Short-term, high-dose glucocorticoid treatment does not contribute to reduced bone mineral density in patients with multiple sclerosis.

BACKGROUND: Patients with multiple sclerosis (MS) are at increased risk of reduced bone mineral density (BMD). A contributing factor might be treatment with high-dose glucocorticoids (GCs). OBJECTIVES: The objective of this paper is to assess bone mass in patients with MS and evaluate the importance of short-term, high-dose GC treatment and other risk factors that affect BMD in patients with MS. METHODS: A total of 260 patients with MS received short-term high-dose GC treatment and had their BMD measured by dual x-ray absorptiometry. BMD was compared to a healthy age-matched reference population (Z-scores). Data regarding GCs, age, body mass index (BMI), serum 25(OH)D, disease duration and severity were collected retrospectively and analysed in a multiple linear regression analysis to evaluate the association between each risk factor and BMD. RESULTS: Osteopenia was present in 38% and osteoporosis in 7% of the study population. Mean Z-score was significantly below zero, indicating a decreased BMD in our MS patients. Multiple linear regression analysis showed no significant association between GCs and BMD. In contrast, age, BMI and disease severity were independently associated with both lumbar and femoral BMD. CONCLUSION: Reduced BMD was prevalent in patients with MS. GC treatment appears not to be the primary underlying cause of secondary osteoporosis in MS patients.

Cardiovascular outcomes and their relationships to lipoprotein components in patients with and without chronic kidney disease: results from the IDEAL trial.

OBJECTIVES: In Incremental Decrease in Endpoints through Aggressive Lipid-lowering (IDEAL), we compared cardiovascular outcomes in patients with and without chronic kidney disease (CKD) (estimated glomerular filtration rate <60 mL min(-1) 1.73 m(-2)) and analysed relationships between lipoprotein components (LC) and major coronary events (MCE) and other cardiovascular (CV) events. DESIGN: Exploratory analysis of CV endpoints in a randomized trial comparing high dose of atorvastatin to usual dose of simvastatin on MCE. SETTINGS: Patients with CKD were compared with the non-CKD patients. Cox regression models were used to study the relationships between on-treatment levels of LC and incident MCE. FINDINGS: Chronic kidney disease was strongly associated with cardiovascular end-points including total mortality. In patients with CKD, a significant benefit of high dose atorvastatin treatment was found for any CV events, stroke and peripheral artery disease, but not for MCE. However, all cardiovascular end-points except stroke and CV mortality were reduced in the non-CKD group. Differential changes in LC or relationships to LC could not explain the different treatment outcomes in MCE in the two groups. INTERPRETATION: Chronic kidney disease was a powerful risk factor for all cardiovascular end-points. The reason why the significant reductions achieved by high-dose statin treatment in most CV end-points in the non-CKD group were only in part matched by similar reductions in the CKD patients is not apparent. This difference did not result from differential changes in or relations to LC, but limited power may have increased the possibility of chance findings.

Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed dyslipidaemia.

BACKGROUND: Improving lipids beyond low-density lipoprotein cholesterol (LDL-C) lowering with statin monotherapy may further reduce cardiovascular risk. Niacin has complementary lipid-modifying efficacy to statins and cardiovascular benefit, but is underutilised because of flushing, mediated primarily by prostaglandin D(2) (PGD(2)). Laropiprant (LRPT), a PGD(2) receptor (DP1) antagonist that reduces niacin-induced flushing has been combined with extended-release niacin (ERN) into a fixed-dose tablet. METHODS AND RESULTS: Dyslipidaemic patients were randomised to ERN/LRPT 1 g (n = 800), ERN 1 g (n = 543) or placebo (n = 270) for 4 weeks. Doses were doubled (2 tablets/day; i.e. 2 g for active treatments) for 20 weeks. ERN/LRPT 2 g produced significant changes vs. placebo in LDL-C (-18.4%), high-density lipoprotein cholesterol (HDL-C; 20.0%), LDL-C:HDL-C (-31.2%), non-HDL-C (-19.8%), triglycerides (TG; -25.8%), apolipoprotein (Apo) B (-18.8%), Apo A-I (6.9%), total cholesterol (TC; -8.5%), TC:HDL-C (-23.1%) and lipoprotein(a) (-20.8%) across weeks 12-24. ERN/LRPT produced significantly less flushing than ERN during initiation (week 1) and maintenance (weeks 2-24) for all prespecified flushing end-points (incidence, intensity and discontinuation because of flushing). Except for flushing, ERN/LRPT had a safety/tolerability profile comparable with ERN. CONCLUSION: Extended-release niacin/LRPT 2 g produced significant, durable improvements in multiple lipid/lipoprotein parameters. The improved tolerability of ERN/LRPT supports a simplified 1 g-->2 g dosing regimen of niacin, a therapy proven to reduce cardiovascular risk.

Determination of intrathyroidal iodine by X-ray fluorescence analysis in 60- to 65-year olds living in an iodine-sufficient area.

OBJECTIVES: X-ray fluorescence (XRF) is a non-invasive method for determining the iodine content of the thyroid gland in vivo. In spite of the obvious clinical value of such a method in situations of iodine deficiency or iodine overload, the method has not so far been widely used. The objective was to investigate the applicability of the XRF method in a larger number of subjects. DESIGN AND SUBJECTS: The study comprised 37 individuals, aged 60-65 years, who had spent their entire life with iodine supplementation through iodinated table salt. Individuals with (previous) thyroid disease were excluded. The individual thyroid function had previously been evaluated by measurements of thyroid-related hormones, thyroid volume and 131-Iodine (131I) uptake which indicated a sufficient iodine intake of the population in the area. Iodine in the right thyroid lobe in each subject was examined using XRF. RESULTS: The mean thyroid iodine concentration was 0.4 mg mL(-1), corresponding to a mean total iodine content of 5.2 mg (range 0.9-20.2). There was a pronounced difference between individuals. No correlation was found between iodine concentration and 131I uptake or thyroid volume. Neither was iodine content and 131I uptake correlated. CONCLUSIONS: In a population living under iodine-sufficient conditions, a large variation of iodine stored in the thyroid is compatible with euthyroidism. Determination of the iodine pool by XRF investigation is feasible in a clinical setting and the method offers a unique possibility to study the intrathyroidal iodine pool in subjects with thyroid disease. The low radiation dose enables the use of the method in pregnant women and also in young individuals.

Autosomal recessive hypercholesterolaemia: normalization of plasma LDL cholesterol by ezetimibe in combination with statin treatment.

BACKGROUND: Severe hereditary hypercholesterolaemia is most frequently due to familial hypercholesterolaemia (FH), caused by mutations in the LDL receptor (LDLR) gene. However, a phenotype very similar to FH may also be caused by defects in other genes like the genes for apolipoprotein (apo) B-100 or autosomal recessive hypercholesterolaemia (ARH). SUBJECT: An 8-year-old male of Lebanese origin was diagnosed with severe hypercholesterolaemia and extensive cutaneous and tendon xanthomas. Plasma LDL cholesterol before treatment was 17 mmol L(-1), whilst parents and both siblings had normal levels. DIAGNOSIS: Degradation of (125)I-labelled LDL in blood lymphocytes was reduced, but not abolished. Sequencing analysis of the LDLR and apoB-100 genes were negative, whilst a splice acceptor mutation in intron 1 (IVS 1 -1G>C) was detected in the ARH gene. The patient was homozygous for the mutation, whilst the parents were heterozygous. These findings were in agreement with a diagnosis of ARH. TREATMENT AND CLINICAL COURSE: Monthly LDL apheresis and atorvastatin 120 mg daily reduced LDL cholesterol preapheresis level to 4.8 mmol L(-1). When ezetimibe was given 10 mg day(-1) in combination with rosuvastatin 80 mg day(-1), LDL cholesterol was further lowered to 1.6 mmol L(-1), which made apheresis unnecessary. Cutaneous and tendon xanthomas disappeared completely and the intima-media thickness of the common carotid arteries decreased. At age 23 he developed a small myocardial infarction. CONCLUSION: ARH should be considered in cases of severe hypercholesterolaemia with a pattern of recessive inheritance. Combination therapy with high-dose statin and ezetimibe seems to be the treatment of choice in ARH and may reduce or eliminate the need for LDL apheresis treatment.

Molecular cloning of complementary DNA encoding mouse seminal vesicle-secreted protein SVS I and demonstration of homology with copper amine oxidases.

The primary structure of mouse SVS I was determined by peptide sequencing and nucleotide sequencing of cloned cDNA. The precursor molecule consists of 820 amino acid residues, including a signal peptide of 24 residues, and the mature polypeptide chain of 91 kDa has one site for potential N-linked glycosylation. The SVS I is homologous with amiloride-binding protein 1 (ABP1), a diamine oxidase. However, it probably lacks enzymatic activity, because the cDNA codes for His instead of Tyr at the position of the active-site topaquinon. The SVS I monomer probably binds one molecule of copper, because the His residues coordinated by Cu(II) are conserved. The SVS I gene consists of five exons and is situated on mouse chromosome 6,B2.3. It is located in a region of 100 kilobases (kb) containing several genes with homology to SVS I, including the gene of ABP1 and two other proteins with homology to diamine oxidase. The locus is conserved on rat chromosome 4q24, but the homologous region on human chromosome 7q34-q36 solely contains ABP1. The other genes with homology to diamine oxidase were probably present in a progenitor of primates and rodents but were lost in the evolutionary lineage leading to humans-presumably during recombination between chromosomes. The estimated molecular mass of rat SVS I is 102 kDa (excluding glycosylation). The species difference in size of SVS I is caused by tandem repeats of 18 amino acid residues in the central part of the molecule: The mouse has seven repeats, and the rat has 12 repeats.

Are early clinical effects of cholesterol lowering mediated through effects on inflammation?

In a randomized, double-blind trial in 3086 patients with unstable angina pectoris or non-Q wave myocardial infarction we investigated if 80 mg of atorvastatin daily could improve outcome of cardiovascular events during a short period of time (16 weeks) compared with placebo. Baseline LDL cholesterol was 3.2 mmol L-1 (124 mg dL-1) and decreased by 40% to 1.9 mmol L-1 (72 mg dL-1) during atorvastatin treatment. The primary endpoint, which was a composite of death, non-fatal acute myocardial infarction, cardiac arrest with resuscitation or recurrent symptomatic myocardial ischaemia with objective evidence and requiring emergency rehospitalization occurred in 228 patients (14.8%) in the atorvastatin group and 269 patients (17.4%) in the placebo group. The relative risk was 0.84 and 95% confidence interval was 0.70-1.00 (P = 0.048). Thus for patients with acute coronary syndromes, lipid-lowering therapy with high dose atorvastatin reduces recurrent ischaemic events in the short-term. A possible mechanism behind this rapid clinical effect induced by statin treatment is on inflammatory processes. Recent studies strongly suggest that acute T-cell activation is involved in the pathogenesis of unstable angina. In another study we investigated whether circulating T cells showed signs of activation in patients with stable angina pectoris (SA). Systemic venous blood samples were taken from 38 men with SA and 42 healthy controls. The T-cell receptor expression was assessed by three-colour flow cytometry using monoclonal antibodies against CD3,CD4, CD8, CD25 and human leucocyte antigen (HLA)-DR. Soluble interleukin-2 receptor (sIL-2R) was measured as the circulating form in serum. Levels of circulating CD3+ and CD4+ T cells tended to be higher in patients compared with controls. Patients were also shown to have a significant increase in CD4+ T cells expressing the activation markers CD25 (P < 0.05) and HLA-DR (P < 0.01). Furthermore, serum levels of sIL-2R were significantly higher (P < 0.001) in patients than in controls. We also observed that the T-cell response was more pronounced in patients without simvastatin treatment (n = 18) compared with simvastatin-treated patients (n = 20). In conclusion, our findings indicate that a continuous immune system activation takes place in patients with chronic angina pectoris, predominantly involving proliferation of CD4+ T cells. Statin treatment seems to be able to decrease this inflammatory response.

Adipose tissue fatty acids in men from two populations with different cardiovascular risk: the LiVicordia study.

The LiVicordia study was set up to investigate possible causes for coronary heart disease mortality in middle-aged Lithuanian men being four times higher than in Swedish men. In a previous part of this study we found lower total and low density lipoprotein (LDL) cholesterol in the Lithuanian men in spite of them having a higher fat intake than in the Swedish men. Their LDL was also more susceptible to oxidation in vitro than was that of the Swedish men. Fat quality can influence LDL oxidation. In order to obtain data on long-term fat quality intake we measured the fatty acid composition of abdominal wall adipose tissue by gas chromatography in men aged 50 years from Vilnius, Lithuania (n=50) and Linköping, Sweden (n=50). Men from Vilnius had a significantly higher percentage of adipose tissue long chain polyunsaturated fatty acids (PUFA) (20:4n6, 20:5n3, 22:5n5, 22:6n3) and lower percentage of saturated fatty acids, especially myristic acid (14:0), 3.4+/-0.7 versus 4.6+/-0.8, p<0.0001. The percentage content of adipose tissue linoleic acid (18:2n6) was 11.5+/-2.1 versus 11.0+/-1.4 (n.s.) and of linolenic acid (18:3n3) 0.7+/-0.3 versus 0.6+/-0.2 (n.s.) in men from Vilnius and Linköping, respectively. It is concluded that the adipose tissue content of essential fatty acids is similar in men from Vilnius and men from Linköping and therefore the intake is also likely to be similar. The higher contents of long chain highly unsaturated fatty acids in men from Vilnius may be of importance in the oxidation process of LDL.

DNA repair enhancement by a combined supplement of carotenoids, nicotinamide, and zinc.

Four volunteers were involved for 5 weeks of a baseline period, followed by 7 weeks of a combined supplementation of nicotinamide, zinc, and carotenoids (Nicoplex). Blood sampling and bioassays were carried out every week during the evaluation period. The supplementation of Nicoplex resulted in statistically significant increased resistance to DNA single-strand breaks induced by H2O2 (DNA retained on filter % from 46.7 +/- 1.9 to 59.4 +/- 4.3; p < 0.01), increased DNA repair 60 min after induction of damage (DNA retained on filter % from 74.6 +/- 4.8 to 88.3 +/- 4.2; p < 0.01), elevated poly (ADP-ribose) polymerase (PARP) activity (p < 0.05), and an increased proliferative response to phytohemagglutinin (PHA) (p < 0.05) when compared with the levels before supplementation. However, when the same subjects were supplemented with nicotinamide, zinc, and carotenoids together with another 17 nutrients or minerals, there were no changes in DNA damage, DNA repair, or proliferative response to PHA. Through the use of a rat model, DNA repair of splenocytes 3 h after 12 Gy whole-body irradiation was significantly enhanced in rats supplemented with Nicoplex for 6 weeks (p < 0.05) and 8 weeks (p < 0.01). Comparison of Nicoplex and its components administered separately revealed that there was an additive effect on DNA repair for both single- and double-strand breaks (both p < 0.05). On the basis of the results, it is hypothesized that the enhanced effect of combined supplement of nicotinamide, zinc, and carotenoids on DNA repair depends on their diversified mechanisms of action while multinutrient supplementation may compromise the effects by inhibitory interactions including uptake and absorption.

Caring for demented people in their homes or in sheltered accommodation as reflected on by home-care staff during clinical supervision sessions.

This study aimed to illuminate both the content of and the care given to demented people and the reflections of home care staff about it as revealed in two clinical group supervision sessions (n = 36). Verbatim transcriptions were analysed using a phenomenological hermeneutic approach and the following were found to be reflected on: the pensioners' personal situation--disease-related behaviour, ADL-functions, social network and self-esteem; the pensioners' environment--their relationships to significant others, adequate level of housing/care, access to activities, and satisfactory personal space; pensioner/staff interaction--their relations to each other, the staffs' relation to the pensioners' family, and the balance between reality-orientation vs. validation; the staff's situation--co-operation with other professionals, in primary health care, hospital, and within the social services; job satisfaction, lack of knowledge and sharing of knowledge, and lack of resources, especially time. The reasoning of the participants under supervision was found to be based on medical, historical, psychological, and environmental explanations, or personal beliefs. Feelings explored during supervision were directed towards the pensioners or the pensioners' families, towards themselves or towards the management. The findings were interpreted within a nursing model based on the four central concepts of nursing; person, environment, nursing intervention and health. The reasoning about nursing care revealed in the supervision sessions reflected a holistic approach and the relationship between the staff and the demented person stood out as central for care quality. Thus focusing on what promotes or, respectively, obstructs this relationship is likely to be one important focus in clinical supervision not only to achieve improvement and high quality in home care but also to develop and enhance the quality of the working life of the staff. Since the results could be understood within a theoretical nursing care model, it may well be that if the supervisor functions within some theoretical model the participants may reach a more conscious approach and the risk of losing important aspects of caring will decrease.

Plasma homocysteine in women on oral oestrogen-containing contraceptives and in men with oestrogen-treated prostatic carcinoma.

The mechanism by which oral oestrogen-containing contraceptives in women and oestrogen treatment of prostatic carcinoma in men increases the risk of vascular disease is unclear. These agents decrease serum concentrations of vitamin B12, pyridoxal 5-phosphate, and folate, all of which are essential for the metabolism of the atherogenic amino acid homocysteine. We found serum vitamin B12 concentrations to be lower in 17 women using oral contraceptives (219 +/- 84 pmol l-1) than in 13 age-matched female controls (385 +/- 129, p less than 0.001), but similar values were obtained in the two groups both for fasting plasma homocysteine concentrations (9.1 +/- 2.4 vs 9.2 +/- 3.6 mumol l-1) and for the increase in these concentrations after methionine loading (19.2 +/- 7.5 vs 17.8 +/- 5.2 mumol l-1). In five men with prostatic carcinoma, high-dose oestrogen treatment decreased serum vitamin B12 concentrations by a mean of 30% (p less than 0.05) within 4 weeks, during which fasting plasma homocysteine concentrations decreased (13.8 +/- 4.5 vs 10.5 +/- 2.8 mumol l-1) and response to methionine loading increased (12.4 +/- 3.4 vs 17.3 +/- 5.1 mumol l-1), though the latter changes were non-significant. Our findings do not support the hypothesis that hyperhomocysteinemia explains cardiovascular risk in women using oral oestrogen-containing contraceptives, or in oestrogen-treated men with prostatic carcinoma.

Hyperhomocyst(e)inaemia: an independent risk factor for intermittent claudication.

The aim of this study was to test the question of hyperhomocyst(e)inaemia as a risk factor for intermittent claudication (IC) independent of other important risk factors for peripheral atherosclerotic disease, such as smoking, hypertension, diabetes mellitus, hypercholesterolaemia, hypertriglyceridaemia, low levels of high-density-lipoprotein (HLD) cholesterol and age. The study population was recruited from an epidemiological study in Linköping County, Sweden, where all middle-aged men (n = 15,253, 45-69 years of age) were screened for IC. Seventy-eight subjects with verified IC and 98 healthy sex- and age-matched controls were randomly selected. Plasma levels of homocyst(e)ine (including the sum of free and bound forms of homocysteine and their disulphide oxidation products, homocystine, and homocysteine-cysteine mixed disulphide) were significantly higher (16.74 +/- 5.45 mumol l-1, mean value +/- SD, P = 0.0002) in IC subjects than in controls (13.80 +/- 3.21 mumol l-1), with 23% of the claudicants above the 95th percentile for controls. Stepwise logistic regression analysis revealed that the difference in plasma homocyst(e)ine was independent of the other above-mentioned risk factors. Moreover, the elevation of plasma homocyst(e)ine in claudicants was mainly confined to subjects with serum folate levels of less than or equal to 11.0 nmol l-1. The results suggest that folic acid supplementation should be tried in IC subjects with hyperhomocyst(e)inaemia.

Effect of fish oil treatment on plasma lipoproteins in type III hyperlipoproteinaemia.

Nine patients with type III hyperlipoproteinaemia and homozygosity for the apolipoprotein E2 isoform were treated with 15 g daily of MaxEPA, a fish oil preparation rich in eicosapentaenoic acid (2.7 g daily) and docosahexaenoic acid (1.8 g daily) for 16 weeks. Plasma lipoprotein and apolipoprotein concentrations were compared with those obtained during treatment with an olive oil preparation. MaxEPA treatment decreased plasma median total cholesterol, triglyceride and apolipoprotein B concentrations by 16, 53 and 19%, respectively. Plasma median very low density lipoprotein (VLDL)-cholesterol, triglyceride and apolipoprotein B concentrations were reduced by 45, 62 and 75% respectively, while the abnormal VLDL-cholesterol/triglyceride ratio remained unchanged. Individual reductions of VLDL concentrations varied considerably, for VLDL-cholesterol between 10 and 75%. In the majority of cases the abnormal late pre beta-bands on agarose electrophoresis, typical for type III hyperlipoproteinaemia normalized to pre beta-mobility on MaxEPA treatment. LDL-cholesterol and apolipoprotein B tended to increase after 8 weeks on MaxEPA but decreased again after 16 weeks. Median plasma high density lipoprotein cholesterol and apolipoprotein A-I did not change during MaxEPA treatment. It is concluded that MaxEPA have decreasing effects on plasma VLDL lipid and apolipoprotein concentrations in apolipoprotein E2 homozygous type III hyperlipoproteinaemia but that this effect is variable and unpredictable.

Effects of terbutaline and isoproterenol on hyperkalemia in nephrectomized rabbits.

Terbutaline, an adrenergic beta2-receptor-stimulating substance, resembled isoproterenol in its hypokalemic effect on rabbits made hyperkalemic by nephrectomy three days prior to the experiments. Both agents lowered the serum potassium values. The duration of the terbutaline effect was longer and had less influence on the cardiovascular system than had isoproterenol.