Sven A. Gustafsson

Estrogen receptor concentrations in 269 cases of histologically classified human breast cancer

This report provides a histological review of 264 female primary breast cancers analyzed for estrogen receptor protein (ER). We also describe 5 cases of male breast cancer all of which bound estradiol specifically. Generally the ER concentrations were lower in the tumors of premenopausal women than in those of postmenopausal women. Three types of cancer with specific morphological features were shown to have ER concentrations that differed significantly from the other types of cancer. Medullary and comedo carcinoma had very low and papillary carcinoma very high levels of ER. No obvious trend in ER concentration was found in unspecified ductal carcinoma, colloid carcinoma, nor in lobular carcinoma. A positive correlation was demonstrated between ER content and degree of differentiation in ductal carcinoma. Cancer with lymphoid infiltration generally showed low ER levels.

Elevated cardiac troponin T in predialysis patients is associated with inflammation and predicts mortality

Abstract.  Löwbeer C, Stenvinkel P, Pecoits‐Filho R, Heimbürger O, Lindholm B, Gustafsson SA, Seeberger A (Karolinska Institutet at Huddinge University Hospital; Capio Diagnostik, St Görans Hospital, Stockholm, Sweden). Elevated cardiac troponin T in predialysis patients is associated with inflammation and predicts mortality. J Intern Med 2003; 253: 153–160.

Depressed adolescents in a case-series were low in vitamin D and depression was ameliorated by vitamin D supplementation

Aim:  The relationship between depression in adolescents and vitamin D was studied in a case‐series that included effects of vitamin D supplementation.

Serum cardiac troponin T in patients hospitalized with heart failure is associated with left ventricular hypertrophy and systolic dysfunction

Background: Cardiac troponin T (cTnT) is a highly sensitive and specific marker of acute myocardial infarction. Serum cTnT is also slightly elevated in patients with severe heart failure and is associated with left ventricular hypertrophy (LVH) in patients treated with haemodialysis. In this study serum cTnT concentrations and echocardiographic findings were investigated in heart failure patients without acute coronary syndrome. cTnT was also compared with other cardiac markers and plasma levels of brain natriuretic peptide (BNP). Methods: Twenty-six patients hospitalized with heart failure were included in the study. Echocardiographic measurements and blood sampling were carried out 12-36 h after admission. Serum cTnT (3rd generation assay), cardiac troponin I (cTnI), creatine kinase MB (CKMB) and CK were measured. Plasma BNP was analysed using the Shionoria assay. LVH was defined as left ventricular mass index (LVMI)>125 g/m<formula>2</formula> for males and>110 g/m<formula>2</formula> for females. Left ventricular systolic function was estimated from the mitral annulus motion (AV-mean LV). Results: Median cTnT was 0.012 (<0.010-0.032) μg/L. Sixty-two percent of the patients (16 of 26) had elevated serum cTnT≥0.010 μg/L. cTnT was positively correlated with CKMB (ρ=0.40, p=0.04) and BNP (ρ=0.43, p=0.03), but not with cTnI and CK. A negative correlation was found between cTnT and AV-mean LV (ρ=−0.58, p=0.007), and there was a positive correlation between cTnT and LVMI (ρ=0.44, p=0.03). No other analyte was correlated to LVMI. Conclusions: Serum cTnT but not cTnI was associated with left ventricular dysfunction and LVH in patients hospitalized with heart failure. This explains why cTnT tends to be slightly elevated in patients with heart failure without symptoms of acute myocardial ischaemia.

Intratumoral variation of cytoplasmic and nuclear estrogen receptor concentrations in human mammary carcinoma

21 mastectomy specimens were investigated none of which had received preoperative radiation chemotherapy or endocrine therapy to determine the cytoplasmic and nuclear estradiol receptor content in different parts of human mammary carcinomas. The study found cytoplasmic-specific estradiol receptor values to vary widely but predictably throughout the tumor with the central areas of the tumor containing the lowest and the peripheral parts the highest levels of receptor. The receptor content varied from 3-fold to 20-fold. Menopausal status was not a factor for the same intratumoral difference was found in pre- or postmenopausal tumors. Intranuclear receptor level however showed a different pattern of variety with its highest levels occurring in the central parts of breast carcinomas. These findings point out the need to collect tissue specimens and assay them in a more standardized way than before.

Efficacy of vitamin D in treating multiple sclerosis-like neuroinflammation depends on developmental stage

The association of vitamin D deficiency with higher prevalence, relapse rate and progression of multiple sclerosis (MS) has stimulated great interest in using vitamin D supplementation as a preventative measure and even a therapy for established MS. However, there is a considerable lack of evidence when it comes to an age/developmental stage-dependent efficacy of vitamin D action and a time-window for the most effective prophylactic treatment remains unclear. We studied the effect of vitamin D supplementation in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), an animal model of MS, at three different developmental stages in rats. Supplementation treatment was initiated: i) prior to gestation and maintained throughout pre- and early postnatal development (gestation and lactation); ii) after weaning, throughout juvenile/adolescence period and iii) in adult age. We observed a marked attenuation of EAE in juvenile/adolescent rats reflected in a less severe CNS inflammation and demyelination, accompanied by a lower amount of IFN-γ producing MOG-specific T cells. Moreover, the cytokine expression pattern in these rats reflected a more anti-inflammatory phenotype of their peripheral immune response. However, the same supplementation regimen failed to improve the disease outcome both in adult rats and in rats treated during pre- and early post-natal development. Our data demonstrate a developmental stage-dependent efficiency of vitamin D to ameliorate neuroinflammation, suggesting that childhood and adolescence should be the target for the most effective preventive treatment.

Oestrogen receptors and peripheral serum levels of oestradiol-17β in patients with mammary carcinoma

Estradiol receptors were determined by isoelectric focusing in cytosol from breast cancer tissue from 12 pre- and 70 postmenopausal patients. 12 pre- and 57 postmenopausal patients were simultaneously assayed for periperal serum levels of estradiol 17 beta. When estradiol 17 beta levels were below 150 pM receptor values ranged from less than .01-7.19 fmole bound tritiated estradiol 17 beta/mcg of deoxyribonucleic acid (DNA). Only low receptor values (< .25 fmole bound tritiated estradiol 17 beta/mcg of DNA) were recorded when estradiol 17 beta levels were above 150 pM. Apparently endogenous estrogen influenced the receptor assay perhaps by a blockade of the hormone binding site. In any case endocrine evaluation performed together with estrogen receptor assay is recommended. These results confirm the tendency to low binding of tritiated estradiol 17 beta at high peripheral estrogen values.

Progestin-receptor analysis in human breast cancer cytosol by isoelectric focusing in slabs of polyacrylamide gel

Abstract A method is described for the analysis of progestin receptor in human breast cancer cytosol by isoelectric focusing in slabs of polyacrylamide gel. The synthetic progestin [ 3 H]-R 5020 was used as a ligand. The progestin receptor focused at pH 6.2 and was separated from non-specifically bound [ 3 H]-R 5020 that focused at pH 5.0–5.4 (contaminating protein from serum). A comparison to sucrose gradient centrifugation showed a good correlation between the two methods. Both the 8 S complex and the 4 S complex seen in tumor cytosols focused at pH 6.2. Limited trypsin digestion resulted in disappearance of the 8 S complex and increase in the 4 S complex seen by sucrose gradient centrifugation. Further proteolysis resulted in the formation of an R 5020-binding complex sedimenting in the 4 S region which was not possible to analyse by isoelectric focusing. The time needed for focusing of the progestin receptor was 1.5h. Conditions were established where only one incubation was needed per receptor analysis reducing the amount of tissue required.

Validation of radioimmunoassay for estradiol-17/3 by isotope dilution-mass spectrometry and by a test of radiochemical purity

Isotope dilution-mass spectrometry (ID-MS) was used as a reference method to determine the concentration of estradiol-17 beta (E2) in five different plasma pools (concentrations ranging from 0.040 to 65 nmol/l). The same plasma pools were also subjected to radioimmunoassay (RIA) using five different antisera of largely varying specificity. With the best antiserum (E), a direct RIA apparently gave accurate results (i.e. results statistically indistinguishable from those obtained by ID-MS) at all levels except the lowest one (0.040 nmol/l). It was shown, however, that the apparent accuracy of this RIA to some extent could be due to a lowering effect of lipids in the serum masking a lack of specificity of the antibodies. With the least specific antiserum (A), accurate results were obtained only after chromatography. However, in the assay of the lowest concentration of E2 with this antiserum there was a significant overestimation, even after chromatography. The other three antisera (B, C, D) of average quality gave accurate results in assays of plasma diethyl ether extracts in various numbers of the plasma pools tested, depending on their intrinsic specificity. This specificity was not correlated with the cross-reaction reported for individual antisera. ID-MS is difficult to use in most laboratories. We demonstrate here that the validity of a RIA may in this case be assessed by a relatively simple method, the test of radiochemical purity (RP-test). This test is based on the measurements of specific activity (e.g. dpm/pg) in small consecutive fractions of the chromatographic zone which is usually employed for the RIA.

Serum 25-Hydroxyvitamin D Concentration in Subclinical Carotid Atherosclerosis

Objective—Vitamin D deficiency has been implicated in cardiovascular disease and is associated with multiple cardiovascular risk factors. We investigated the serum 25-hydroxyvitamin D (25(OH)D) concentration in relation to latitude, baseline carotid intima-media thickness (IMT), and IMT progression, the carotid IMT measures being surrogate markers of subclinical atherosclerosis and cardiovascular disease risk. Approach and Results—Serum 25(OH)D concentration was related to high-resolution carotid IMT measures in 3430 middle-aged and elderly subjects with high cardiovascular risk but no prevalent disease, who were recruited at 7 centers in Finland, Sweden, The Netherlands, France, and Italy. Participants underwent carotid ultrasound examination at baseline and at months 15 and 30 after entry into the study, whereas blood samples, clinical data, and information about lifestyle were collected at baseline. Serum 25(OH)D levels were positively associated with latitude (Jonckheere–Terpstra &khgr;=166.643; P<0.001) and, as previously reported, associated with a range of cardiovascular risk factors. There were no independent relationships between 25(OH)D and segment-specific or composite IMT measures in the entire cohort. In analyses stratified by sex, diabetes mellitus, and statin treatment, weak associations with some baseline and progression measures of carotid IMT were observed in males, diabetics, and nonstatin-treated individuals. Conclusions—Levels of 25(OH)D differed across Europe, were highest in the North, showed multiple associations with established and emerging cardiovascular risk factors but were not consistently, independently related to measures of carotid IMT. This argues against a protective role of vitamin D against subclinical atherosclerosis in high-risk individuals.