Journal of Internal Medicine

Published by Wiley
Online ISSN: 1365-2796
Print ISSN: 0954-6820
Publications
Sarcoidosis is a heterogeneous disorder with a strong genetic influence. Genetic factors are also thought to influence disease severity and outcome. We sought to determine whether polymorphisms within CCR2 gene predispose to Löfgren's syndrome--a clinically and genetically distinct sarcoidosis phenotype--and, importantly, whether this association is independent of the known association with the HLA-DRB1*0301 allele. We investigated 5 CCR2 variants and HLA-DRB1*0301 by sequence-specific primer (SSP) polymerase chain reaction (PCR) in 176 Spanish (76 Löfgren's syndrome, 100 controls) and 387 Swedish subjects (126 Löfgren's syndrome, 77 non-Löfgren sarcoidosis, 184 controls). One of the deduced haplotypes (CCR2 haplotype 2) was associated with Löfgren's syndrome in both Spanish (OR: 2.03, uncorrected P = 0.02; permuted P = 0.041 vs. controls) and Swedish patients (OR: 3.02, uncorrected P = 0.0007; permuted P = 0.0027 vs. non-Löfgren sarcoidosis; OR: 2.46, uncorrected P = 0.0005; permuted P = 0.0031 vs. controls). HLA-DRB1*0301 allele frequency was also increased in Spanish (OR: 3.52, P = 0.0004 vs. controls) and Swedish patients with Löfgren's syndrome (OR: 10.98, P < 0.0001 vs. non-Löfgren sarcoidosis, OR: 7.71, P < 0.0001 vs. controls). Finally, multivariate analysis revealed that the CCR2 association was independent of HLA-DRB1*0301 in both Spanish (P = 0.02 vs. controls) and Swedish cohorts (P = 0.002 vs. non-Löfgren sarcoidosis, P = 0.001 vs. controls). This study confirms that CCR2 haplotype 2 and HLA-DRB1*0301 are independent genetic risk factors for Löfgren's syndrome.
 
The association between HLA class II alleles and susceptibility to sarcoidosis is well documented. Further, the HLA-DRB1 15 and DQB1 0602 haplotype has been considered as a marker for both chronic and severe disease. Splenomegaly has been proposed as a marker for severity and activity in sarcoidosis, although its functional mechanism is unknown. In other diseases, HLA class II alleles can be markers for splenomegaly. We therefore set out to test the hypothesis that the primary DRB1 15-DQB1 0602 link in sarcoidosis would be to splenomegaly. We performed abdominal ultrasonography to evaluate the prevalence and extent of splenomegaly and genotyped for HLA-DRB1 and DQB1 using allele or allele group specific primers in polymerase-chain-reaction on 138 Japanese sarcoidosis patients as case comparison study. Furthermore, we explored their relationship with other clinically important indices, e.g. chest radiograph stage, serum angiotensin-converting enzyme (ACE) concentration and duration of disease. Splenomegaly was detected in 37 (26.8%) sarcoidosis patients. DQB1 0602 showed associations with splenomegaly (P < 0.0001) and longer disease duration (P = 0.007). In addition, higher chest radiograph staging was associated with both DQB1 0602 (P = 0.02) and splenomegaly (P = 0.003). The presence of splenomegaly was associated with higher serum ACE concentration (P < 0.0001). We conclude that in the Japanese population the primary association of HLA class II DQB1 0602 is with splenomegaly. This allele is also a marker for chronicity and lung disease severity. On the other hand, the presence of splenomegaly is a marker for severity and activity. Further studies are needed to explore the relationship between splenomegaly and sarcoidosis in other ethnic groups and its association with HLA-DQB1 0602.
 
The spontaneous seasonal variations in the calcium regulating hormones 1,25-dihydroxy-cholecalciferol (1,25-DHCC) and parathyroid hormone (PTH) were investigated in patients with sarcoidosis. Controlled, prospective observational study with measurements in the winter and summer seasons, respectively. Twelve patients (age: median 33, range 21-54 years) with biopsy-verified (n = 8) sarcoidosis were included as well as 11 age-matched healthy control subjects. Serum values of calcium, ionized calcium, phosphate, chloride, bicarbonate, creatinine, albumin, angiotensin-converting enzyme, alkaline phosphatase, 1,25-DHCC, and PTH. Also, 24-h whole body retention of 99mTc methylene-diphosphonate was assessed. The patient group showed an increased level of 1,25-DHCC in the summer season (w:146 +/- 67, s:198 +/- 73 pmol L-1; P < 0.01) in contrast to the opposite finding among controls (w:161 +/- 34, s:144 +/- 43 pmol L-1; P < 0.05). Comparing the individual seasonal changes between the two groups, the difference was marked (P < 0.001). Compared with controls, total serum calcium was elevated in the summer season in the patient group (P < 0.05), in which the same parameter correlated positively with 1,25-DHCC (r = 0.658; P < 0.01). PTH was increased two to three times above the control values throughout the year (patients: w:0.37 +/- 0.13, s:0.24 +/- 0.08 micrograms L-1; controls: w:0.14 +/- 0.09, s:0.10 +/- 0.04 micrograms L-1; P < 0.001); although, the level of this hormone was still found within the reference interval. 24-h whole body bone scintigraphy failed to show any seasonal variation in bone metabolism. In contrast, serum alkaline phosphatase was found to be increased during the summer season compared with the control group (P < 0.001). Angiotensin-converting enzyme showed no seasonal variation. In sarcoidosis, 1,25-DHCC is abnormally regulated throughout the year, with a significantly higher serum level in the summer season. Uncontrolled production of 1,25-DHCC in sarcoid pulmonary alveolary macrophages is possibly responsible for hypercalcaemic episodes, and this parameter should be used as a marker of disease activity.
 
Previous studies have suggested a link between circulating levels of 25-hydroxyvitamin D (25-D) and dyslipidaemias. However, it is not known whether 25-D and the active hormone 1,25-dihydroxyvitamin D (1,25-D) have similar associations with dyslipidaemias. Therefore, we studied the associations between both 25-D and 1,25-D and total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides in a population-based study. Cross-sectional population-based study. Kuopio, Eastern Finland. A total of 909 men, aged from 45 to 70 years, who were not receiving antidiabetic medication were enrolled. Fasting serum samples were obtained for measurement of 25-D, 1,25-D and lipid levels. An oral glucose tolerance test was performed, and insulin sensitivity was evaluated using the Matsuda insulin sensitivity index (Matsuda ISI). We found a significant inverse association between 25-D and total-C, LDL-C and triglycerides (β = -0.15, -0.13 and -0.17, respectively, P < 0.001), but no association between 25-D and HDL-C was observed. By contrast, 1,25-D was associated with HDL-C (β = 0.18, P < 0.001), whereas no relationship was found between 1,25-D and LDL-C or triglycerides. The associations remained significant after the exclusion of subjects receiving statin treatment and after adjustment for age, waist circumference, body mass index, alcohol consumption, smoking, renal function, glucose tolerance and Matsuda ISI. Low levels of active vitamin D (1,25-D) are associated with low HDL-C levels, whereas low levels of the storage form 25-D are associated with high levels of total-C, LDL-C and triglycerides. Our findings may provide new insights into the understanding of the link between vitamin D deficiency and cardiovascular disease.
 
We report a case of a female patient with sarcoidosis who presented with a generalized lymphadenopathy and a strong IgG serological test of toxoplasmosis. Progressive lymphadenopathy with a rising plasma calcium (up to 15 mg dL-1) with a normal plasma 1,25-dihydroxy vitamin D concentration occurred later. Corticosteroid therapy resulted in prompt clinical and biochemical responses with normalization of plasma calcium and a significant reduction in 1,25-dihydroxy vitamin D concentration. This is an exceptional presentation of sarcoidosis with severe hypercalcaemia and normal vitamin D metabolites.
 
Vitamin D, estimated glomerular filtration rate (eGFR) and parathyroid hormone (PTH) are related to cardiovascular disease risk. We examined the associations between the levels of 25-hydroxyvitamin D (25-D) and 1,25-dihydroxyvitamin D (1,25-D) and both eGFR and PTH. Cross-sectional population-based study in Kuopio, Eastern Finland. A total of 909 men without known chronic kidney disease (CKD) and not receiving antidiabetic medication, aged from 45 to 73 years, were included in the study. Main outcome measures. Fasting levels of 25-D, 1,25-D, creatinine and PTH were measured, and an oral glucose tolerance test (OGTT) was performed. High levels of 25-D were associated with low levels of eGFR and PTH (β = -0.17, P = 9 × 10(-7) and β = -0.28, P = 6 × 10(-17) , respectively, adjusted for age, body mass index and levels of calcium, phosphorus and glucose in a 2-h OGTT, and also for either eGFR or PTH). By contrast, high 1,25-D levels were associated with high levels of eGFR and PTH (β = 0.17, P = 2 × 10(-6) and β = 0.19, P = 5 × 10(-8) , respectively, adjusted as mentioned earlier and additionally for 25-D). Eighteen per cent of men in the highest 25-D quartile were in the lowest 1,25-D quartile and also had a lower eGFR than men with high levels of both 25-D and 1,25-D (P = 4 × 10(-5) ). Finally, 15% of men in the lowest 25-D quartile were in the highest 1,25-D quartile and also had higher PTH levels than men with low levels of both 25-D and 1,25-D (P = 2 × 10(-3) ). Our findings suggest that both eGFR and PTH are significantly associated with vitamin D metabolism in men without known CKD.
 
To find out whether insulin-like growth factor-I (IGF-I) mimics the stimulatory effects of growth hormone (GH) on bone turnover and renal tubular phosphate reabsorption. Randomized, crossover study. University Hospital, Zürich, Switzerland. Seven young healthy male subjects. Each subject was studied three times at 2-week intervals, treated with saline 0.9% (S), IGF-I [8 micrograms kg-1 h-1] by a continuous subcutaneous infusion and finally with GH (6 U. twice daily s.c.) for 5 days. 36 h after the start of treatment, IGF-I, biochemical markers of bone turnover, calcium, calcium regulating hormones, kidney function and phosphate reabsorption were measured in serum and in 2 h urine in fasting state. Serum levels of IGF-I were 26.8 +/- 7.3 (S), 119.4 +/- 11.4 (IGF-I) (P < 0.02) and 58.4 +/- 12.9 nmol L-1 (GH) (P < 0.02), respectively. Serum osteocalcin and carboxyterminal propeptide of type I collagen (PICP) as well as the urinary deoxypyridinoline/creatinine and the calcium/ creatinine ratios were all significantly higher after IGF-I (P < 0.02) or GH (P < 0.02) than after saline treatment. PTH levels did not change in response to treatment. Total albumin-corrected calcium increased only after GH treatment (P < 0.05). The free calcitriol index rose from 2.2 +/- 0.5 x 10(-5) (S) to 2.81 +/- 0.25 x 10(-5) (IGF-I) (P < 0.03) and 2.45 +/- 0.25 x 10(-5) (GH), respectively. Serum phosphate and maximal tubular reabsorption divided by glomerular filtration rate (TmP/GFR) were significantly raised by GH (P < 0.03) but not by IGF-I as compared to saline 0.9%. (i) Similar to GH, IGF-I rapidly activates bone turnover. (ii) IGF-I does not mimic the effect of GH on renal phosphate reabsorption in spite of comparable effects on renal blood flow and glomerular filtration rate. (iii) IGF-I increases free calcitriol index in face of unchanged serum levels of calcium, phosphate and PTH, consistent with a direct stimulatory effect on 25-OHD-1a-hydroxylase.
 
(i) To examine the effect of alphacalcidol [1 alpha(OH)D3] given as an oral dose twice weekly in combination with CaCO3 and low-calcium dialysis (1.25 mmol L-1) on the secondary hyperparathyroidism in continuous ambulatory peritoneal dialysis (CAPD). (ii) To examine the changes in peritoneal mass transfer for calcium, phosphorus, magnesium, lactate, creatinine, urea, glucose, pH and albumin after shift to low-calcium dialysis solution. An open study in patients on CAPD. Renal division, Rigshospitalet, Copenhagen. Thirty-nine patients were included and completed 12 weeks of treatment. Thirty of the patients completed 52 weeks of treatment. A peritoneal equilibrium test (PET) was performed in seven patients. Following two sets of blood samples obtained as basal values the calcium concentration was reduced in the dialysis fluid from 1.75 mmol L-1 to 1.25 mmol L-1. Increasing doses of oral 1 alpha(OH)D3 were then administered under careful control of p-ionized calcium (p-Ca2+) and p-inorganic phosphate (p-P1). Blood samples were obtained every 2-4 weeks for 52 weeks. PET was performed using standard dialysis fluid and 1 week later using low-calcium dialysis fluid after a preceding overnight dwell. Two litres of glucose 22.7 mg mL-1 were used. Intact parathyroid hormone (PTH), p-Ca2+, p-P1, doses of CaCO3, doses of 1 alpha(OH)D3, peritoneal mass transfer for calcium, inorganic phosphate, magnesium, lactate, creatinine, urea, glucose and albumin. Thirty nine patients with initial PTH values 144 +/- 26 pg mL-1 were followed for 12 weeks and 30 patients for 52 weeks. A negative calcium balance was induced after shifting to low-calcium dialysis fluid. After 2 weeks of treatment a significant increase of PTH by approximately 60% and a small but significant decrease of p-Ca2+ was observed. After 12 weeks of treatment with increasing doses of 1 alpha(OH)D3 and CaCO3, PTH was again reduced to levels not significantly different from the initial values. After 52 weeks of treatment no deterioration of the secondary hyperparathyroidism was seen. A calcium concentration of 1.25 mmol L-1 in the CAPD dialysate made it possible to reduce the amount of aluminium-containing phosphate binder, to increase the doses of CaCO3 and to use pulse oral 1 alpha(OH)D3 without causing severe hyper-calcaemia in the patients. After a short elevation of PTH, the PTH levels remained at normal or near normal levels and the long-term results clearly demonstrated that an aggravation of the secondary hyperparathyroidism could be inhibited.
 
Abstract Husted SE, Kraemmer Nielsen H, Krusell LR, Faergeman O (Department of Internal Medicine and Cardiology, Åarhus Amtssygehus, University Hospital, Åarhus, Denmark). Acetylsalicylic acid 100 mg and 1000 mg daily in acute myocardial infarction suspects: a placebo-controlled trial. Of 1078 patients admitted to the coronary care unit with acute chest pain, 293 who had possible acute myocardial infarction and symptoms of median 4 h duration were randomized to treatment with acetylsalicylic acid (ASA) 100 mg daily, 1000 mg daily or placebo for 3 months. During hospitalization, the combined incidence of cardiac death and non-fatal myocardial infarction on-treatment (withdrawals not included) was significantly lower (P < 0.02) in the 100 mg group (7.1%) than in both the 1000 mg group (20.8%) and the placebo group (19.7%). During later time periods of treatment and at all time periods analysed according to the intention-to-treat principle (withdrawals included), data suggested the same trend, but differences were not statistically significant. Collagen-induced platelet aggregation and serum thromboxane B2 were reduced to the same degree in the two ASA groups and were normal in the placebo group. The data suggest that low-dose ASA could be cheap and safe as first-aid therapy in myocardial infarction suspects.
 
One thousand and ten patient years of oral anticoagulant therapy with vitamin-K-antagonists were reviewed with regard to major bleeding complications. The incidence of bleeding that necessitated hospital admission was 2.7% per year (95% confidence limits, 1.7-3.7%). The major source of bleeding was the alimentary tract, whereas no cases of intracranial bleeding were found. Various factors with potential effects on the bleeding risk were evaluated by multivariate statistical analysis, and the following independent risk factors were identified: age greater than 75 years and hypertension increased the bleeding risk by 10.5% and 4.5%, respectively. Each recorded prothrombin value significantly below the therapeutic range increased the bleeding risk by 3.9%, and each year of treatment increased the risk by 2.0%. These figures may be used to estimate the risk of major bleeding in an individual patient. Current treatment with thiazide diuretics was found to increase the bleeding risk by 5.2%. However, this observation requires further documentation and analysis. Although no lethal episodes of bleeding occurred, the developing field of indications for oral anticoagulant therapy should be considered on the basis of a continuous substantial risk of major bleeding.
 
Baggiolini M (Theodor Kocher Institute, University of Bern, and Institute for Research in Biomedicine, Bellinzona, Switzerland). Chemokines in pathology and medicine (Review). J Intern Med 2001; 250: 91–104. About 50 human chemokines and nearly 20 receptors have been identified and characterized in little more than a decade since the discovery of interleukin 8 (IL-8), the first chemotactic cytokine. Research in this field has dramatically changed our understanding of leucocyte traffic in inflammation and immunity. This paper has been written for scientists and practitioners in the field of medicine. It reviews in concise and intelligible form information that I consider useful for understanding the role of chemokines in human pathophysiology. The main areas covered are: (i) the basics of chemokine structures, mode of action, activities and selectivity; (ii) newer aspects of the broad involvement of chemokines in the regulation of immune defence and the housekeeping of the immune system; (iii) the role of chemokines in pathology as illustrated by animal models and studies of human diseases; and (iv) novel therapeutic approaches for a variety of inflammatory conditions, which are based on modulation of chemokine activity.
 
Mechanical ventilation (MV) is imperative in many forms of acute respiratory failure (ARF). The aim of this work was to review all episodes of MV in a Medical Intensive Care Unit (MICU) during the 11-year period 1976-1986. Four per cent (n = 1008) of 24,899 admissions to the MICU were treated with MV. The mean age of ventilator-treated patients was 53 +/- 18 years, and obviously it increased during the period of study. The average duration of MV was 4.7 d. MICU mortality, hospital mortality and 2-year mortality rates for patients subjected to MV were 33%, 38% and 46%, respectively. The mortality rate did not change during the study period. Cerebrovascular and malignant diseases carried the highest mortality rates, 75 and 79%, respectively, whereas mortality in patients ventilated because of drug overdose (n = 313) was only 2%. The results of this study confirm previously published findings concerning the outcome of MV, and we conclude that the effects of MV remain discouraging in medical and neurological patients. Improved quality of ventilator therapy and monitoring, as well as continued research directed at the causes of ARF, are equally important in reducing the mortality in ARF.
 
The Danish Committee on Adverse Drug Reactions received 1100 reports of suspected drug-induced hepatic injury during the decade 1978-1987. The causal relationship between drug and hepatic injury was classified as definite in 57 (5.2%) reports, probable in 989 (89.9%) reports, possible in 50 (4.5%) reports and unclassifiable in four (0.4%) reports. Hepatic injuries accounted for 5.9% of all adverse drug reactions reported, and 14.7% of the lethal adverse drug reactions. A total of 47.2% were classified as acute cytotoxic, 16.2% as acute cholestatic and 26.9% as abnormal hepatic function. In 52 (4.7%) cases the hepatic injury was lethal; only 14 (1.3%) cases were chronic. Halothane accounted for 25% of the cases. The incidence of halothane-induced hepatic injury is decreasing, and only one lethal case has been reported since 1981. Next to halothane, sulfasalazine was the drug most often suspected during the last 2 years of the decade. Based on consumption data, the incidence of hepatic injury due to sulindac was estimated to be 18-fold higher than that due to ibuprofen. Paracetamol was reported to induce acute cytotoxic as well as cholestatic reactions in non-alcoholic subjects taking therapeutic doses.
 
Life-table analysis based on the survival statistics of 118 Hungarian patients with systemic sclerosis suggests that the presence of skin hypo- and/or hyperpigmentation indicates a poor prognosis. Furthermore, truncal skin involvement, lung, cardiac, and renal manifestations, older age at the onset of disease, anaemia, hand deformity, and elevated erythrocyte sedimentation rate values, predict an unfavourable prognosis, whilst patients with exposure to chemicals shows a relatively favourable disease outcome.
 
Long QT syndrome (Romano-Ward syndrome) and insulin-dependent diabetes mellitus (IDDM) have been documented as being linked with gene(s) on chromosome 11p although concurrence of the two disorders has not been reported. Our case is a 13-year-old boy with Romano-Ward syndrome accompanied by IDDM. The long QT syndrome seemed to be transmitted in an autosomal-dominant mode because the Q-T intervals of his father and paternal grandfather were longer than normal. There was no family member with an abnormally high level of blood glucose except the patient. The human leucocyte antigen (HLA) haplotypes of the patient and the father were DR4/DR9 and DR2/DR9, respectively. This study suggests that in our patient IDDM, as well as Romano-Ward syndrome, is linked with chromosome 11p in the presence of HLA-DR4. The results support the previous study that chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility.
 
Oncogenesis of tumours related to multiple endocrine neoplasia type 1 (MEN1) is associated with somatic deletions involving the MEN1 locus at chromosomal region 11q13, suggesting inactivation of a tumour-suppressor gene in this region. Here we describe the localization of the MEN1 gene to a 900-kb region, based on linkage analysis in affected families and deletion mapping of MEN1-associated tumours. In addition, a set of microsatellite markers mapped to the 11q11-13 region were used for linkage analysis in a large Tasmanian MEN1 pedigree, demonstrating the usefulness of these markers for presymptomatic testing in affected families.
 
MCA, CA 15-3, CEA and CA 125 were determined in the serum of 49 patients with metastatic breast cancer and 38 patients with metastatic adenocarcinoma of other primary sites. By using the 99th percentile of the normal value distribution as the cut-off point, the positive predictive value (PV+) was found to be 85% (95% CI 76-94) for MCA, and 71% (95% CI 61-81) for CA 15-3. When receiver-operating-characteristic (ROC) curves were constructed, the PV+ for CA 15-3 was increased to 82% (95% CI 72-92), using 60 U ml-1 as the cut-off point. With the exception of two patients who had a slightly elevated MCA, MCA and CA 15-3 identified the same patients with breast cancer. By combining a positive MCA or CA 15-3 with a negative CEA and CA 125, further improvement of the PV+ could be achieved; 100% (95% CI 91-100). We conclude that MCA and CA 15-3 may play a useful role in discrimination between patients with metastatic breast cancer and those with adenocarcinoma of other primary sites.
 
The objective of the current study was to examine the potential impact of a C right arrow G substitution at position -1291 of the alpha2A-adrenergic receptor gene (ADRA2A) promoter on obesity and estimates of insulin, glucose, and lipid metabolism as well as circulating hormones, including salivary cortisol in 284 unrelated Swedish men born in 1944. The subjects were genotyped by using PCR amplification of the promoter region of the ADRA2A gene followed by digestion with the restriction enzyme MspI. The frequencies were 0.23 for allele C and 0.77 for allele G. The observed genotype frequencies were 45.8 and 54.2% for C/G and G/G, respectively. Heterozygotes (n=121) had significantly (P=0.009) higher salivary cortisol levels after 0.5 mg dexamethasone compared with G/G homozygotes (n=143). Fasting glucose was found to be significantly (P=0.017) higher in heterozygotes than in G/G homozygotes. The latter group had also a borderline significantly (P=0.080) higher mean diastolic blood pressure. These results were all adjusted for the potential confounding effect of body mass index (BMI) and waist-to-hip ratio (WHR). Other measurements such as BMI, WHR, abdominal sagittal diameter, total testosterone, insulin-like growth factor I, serum leptin, fasting insulin and serum lipids were not different across the ADRA2A genotype groups. In conclusion, we have shown that an C --> G polymorphism at position -1291 of the ADRA2A gene is associated with a subnormal cortisol response to dexamethasone, elevated glucose levels and perhaps increased diastolic blood pressure. The pathophysiology could involve an altered density of the alpha2A-AR that destabilizes the sympathetic-hypothalamic-pituitary-adrenal systems in those with genetic vulnerability in the alpha2A-adrenergic receptor gene promoter.
 
Summary estimates for the association between body mass index categories and high job strain. Model 1: adjusted for sex and age; model 2: additionally adjusted for socio-economic status (n = 161 746).
Characteristics of participants in 13 European cohort studies
Evidence of an association between job strain and obesity is inconsistent, mostly limited to small-scale studies, and does not distinguish between categories of underweight or obesity subclasses. To examine the association between job strain and body mass index (BMI) in a large adult population. We performed a pooled cross-sectional analysis based on individual-level data from 13 European studies resulting in a total of 161 746 participants (49% men, mean age, 43.7 years). Longitudinal analysis with a median follow-up of 4 years was possible for four cohort studies (n = 42 222). A total of 86 429 participants were of normal weight (BMI 18.5-24.9 kg m(-2) ), 2149 were underweight (BMI < 18.5 kg m(-2) ), 56 572 overweight (BMI 25.0-29.9 kg m(-2) ) and 13 523 class I (BMI 30-34.9 kg m(-2) ) and 3073 classes II/III (BMI ≥ 35 kg m(-2) ) obese. In addition, 27 010 (17%) participants reported job strain. In cross-sectional analyses, we found increased odds of job strain amongst underweight [odds ratio 1.12, 95% confidence interval (CI) 1.00-1.25], obese class I (odds ratio 1.07, 95% CI 1.02-1.12) and obese classes II/III participants (odds ratio 1.14, 95% CI 1.01-1.28) as compared with participants of normal weight. In longitudinal analysis, both weight gain and weight loss were related to the onset of job strain during follow-up. In an analysis of European data, we found both weight gain and weight loss to be associated with the onset of job strain, consistent with a 'U'-shaped cross-sectional association between job strain and BMI. These associations were relatively modest; therefore, it is unlikely that intervention to reduce job strain would be effective in combating obesity at a population level.
 
To investigate the effects of caloric restriction on the serum concentrations of retinoids in man. Samples were drawn before and during caloric restriction by fasting or 4-6 weeks after gastric surgery. The fasting group included 17 healthy subjects (11 women and six men) and 16 obese patients (10 women and six men) who underwent bariatric surgery (vertical banded gastroplasty). Serum concentrations of all-trans, 13-cis, 4-oxo-13-cis retinoic acids and retinol. The serum concentrations of retinol, all-trans and 13-cis retinoic acids decreased by about 20% after 5 days of fasting. After gastroplasty, the serum concentration of retinol, all-trans, 13-cis retinoic acids, retinol-binding protein and transthyretin also decreased to a similar extent after 1 month. In both groups we found a correlation between the delta values of 13-cis retinoic acid and its metabolite 4-oxo-13-cis retinoic acid. In all subjects there were also correlations between the delta values of the retinoids. However, these correlations were comparatively weak (e.g. r2 = 0.36 for retinol--all-trans retinoic acid). The change in retinoid concentrations did not correlate to the change of weight or body mass index. Our results support the hypothesis that serum retinol is one of the determinants of serum concentrations of all-trans and 13-cis retinoic acid and that the catabolism of 13-cis retinoic acid is not affected by fasting. However, in the individual case, S-Retinol is a poor predictor of S-All-trans retinoic acid.
 
To evaluate the proportion of cardiovascular disease (CVD) incidence that is explained by genetic variation at chromosome 9p21 and to test whether such variation adds incremental information with regard to CVD prediction, beyond traditional risk factors. rs4977574 on chromosome 9p21 was genotyped in 24 777 subjects from the Malmö Diet and Cancer study who were free from CVD prior to the baseline examination. Association between genotype and incident CVD (n = 2668) during a median follow-up of 11.7 years was evaluated in multivariate Cox proportional hazard models. Analyses were performed in quartiles of baseline age, and linear trends in effect size across age groups were estimated in logistic regression models. In additive models, chromosome 9p21 significantly predicted CVD in the entire population (hazard ratio 1.17 per G allele, 95% confidence interval 1.11–1.23, P < 0.001). Effect estimates increased from the highest (Q4) to the lowest quartile (Q1) of baseline age, but this trend was not significant. The overall population attributable risk conferred by chromosome 9p21 in fully adjusted models was 13%, ranging from 17% in Q1 to 11% in Q4. Addition of chromosome 9p21 to traditional risk factors only marginally improved predictive accuracy. The high population attributable risk conferred by chromosome 9p21 suggests that future interventions interfering with downstream mechanisms of the genetic variation may affect CVD incidence over a broad range of ages. However, variation of chromosome 9p21 alone does not add clinically meaningful information in terms of CVD prediction beyond traditional risk factors at any age.
 
To evaluate whether there is an association between calcium intake in adolescent girls and bone mineral density (BMD). Also, the relationships between BMD, various anthropometric factors and grip strength were evaluated. Cross-sectional comparison of BMD, calcium intake and grip strength in 13 and 15 year age groups, randomly selected. Ten secondary elementary schools in the Reykjavik area. One hundred and ninety-seven Icelandic Caucasian girls aged 13 and 15. One hundred and seventy participated and 162 completed the study. Single photon absorptiometry was used to measure BMD and bone mineral content (BMC) in both forearms. Consumption of milk and dairy products was assessed using a food frequency questionnaire. Height and weight were measured and grip strength was determined with a hand-held dynamometer. Calcium intake was found to be significantly correlated to BMD in the older group after adjustment for menarcheal age and weight (r = 0.24; P < 0.05). Division into three subgroups yielded a significantly greater coefficient of correlation between calcium intake and BMD in the lowest calcium consumption group (r = 0.44; P < 0.05). No association was found in the younger age group. Significant positive correlations between grip strength and regional bone mineral density accounted for up to 16.8% of the variation in BMD (P < 0.001) and 38.4% of the variation in BMC. This study is consistent with the hypothesis that a threshold effect of calcium intake on BMD might exist. Above this threshold (1000-1200 mg) no further effect on BMD was seen. The results show a strong association between grip strength, a measure representative of total body strength, and BMD.
 
Abstract Höjer J, Baehrendtz S, Gustafsson L (Department of Internal Medicine, Southern Hospital, and Department of Clinical Pharmacology, Huddinge Hospital, Karolinska Institute, Stockholm, Sweden). Benzodiazepine poisoning: experience of 702 admissions to an intensive care unit during a 14-year period. A retrospective study covering a 14-year period was carried out to estimate the incidence and assess the clinical features of benzodiazepine (BZD) poisoning. The annual contribution of BZDs to the total number of drug overdose cases admitted to an intensive care unit displayed an increasing trend over the period, and during the last years BZDs were involved in nearly one-third of all cases. Among the 702 cases of BZD overdosage, 144 had ingested BZD alone, 200 had poisoned themselves with BZD combined with alcohol and 358 had taken BZD with other miscellaneous drugs. In 56% of all the cases the patients had severe central nervous system depression on admission. In 47% orotracheal intubation was performed and in 18% artificial ventilation was administered. Complications were recorded in 69 of the 702 cases (9.8%) and five cases were fatal. These clinical features were essentially the same in the group that had overdosed with just BZD. In conclusion, patients with drug overdosage involving BZD have a low hospital mortality, but the acute somatic risk is not negligible. Moreover, they consume a substantial proportion of the resources in the emergency room and the intensive care unit.
 
We evaluated mortality from cardiovascular disease (CVD), coronary heart disease (CHD) and all causes in relation to use of any hormone therapy (HT) and HT with oestradiol and norethisterone or levonorgestrel. Population-based cohort study. Women in three Norwegian counties were invited to a health survey in 1985-88 and 82.8% participated. In all 14 324 post- or perimenopausal women aged 35-62 years, including 702 HT users with a mean age of 48.8 years, were followed for 14 years. Women using HT had mortality from all causes and CVD comparable with that of nonusers. The relative risk (RRs) for CVD mortality amongst all women were 0.69 (95% CI: 0.35-1.33) for users of HT, and 0.96 (95% CI: 0.43-2.17) for users of HT with norethisterone or levonorgestrel. Amongst women free of self-reported cardiovascular health problems at baseline all-cause, CVD and CHD mortality tended to be lower amongst users of HT whilst HT use was linked with increased mortality amongst women with cardiovascular health problems. In this cohort of women around the usual age of menopause all-cause or CVD mortality amongst users of HT, most often oestradiol combined with norethisterone or levonorgestrel, was not markedly different from that of nonusers. Early CHD events amongst HT users prior to the baseline survey, together with selective inclusion of healthy subjects, may in part explain protective effects of HT on CHD reported from previous observational studies.
 
In 4929 consecutive autopsies performed during a period of 4 years, 222 cases (4.5%) of cirrhosis were found, of which 149 (3%) were detected while the patients were alive (diagnosed cirrhosis) and 73 (1.5%) were not detected while the patients were living (undiagnosed cirrhosis). Fifty-three of the 73 undiagnosed patients appeared to be completely without signs of cirrhosis (silent cirrhosis). In the diagnosed group, 70% of patients died from hepatic causes, in contrast to 16% in the undiagnosed group. At autopsy, the following complications of cirrhosis were found more frequently in the diagnosed group than in the undiagnosed group: ascites (41% vs. 8%), oesophageal varices (44% vs. 10%), splenomegaly (52% vs. 29%). The prevalence of hepatocellular carcinoma did not differ significantly in the two groups (12% vs. 8%). It is concluded that cirrhosis without obvious signs occurs relatively frequently, and that no sensitive non-invasive screening methods are available at present.
 
The history of the Journal of Internal Medicine starts in 1863 when Medicinskt Archiv was published as the first journal dedicated to medical sciences in Sweden. The most important person in planning and initiating the journal was Axel Key, Professor of Pathological Anatomy at Karolinska Institutet. Key was the chairman, Editor-in-Chief and a devoted promoter of the journal from the beginning in 1863 until his death in 1901. This article is protected by copyright. All rights reserved.
 
Microvessels and neurons respond rapidly and simultaneously in focal regions of ischaemic injury in such a way as to suggest that the responses could be coordinated. The ability of neurons to modulate cerebral blood flow in regions of activation results from neurovascular coupling. But little is known about the microvessel-to-neuron direction of the relationship. The presence and participation of intervening glial cells implies the association of microvessels, glia, and neurons in a 'neurovascular unit'. The interdependent functions of the cellular and matrix components of this theoretical unit have not been rigorously explored, except under conditions of injury where, for the most part, only single components or tissue samples have been studied. Whereas maintenance or timely re-establishment of flow reduces tissue and neuron injury in both humans and animal models, protection of neuron function in humans has not prevented the evolution of injury despite the inherent mechanisms of neurovascular coupling. However, occlusion of flow to the brain rapidly identifies regions of neuron-vascular vulnerability within the vascular territory-at-risk. These coalesce to become the mature ischaemic lesion. The failure, so far, of clinical trials of neuron protectant agents to achieve detectable tissue salvage could be explained by the vulnerability (and lack of protection) of essential components of the 'unit'. This presentation summarizes evidence and thoughts on this topic. These support the need to understand component interactions within the neurovascular unit.
 
In a representative sample of Danish school children (124 boys and 169 girls), 16-19 years of age, blood pressure, blood lipids, body fat content, maximal aerobic power, alcohol consumption and smoking habits were studied. No systematic variation was noticed within this age in the risk factor profile. The mean values for blood pressure (BP) (systolic/diastolic) were 125/73 mmHg for the boys and 117/71 mmHg for the girls. As much as 14% of the boys and 5% of the girls had either a systolic BP above 140 mmHg or a diastolic BP above 90 mmHg. Total serum cholesterol averaged 4.13 mmol l-1 for the boys and 4.53 mmol l-1 for the girls, which is also high compared with adolescents from other countries. The ratios for high density lipoprotein cholesterol to total serum cholesterol were normal and in the range of 0.25-0.28 for both sexes. Other factors associated with coronary heart disease in adults, such as body fat content, serum triglycerides, physical activity, as well as smoking and alcohol habits were similar to that reported for teenagers in other countries. No correlation was found between aerobic power (ml min-1.kg-1) and the risk factors measured.
 
To assess the efficacy of synovectomy in reducing recurrent haemarthroses and joint pain in patients suffering from haemophilic arthropathy. Moreover, to study whether synovectomy could improve joint mobility or postpone progression of joint destruction. A retrospective study was conducted addressing joint-related symptoms and findings, and the need of orthopaedic surgery during follow-up. Oslo Sanitetsforenings Rheumatism Hospital/The National Hospital, the National Centre for Orthopaedic Surgery for approximately 180 Norwegians suffering from severe congenital coagulation deficiencies. Twelve patients with haemophilia A, two patients with von Willebrand's disease and two patients with factor VII deficiency in which 21 synovectomies (nine knees, six ankles and six elbows) were performed. Joint pain, joint mobility, frequency of haemarthroses and radiographic joint scores at follow-up were compared to preoperative figures, and the number of joints in need of total joint replacement or arthrodesis was evaluated. Synovectomy proved efficacious in reducing recurrent haemarthroses and joint pain in all patients. The total range of motion was not improved, but correction of extension deficiency of the knee was accomplished. The progression of arthropathy was not arrested by synovectomy as judged by the radiographic assessment; and in four patients arthroplasty of the knee, and in two patients arthrodesis of the ankle, had been performed. A major wound haemorrhage and subsequent wound rupture was seen in one patient who developed high-titred neutralizing antibodies to factor VIII. Synovectomy for haemophilic arthropathy is safe and efficacious in reducing recurrent haemarthroses and joint pain. Synovectomy should not be performed to improve joint mobility. The progression of the arthropathy is not arrested, and subsequently many patients will be candidates for arthroplasty or arthrodesis.
 
Hypovitaminosis D has been shown to be associated with low bone mineral density in middle-aged and elderly women. The aim of this study was to evaluate whether such an association might exist in adolescent and young adult girls, approaching peak bone mass. Cross-sectional study carried out in late winter. Reykjavik area at latitude 64 degrees N. Two-hundred and fifty-nine Icelandic Caucasian girls, aged 16, 18 and 20 years, randomly selected from the registry of Reykjavik. Bone mineral density in lumbar spine, hip, distal forearm and total skeleton was measured with dual-energy X-ray absorptiometry (DEXA) and compared with 25-hydroxyvitamin D levels [25 (OH)D] in serum, measured by radioimmunoassay. Calcium and vitamin-D intake were also assessed by a questionnaire. 18.5% of the girls were below 25 nmol L-1 in serum 25 (OH)D which has been recognized as the lower normal limit for adults. No significant association was found between 25 (OH)D levels and bone mineral density. Normal calcium and phosphate concentrations in plasma and normal bone mineral density are maintained in adolescent and young adult girls at lower 25 (OH)D levels than published 'normal' levels for middle-aged and elderly.
 
The aim of the study was to quantify the inter-relationship between bone mineral density and physical activity, muscle strength, and body mass composition in a group of healthy 16-20-year-old women. A cross-sectional study. Reykjavik area. Two-hundred and fifty-four Icelandic Caucasian women aged 16, 18 and 20 years, randomly selected from the registry of Reykjavik. Bone mineral content (BMC) and density (BMD) in lumbar spine, hip, distal forearm and total skeleton and lean mass and fat mass were measured with dual energy X-ray absorptiometry (DEXA) and compared with grip strength measured with a dynamometer and physical activity as assessed by a questionnaire. The lean mass had the strongest correlation with BMC and BMD, stronger than weight, height and fat mass, both in univariate analysis (r = 0.41-0.77; P<0.001) and in linear regression analysis. The total skeletal BMD was logarithmically higher by hours of exercise per week (P<0.001)). About 30% of variability in total skeletal BMD in this age group can be predicted by lean mass and physical exercise. Modifiable factors, such as exercise and adequate muscle seem to be significant predictors of the attainment of peak bone mass in women.
 
Although many studies have described prognosis in patients with coronary heart disease (CHD), few have compared outcome in men with clinical evidence of CHD with healthy men from the general population over an extended follow-up. This study aimed to compare long-term prognosis in men with a history of myocardial infarction (MI) and in men with angina pectoris (AP) without MI, with men without clinical signs of CHD. Longitudinal general population study. City of Göteborg, Sweden. From a general population sample, 195 men who had survived an MI for 0-19 years (median 3 years) and 314 men with AP but no MI (uncomplicated AP) at baseline in 1974-77 were identified and compared with 6591 men without clinical coronary disease. All were aged 51-59 years. Incident non-fatal and fatal cases occurring until the beginning of 1983 were also followed (n = 317). Death from CHD, from other causes and from all causes during a follow-up of at least 16 years. Overall survival was 72% amongst men without coronary disease, 53% amongst men with uncomplicated AP and 34% amongst men with past MI at baseline. In survivors of MI the risk-factor-adjusted relative risk (RR) of coronary death during follow-up was 6.67 (95% confidence interval (CI) 5.29-8.39), of dying from non-cardiovascular causes 1.35 (0.96-1.91), and of dying from any cause 3.20 (2.67-3.83). During the first 4 years after the baseline examination, the adjusted RR of CHD death was 15.96 (10. 29-24.74), and of dying from any cause 5.22 (3.68-7.41). During the last 4 years of follow-up, relative risk was still 5.87 (3.44-10.01) for CHD death and 2.93 (2.05-4.18) for death from any cause. In men with uncomplicated AP, the adjusted relative risk of CHD death during the first 4 years was 4.05 (2.27-7.22) and 3.23 (2.10-4.96) during the last 4-year period. After the first year, the incident MI cases had the same average annual mortality (about 5%) as the prevalent cases. In survivors of MI, mortality risk remained high even after an extended follow-up. Men with angina had a better prognosis, but still a compromised survival compared with the general population.
 
Matrix metalloproteinase-3 (MMP-3) is implicated in the formation of atherosclerotic plaques, and the MMP-3 -1612 5A/6A polymorphism is associated with myocardial infarction (MI) and stable coronary artery disease (CAD). The present study examined whether the -1612 5A/6A polymorphism in the promoter region of the MMP-3 gene influences serum concentrations of MMP-3 and whether serum concentrations of MMP-3 are related to extent of coronary atherosclerosis and risk of MI. This case-control study was conducted in three hospitals in the northern part of Stockholm. A total of 755 MI patients aged below 60 were screened, 433 entered and 387 completed the study. Three hundred and eighty-seven sex- and age-matched control subjects were recruited from the general population of the same county. The MMP-3 genotype was determined by Pyrosequencing(TM) and the serum MMP-3 concentration was quantified with an immunoassay. Severity and extension of CAD was assessed by quantitative coronary angiography in a subgroup of patients (n=243). Patients had lower serum MMP-3 concentration than controls. There was a strong association between MMP-3 -1612 5A/6A genotype and serum concentrations of MMP-3. The presence of one or two copies of the 6A-allele was associated with a graded increase in serum MMP-3. In female patients there was an inverse correlation (r=-0.39, P<0.05) between serum MMP-3 concentration and plaque area. Conclusion. In conclusion, the serum concentration of MMP-3 is influenced by MMP-3 -1612 5A/6A genotype and associated with MI.
 
Mitochondrial dysfunction is heavily implicated in the ageing process. Increasing age in mammals correlates with accumulation of somatic mitochondrial DNA (mtDNA) mutations and decline in respiratory chain function. The age-associated respiratory chain deficiency is typically unevenly distributed and affects only a subset of cells in various human tissues, such as heart, skeletal muscle, colonic crypts and neurons. Studies of mtDNA mutator mice has shown that increased levels of somatic mtDNA mutations directly can cause a variety of ageing phenotypes, such as osteoporosis, hair loss, greying of the hair, weight reduction and decreased fertility. Respiratory-chain-deficient cells are apoptosis prone and increased cell loss is therefore likely an important consequence of age-associated mitochondrial dysfunction. There is a tendency to automatically link mitochondrial dysfunction to increased generation of reactive oxygen species (ROS), however, the experimental support for this concept is rather weak. In fact, respiratory-chain-deficient mice with tissue-specific mtDNA depletion or massive increase of point mutations in mtDNA typically have minor or no increase of oxidative stress. Mitochondrial dysfunction is clearly involved in the human ageing process, but its relative importance for mammalian ageing remains to be established.
 
The Copenhagen Male Study is a prospective, cardiovascular cohort study initiated in 1970 and consisting of 5249 employed men aged 40-59 years. A total of 4710 men, who had reported their smoking habits and were free of ischaemic heart disease, had their mortality recorded over a 17-year period: 585 men suffered a first incident of ischaemic heart disease (IHD), and 248 cases were fatal. There was a strong social gradient in the risk of IHD (Kendall's Tau B = 0.12, P less than 0.001). Adjusting for age, blood pressure, physical activity, body mass index and alcohol consumption in a multiple logistic regression equation, men in the lowest social class had a relative risk (95% confidence interval) of IHD of 3.6 (2.5-5.3) compared to men in the highest social class. We determined whether differences in smoking habits could explain at least some of this large increase in risk. Adjustment for the above factors and also inclusion of the form of tobacco smoked, the amount of tobacco smoked and presence or absence of inhalation, had very little effect on the estimate: the relative risk was 3.5 (2.4-5.2). There was no social gradient in age at the start of smoking. According to smoking habits, comparing social class V with social class I, the relative risk was 7.7 (2.6-22.4) in cigarette smokers, 6.0 (1.1-32.1) in pipe smokers, 3.5 (1.7-7.1) in mixed smokers, 2.25 (0.4-12.9) in cheroot smokers, 3.8 (2.4-5.9) in all smokers, 1.95 (0.8-4.6) in ex-smokers, and 4.7 (1.01-22.2) in non-smokers. In the upper social classes, 50-75% of IHD events could be ascribed to smoking, and in the lowest classes only about 20%. We conclude that the substantial social inequalities in risk of ischaemic heart disease are not accounted for by differences in smoking habits.
 
The prevalence of thyroid disease in Swedish schoolchildren is today insufficiently known. The aim of the study was therefore to determine the prevalence of abnormal thyroid function and thyroid autoimmunity in teen-age schoolchildren and to compare the findings with a healthy control group of 60-65-year-old inhabitants from the same community. A semirural community of approximately 15,000 inhabitants. Cross-sectional study. Thyroid volume and serum concentrations of serum thyrotropin (TSH), total and free thyroxine (T4), total and free 3,5,3'-triiodothyronine (T3), and antithyroperoxidase antibodies (TPOAb). Four schoolchildren (7%, 59 screened) had elevated TPOAb concentration, three of the subjects being girls (8%). One girl with a goitre was overtly hypothyroid and one girl showed borderline-high serum TSH concentration suggesting subclinical autoimmune thyroid disease. One euthyroid boy had a goitre and high concentration of TPOAb. The serum free T3 concentration was significantly higher in 15-17-year-old than 60-65-year-old (7.4 vs. 6.4 pmol L(-1), P < 0.001). The concentrations of other thyroid hormones and of TSH in 15-17-year-old did not differ from those of the 60-65-year-old. We found three cases of thyroid disease in need of immediate attention or later follow-up. The prevalence of autoimmune thyroid disease was high as indicated from TPOAb measurements. Thyroid tests including TPOAb measurement should be performed on wide indications when teenagers seek medical advice. The reference intervals for teen-age children for commonly used first line tests (TSH and free T4) do not differ from those for adults.
 
The main aim of this study was to estimate the independent risk for coronary heart disease (CHD) death associated with non-insulin dependent (Type 2) diabetes (NIDDM) and effect on life expectancy. The Reykjavik Study is a prospective cardiovascular population study which started in 1967. A randomized selection procedure identified individuals for invitation to participate, based on their year and date of birth. Participants were examined in the years 1967-91 in one research clinic in Reykjavik. The population in this survey were Icelandic Caucasian males and females, born 1907-35 and therefore 34-79 years old when their examination was performed. Altogether 9139 males and 9773 females attended, and of those 267 males and 210 female were NIDDM as defined by a questionnaire or an oral glucose tolerance test. Other factors measured in the study included systolic and diastolic blood pressure, fasting total cholesterol, triglycerides, uric acid, smoking habits, height, and weight. The causes of death were determined by a review of all death certificates. Results. The relative risk of death from CHD (95% confidence limits), independently associated with NIDDM, was 2.0 (1.5-2.6) for males and 2.4 (1.6-3.6) for females. The relative risk of death from all causes was 1.9 (1.6-2.3) and 1.7 (1.3-2.1), respectively, for male and female diabetic patients. Non-insulin dependent diabetes mellitus carried twice the risk of CHD death in both sexes, independently of other risk factors. The diagnosis of NIDDM at the age 55 years reduced an individual's life expectancy by about five years, mostly because of increased CHD death rate.
 
Physical fitness and leisure time physical activity are strongly correlated, and both are inversely correlated with risk of ischaemic heart disease. Does this mean, however, that a very fit man has a lower risk of ischaemic heart disease (IHD), even if he is inactive? And does it also mean that an unfit, but active man, does not have a lower risk of IHD than an unfit, inactive man? In the Copenhagen Male Study, we analysed the joint effect of fitness and leisure time activity. In 1970/71, 4999 men aged 40-59 years, were classified according to level of physical fitness, i.e. indirectly measured maximal oxygen uptake, and physical activity, and their mortality was recorded over the following 17 years. In sedentary men, fitness was no predictor of future risk of IHD whatsoever. Age-adjusted baseline values were similar in later IHD cases and survivors (32.3 and 32.1 ml O2 kg-1 min-1, respectively: P = 0.91). In medium or highly active men, however, fitness was a strong predictor. The corresponding fitness values were 33.1 and 34.8 ml O2 kg-1 min-1 (P < 0.001). The least fit (two least fit quintiles) physically active men had a lower IHD mortality rate (6%) than the least fit sedentary men (10%). Adjusted for age, social class and smoking in a multiple logistic regression equation, this was estimated to an RR (95% C.I.) of 1.67 (1.06-2.64) (P = 0.027). The two major new findings of this study were (a) that being very fit, provides no protection against IHD--nor all-cause mortality--in sedentary men, and (b) that unfit but sedentary men have a higher risk of IHD than unfit but active men, i.e. those performing light physical activity for at least 4 h per week.
 
The purpose of the study was to evaluate the effect of transdermal 17 beta-oestradiol with oral progestogen on the plasma levels of lipids, lipoproteins and apolipoproteins in hypercholesterolaemic postmenopausal women. During 6 months of replacement therapy with transdermal 17 beta-oestradiol combined with oral progestogen, plasma lipids, lipoproteins and apolipoproteins after 3 and 6 months were measured and compared with pretreatment values by Student's t-test. From January 1992 until September 1992 patients were diagnosed and treated in an out-patient clinic of the Department of Endocrinology Medical Centre for Postgraduate Education, Warsaw. The patients studied were 11 non-obese postmenopausal women with hypercholesterolaemia based on the World Health Organization criteria. Venous blood samples were obtained before and 3 and 6 months after the beginning of cyclic replacement therapy with transdermal 17 beta-oestradiol (E2 100 micrograms day-1 combined with oral chlormadinone acetate (2 mg day-1 for 7 days in each cycle). The antiatherogenic effect of transdermal oestrogen replacement therapy exerted by increased levels of high-density lipoprotein subfraction 2 cholesterol (HDL2-C) leading to the decrease of the total cholesterol level was anticipated. After 6 months of the treatment the concentrations of HDL2 cholesterol (HDL2-C) increased from 0.45 +/- 0.07 mmol l-1 to 0.73 +/- 0.03 mol l-1 (P < 0.05) but the levels of HDL3 cholesterol (HDL3-C) decreased from 1.15 +/- 0.06 mmol l-1 to 0.89 +/- 0.07 mmol l-1 (P < 0.05). The concentrations of total cholesterol decreased from 6.9 +/- 0.13 mmol l-1 to 6.2 +/- 0.2 mmol l-1 (P < 0.05). No changes were observed in the plasma levels of total triglycerides, HDL cholesterol, low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL) cholesterol, VLDL triglycerides, apolipoproteins A-I and B. In hypercholesterolaemic postmenopausal women, transdermally administered 17 beta-oestradiol 100 micrograms daily in combination with oral chlormadinone acetate has a beneficial effect through raising the level of the antiatherogenic HDL2-C subfraction and decreasing the level of total cholesterol.
 
Although the precise aetiology of inflammatory bowel disease (IBD) remains unclear, recent discoveries have led to an improved understanding of disease pathogenesis. Whilst these findings have underscored the central role of innate and adaptive immune responses in intestinal inflammation, they have also precipitated a paradigm shift in the key cytokine pathways that drive disease. The prevailing dogma that IBD was mediated by interleukin (IL)-12-driven T-helper (Th)1 CD4 T cell responses towards the bacterial flora has been largely dispelled by findings that the closely related cytokine IL-23 appears to be the key mediator of intestinal inflammation. IL-23 is associated with a novel subset of IL-17-secreting CD4 T cells termed Th17 cells and rodent studies have implicated the IL-23/IL-17 axis in autoimmune inflammation. Genome-wide association studies in IBD patients have confirmed the predominant role of the IL-23 pathway, indicating that this could represent an important future therapeutic target.
 
To test the relationship between physical activity and physical fitness, and the relationship between these variables and the primordial risk factor blood pressure (BP). A cross-sectional study of all Danish pupils in the same grade at 'gymnasium' (the Danish upper secondary school). Tests and questionnaires were administered by physical education and biology teachers according to a prescribed scheme. Study subjects were 13810 adolescents with a mean age of 17.1 years. Physical activity, smoking habits, and physical performance were measured in 4862 boys and 6573 girls. Blood pressure was measured in 2474 boys and 3535 girls. No difference was found in BP, physical activity and fitness variables between this group and a representative group of Danish school children at the same age. Blood pressure and health-related physical performance such as strength, muscle endurance, flexibility and maximal oxygen uptake (VO2max) estimated from heart rate at submaximal workload were measured. Sports activity, other physical activity and smoking habits were assessed by questionnaires. There was a negative relationship between BP and VO2max up to the 50% percentile (50 ml min-1 kg-1) in boys and up to the upper 80-90% percentile (45 ml min-1 kg-1) in girls. In a multiple regression model with BP as dependent variable, VO2max related highly significant, also after adjustment for body weight and physical activity (P < 0.001). Other performance variables only explained a small part of the variance in BP. No relationship was found between BP and total physical activity or sports activity. In the adolescent population VO2max related negatively to BP after adjustment for body weight, physical activity, other fitness measures and sex, but physical activity or other fitness measures did not relate. Lower blood pressure was found with higher VO2max until levels of 50 and 45 ml min-1 kg-1 in boys and girls, respectively.
 
To investigate how variation in the dose of the progestogen influence the impact of 17beta-oestradiol plus drospirenone (DRSP) treatment on adipose tissue and its secretor function with direct implications for atherogenic metabolites. Randomized, double-blind, placebo-controlled trial. Primary care, single study site. A total of 240 healthy postmenopausal women 53-65 years old, 178 completer. Daily treatment with 1 mg 17beta-oestradiol plus 1, 2, or 3 mg DRSP, or placebo for 2 years. Absolute changes in central (CFM) and peripheral fat mass (PFM; dual-energy X-ray absorptiometry, DEXA), adipokines [interleukin (IL)-6 and adiponectin], atherogenic metabolites [triglycerides, high-density lipoprotein cholesterol (HDL-C), glucose] and blood pressure. Oestradiol plus 1 mg DRSP evoked significant decreases in CFM and the CFM/PFM ratio from baseline. These benefits virtually decreased with increasing dose of DRSP confounded by dose-dependent increases in CFM and PFM in smokers (P-value for trends <0.001), in whom the increases in bioavailable oestradiol were half of that in nonsmokers (P < 0.001). Treatment with 3 mg DRSP induced decreases in serum adiponectin by month 6 (P < 0.05), which persisted in nonsmokers only and led to significant increases in glucose and triglycerides and decreases in HDL-C (P < 0.05). Adiponectin in smokers normalized by the end of the study parallel with the increases in body fat mass. Interactions of the sex steroids with adipose tissue and its secretor function are important determinants of the overall impact of hormone therapy on cardiovascular risk. A DRSP dose up to 2 mg does not seem to exert adverse effects when combined with 1 mg 17beta-oestradiol.
 
Top-cited authors
Bengt Winblad
  • Karolinska Institutet
Carol Brayne
  • University of Cambridge
Kevin J Tracey
  • The Feinstein Institute for Medical Research
Wiek H van Gilst
  • University of Groningen
Hans Hillege
  • University of Groningen