyte membranes. In study II we examined the effect in five healthy volunteers who had only 5 capsules of seal oil daily for six weeks. As an additional test in study II, the effect on the proinflammatory TNF-alpha cytokine in lymphocytes was determined. A slightly decreased, however, not significant effect was observed for each of the cholesterol's after seal oil supplementation. In both studies plasma triglyceride, and the n-6/n-3 fatty acid ratio of plasma and erythrocytes were significantly reduced upon seal oil intake. During the intervention period of study II a distinct reduced level of TNF-alpha was observed in isolated lymphocytes. The examinations suggest that supplementation of seal oil, 10 capsules or 5 capsules/day, may have beneficial effects on factors thought to be associated with cardiovascular and thrombotic diseases.

Nucleosomes and the chromatin fiber.

During the past year and a half, significant progress has been made in understanding the structure and dynamics of nucleosomes and the chromatin fiber, the mechanism of action of the core histone amino termini, the structure and function of histone variants, and the function of linker histones in the chromatin fiber.

Role of histone acetylation in the assembly and modulation of chromatin structures.

The acetylation of the core histone N-terminal "tail" domains is now recognized as a highly conserved mechanism for regulating chromatin functional states. The following article examines possible roles of acetylation in two critically important cellular processes: replication-coupled nucleosome assembly, and reversible transitions in chromatin higher order structure. After a description of the acetylation of newly synthesized histones, and of the likely acetyltransferases involved, an overview of histone octamer assembly is presented. Our current understanding of the factors thought to assemble chromatin in vivo is then described. Genetic and biochemical investigations of the function the histone tails, and their acetylation, in nucleosome assembly are detailed, followed by an analysis of the importance of histone deacetylation in the maturation of newly replicated chromatin. In the final section the involvement of the histone tail domains in chromatin higher order structures is addressed, along with the role of histone acetylation in chromatin folding. Suggestions for future research are offered in the concluding remarks.

The core histone N termini function independently of linker histones during chromatin condensation.

The relationships between the core histone N termini and linker histones during chromatin assembly and salt-dependent chromatin condensation were investigated using defined chromatin model systems reconstituted from tandemly repeated 5 S rDNA, histone H5, and either native "intact" core histone octamers or "tailless" histone octamers lacking their N-terminal domains. Nuclease digestion and sedimentation studies indicate that H5 binding and the resulting constraint of entering and exiting nucleosomal DNA occur to the same extent in both tailless and intact chromatin arrays. However, despite possessing a normal chromatosomal structure, tailless chromatin arrays can neither condense into extensively folded structures nor cooperatively oligomerize in MgCl(2). Tailless nucleosomal arrays lacking linker histones also are unable to either fold extensively or oligomerize, demonstrating that the core histone N termini perform the same functions during salt-dependent condensation regardless of whether linker histones are components of the array. Our results further indicate that disruption of core histone N termini function in vitro allows a linker histone-containing chromatin fiber to exist in a decondensed state under conditions that normally would promote extensive fiber condensation. These findings have key implications for both the mechanism of chromatin condensation, and the regulation of genomic function by chromatin.

Elements in autopsy liver tissue samples from Greenlandic Inuit and Danes. II. Iron measured by X-ray fluorescence spectrometry.

The purpose of this study was to measure the content of iron (Fe) in liver tissue samples from urbanized Greenlandic Inuit using X-ray fluorescence spectrometry, and compare the results with those obtained in liver tissue samples from urbanized Danes. Normal liver tissue samples were obtained at autopsy from 50 Greenlandic Inuit (27 men, 23 women) with a median age of 61 years (range 23-83) and from 72 Danes (42 men, 30 women) with a median age of 62 years (range 15-87). In the entire series, there was no significant difference between liver iron in Inuit compared with Danes. Likewise, there was no significant gender difference concerning liver iron content, either in Inuit or in Danes. The median iron content (with 5-95 percentile) in Inuit was 17.23 mmol/kg dry liver (5.80-91.80) and in Danes 16.51 mmol/kg dry liver (7.83-39.05). However, when stratified according to age, a trend was revealed showing that Inuit men and women < or = 50 years had a lower liver iron content than Danes (p = 0.05 and p = 0.08) whereas Inuit men and women > 50 years had a higher liver iron content than Danes (p = 0.18 and p = 0.02). There was a significant correlation between liver iron content and age in both Inuit men (rs = 0.49, p = 0.01) and in women (rs = 0.64, p = 0.003), but not in Danes. In Inuit, the median hepatic iron index (liver iron content divided by age) was 0.33 in men and 0.32 in women. The median estimated iron content in the whole liver was 6.54 mmol (365 mg) in Inuit men and 5.41 mmol (302 mg) in Inuit women (p = 0.6). There was no correlation between hepatic iron index and age. In Danes, the median hepatic iron index was 0.46 in men and 0.29 in women (p = 0.01). There was a significant inverse correlation between hepatic iron index and age in the two genders and in the entire series (rs = -0.71, p = 0.0001). The results indicate that young and middle-aged urbanized Inuit have slightly smaller iron stores than urbanized Danes, whereas elderly Inuit have higher iron stores than Danes. In Danes, iron stores plateau at 30 to 40 years of age in men and some years after the menopause in women. In Inuit, iron stores continue to increase in old age, probably to due a lifelong dietary intake of haem iron.

Analytical sedimentation of the IIAChb and IIBChb proteins of the Escherichia coli N,N'-diacetylchitobiose phosphotransferase system. Demonstration of a model phosphotransfer transition state complex.

The phosphoenolpyruvate:glycose transferase system (PTS) is a prototypic signaling system responsible for the vectorial uptake and phosphorylation of carbohydrate substrates. The accompanying papers describe the proteins and product of the Escherichia coli N, N-diacetylchitobiose ((GlcNAc)(2)) PTS-mediated permease. Unlike most PTS transporters, the Chb system is composed of two soluble proteins, IIA(Chb) and IIB(Chb), and one transmembrane receptor (IIC(Chb)). The oligomeric states of PTS permease proteins and phosphoproteins have been difficult to determine. Using analytical ultracentrifugation, both dephospho and phosphorylated IIA(Chb) are shown to exist as stable dimers, whereas IIB(Chb), phospho-IIB(Chb) and the mutant Cys10SerIIB(Chb) are monomers. The mutant protein Cys10SerIIB(Chb) is unable to accept phosphate from phospho-IIA(Chb) but forms a stable higher order complex with phospho-IIA(Chb) (but not with dephospho-IIA(Chb)). The stoichiometry of proteins in the purified complex was determined to be 1:1, indicating that two molecules of Cys10SerIIB(Chb) are associated with one phospho-IIA(Chb) dimer in the complex. The complex appears to be a transition state analogue in the phosphotransfer reaction between the proteins. A model is presented that describes the concerted assembly and disassembly of IIA(Chb)-IIB(Chb) complexes contingent on phosphorylation-dependent conformational changes, especially of IIA(Chb).

The yeast histone acetyltransferase A2 complex, but not free Gcn5p, binds stably to nucleosomal arrays.

We have investigated the structural basis for the differential catalytic function of the yeast Gcn5p-containing histone acetyltransferase (HAT) A2 complex and free recombinant yeast Gcn5p (rGcn5p). HAT A2 is shown to be a unique complex that contains Gcn5p, Ada2p, and Ada3p, but not proteins specific to other related HAT A complexes, e.g. ADA, SAGA. Nevertheless, HAT A2 produces the same unique polyacetylation pattern of nucleosomal substrates reported previously for ADA and SAGA, demonstrating that proteins specific to the ADA and SAGA complexes do not influence the enzymatic activity of Gcn5p within the HAT A2 complex. To investigate the role of substrate interactions in the differential behavior of free and complexed Gcn5p, sucrose density gradient centrifugation was used to characterize the binding of HAT A2 and free rGcn5p to intact and trypsinized nucleosomal arrays, H3/H4 tetramer arrays, and nucleosome core particles. We find that HAT A2 forms stable complexes with all nucleosomal substrates tested. In distinct contrast, rGcn5p does not interact stably with nucleosomal arrays, despite being able to specifically monoacetylate the H3 N terminus of nucleosomal substrates. Our data suggest that the ability of the HAT A2 complex to bind stably to nucleosomal arrays is functionally related to both local and global acetylation by the complexed and free forms of Gcn5p.

High human plasma levels of organochlorine compounds in Greenland. Regional differences and lifestyle effects.

INTRODUCTION: The purpose of the study has been to analyse data, collected for surveillance purposes under the Human Health Programme of AMAP (Arctic Monitoring and Assessment Programme, in Greenland, regarding geographical differences and lifestyle versus pollution load from persistent organic pollutants (POP), and to make possible exposure assessments. It comprises a regional study from six districts and an ongoing study of pregnant women and infants. METHODOLOGY: Biostatistical analyses of data collected in Greenland from 61 men and 10 women from six different districts (1997-98) and from 110 mother-infant pairs in the Disko Bay area (1996-97) and 223 mother-infant pairs (1994-96). The data consisted of questionnaire answers and bloodsamples from men, women, and newborn infants (cord blood) analysed for fatty acids, selenium and 26 POPs including 14 PCB-congeners and four toxaphenes. RESULTS: Strong regional differences were found, related to different intakes of marine food with very high PCB-loads among men from the East coast. The various POP-plasma levels were mutually correlated and strong correlations were found between POP-plasma concentrations in mothers and new-born, R > 0.9, p < 0.0001. Among the pregnant women 95% surpassed the Canadian concern level for PCB, and 60% of the men from Scoresbysund surpassed the action level. The association between reported monthly food frequency and POPs was relatively weak, but the POPs were strongly correlated with plasma and erythrocyte n-3/n-6 fatty acid ratios as biomarkers of marine food intake. Multiple regression analysis showed highly significant positive correlation between smoking, and POP-plasma levels, after correction for age, alcohol intake, marine food, plasma lipids and n-3/n-6 fatty acid ratios. CONCLUSION: As the most important determinants of high POP-plasma levels in Greenlanders we propose: age, high plasma n-3 fatty acids (marine food), East coast region, and being a smoker.