The VITATOPS (vitamins to prevent stroke) Trial: Rationale and design of an international, large, simple, randomised trial of homocysteine-lowering multivitamin therapy in patients with recent transient ischaemic attack or stroke

Background: Epidemiological studies suggest that raised plasma concentrations of total homocysteine (tHcy) may be a common, causal and treatable risk factor for atherothromboembolic ischaemic stroke. Although tHcy can be lowered effectively with small doses of folic acid, vitamin B-12 and vitamin B-6, it is not known whether lowering tHcy, by means of multivitamin therapy, can prevent stroke and other major atherothromboembolic vascular events. Purpose: To determine whether vitamin supplements (folic acid 2 mg, B-6 25 Mg, B-12 500 mug) reduce the risk of stroke, and other serious vascular events, in patients with recent stroke or transient ischaemic attacks of the brain or eye (TIA). Methods: An international, multi-centre, randomised, double-blind, placebo-controlled clinical trial. Results: As of November 2001, more than 1,400 patients have been randomised from 10 countries in four continents. Conclusion: VITATOPS aims to recruit and follow up 8,000 patients between 2000 and 2004, and provide a reliable estimate of the safety and effectiveness of dietary supplementation with folic acid, vitamin B-12, and vitamin B-6 in reducing recurrent serious vascular events among a wide range of patients with TIA and stroke. Copyright (C) 2002 S. Karger AG, Basel.

A Randomized Trial of Sodium Fluoride (60 mg) ± Estrogen in Postmenopausal Osteoporotic Vertebral Fractures

Postmenopausal Caucasian women aged less than 80 years (n = 99) with one or more atraumatic vertebral fracture and no hip fractures, were treated by cyclical administration of enteric coated sodium fluoride (NaF) or no NaF for 27 months, with precautions to prevent excessive stimulation of bone turnover. In the first study 65 women, unexposed to estrogen (-E study), age 70.8 +/- 0.8 years (mean SEM) were all treated with calcium (Ca) 1.0-1.2 g daily and ergocalciferol (D) 0.25 mg per 25 kg once weekly and were randomly assigned to cyclical NaF (6 months on. 3 months off, initial dose 60 mg/day; group F CaD, n = 34) or no NaF (group CaD, n = 3 1). In the second study 34 patients. age 65.5 +/- 1.2 years, on hormone replacement therapy (E) at baseline, had this standardized, and were all treated with Ca and D and similarly randomized (FE CaD, n = 17, E CaD, n = 17) (+E study). The patients were stratified according to E status and subsequently assigned randomly to NaF. Seventy-five patients completed the trial. Both groups treated with NaF showed an increase in lumbar spinal density (by DXA) above baseline by 27 months: FE CaD + 16.2% and F CaD +9.3% (both p = 0.0001). In neither group CaD nor E CaD did lumbar spinal density increase. Peripheral bone loss occurred at most sites in the F CaD group at 27 months: tibia/fibula shaft -7.3% (p = 0.005); femoral shaft -7.1% (p = 0.004); distal forearm -4.0% (p = 0.004); total hip -4.1% (p = 0. 003); and femoral neck -3.5% (p = 0.006). No significant loss occurred in group FE CaD. Differences between the two NaF groups were greatest at the total hip at 27 months but were not significant [p < 0.05; in view of the multiple bone mineral density (BMD) sites, an alpha of 0.01 was employed to denote significance in BMD changes throughout this paper]. Using Cox's proportional hazards model, in the -E study there were significantly more patients with first fresh vertebral fractures in those treated with NaF than in those not so treated (RR = 24.2, p = 0.008, 95% CI 2.3-255). Patients developing first fresh fractures in the first 9 months were markedly different between groups: -23% of F CaD, 0 of CaD, 29% of FE CaD and 0 of E CaD. The incidence of incomplete (stress) fractures was similar in the two NaF-treated groups. Complete nonvertebral fractures did not occur in the two +E groups, there were no differences between groups F CaD and CaD. Baseline BMD (spine and femoral neck) was related to incident vertebral fractures in the control groups (no NaF), but not in the two NaF groups. Our results and a literature review indicate that fluoride salts. if used, should be at low dosage, with pretreatment and co-treatment with a bone resorption inhibitor.

A randomized trial comparing hormone replacement therapy (HRT) and HRT plus calcitriol in the treatment of postmenopausal osteoporosis with vertebral fractures: Benefit of the combination on total body and hip density

We report a prospective, randomized, multi-center, open-label 2-year trial of 81 postmenopausal women aged 53-79 years with at least one minimal-trauma vertebral fracture (VF) and low (T-score below 2) lumbar bone mineral density (BMD). Group HRT received piperazine estrone sulfate (PES) 0.625 - 1.25 mg/d +/- medroxyprogesterone acetate (MPA) 2.5 - 5 mg/d,- group HRT/D received HRT plus calcitriol 0.25 mug bd. All with a baseline dietary calcium (Ca) of < I g/d received Ca carbonate 0.6 g nocte. Final data were on 66 - 70 patients. On HRT/D, significant (P < 0.001) BNID increases from baseline by DXA were at total body - head, trochanter, Ward's, total hip, inter-trochanter and femoral shaft (% group mean Delta 4.2, 6.1, 9.3. 3.7. 3.3 and 3.3%, respectively). On HRT, at these significant Deltas were restricted to the trochanter and sites. si Wards. Significant advantages of HRT/D over HRT were in BMD of total body (- head), total hip and trochanter (all P = 0.01). The differences in mean Delta at these sites were 1.3, 2.6 and 3.9%. At the following, both groups Improved significantly -lumbar spine (AP and lateral), forearm shaft and ultradistal tibia/fibula. The weightbearing, site - specific benefits of the combination associated with significant suppression of parathyroid hormone-suggest a beneficial effect on cortical bone. Suppression of bone turnover was significantly greater on HRT/D (serum osteocalcin P = 0.024 and urinary hydroxyproline/creatinine ratio P = 0.035). There was no significant difference in the number of patients who developed fresh VFs during the trial (HRT 8/36, 22%; HRT/D 4/34, 12% - intention to treat); likewise in the number who developed incident nonvertebral fractures. This Is the first study comparing the 2 treatments in a fracture population. The results indicate a significant benefit of calcitriol combined with HRT on total body BMD and on BNID at the hip, the major site of osteoporotic fracture.

Homocysteine-lowering treatment with folic acid, cobalamin, and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction, or hypercoagulability in patients with previous transient ischemic attack or stroke - a randomized substudy

Background and Purpose - Epidemiological and laboratory studies suggest that increasing concentrations of plasma homocysteine ( total homocysteine [tHcy]) accelerate cardiovascular disease by promoting vascular inflammation, endothelial dysfunction, and hypercoagulability. Methods - We conducted a randomized controlled trial in 285 patients with recent transient ischemic attack or stroke to examine the effect of lowering tHcy with folic acid 2 mg, vitamin B-12 0.5 mg, and vitamin B-6 25 mg compared with placebo on laboratory markers of vascular inflammation, endothelial dysfunction, and hypercoagulability. Results - At 6 months after randomization, there was no significant difference in blood concentrations of markers of vascular inflammation (high-sensitivity C-reactive protein [P = 0.32]; soluble CD40L [ P = 0.33]; IL-6 [P = 0.77]), endothelial dysfunction ( vascular cell adhesion molecule-1 [P = 0.27]; intercellular adhesion molecule-1 [P = 0.08]; von Willebrand factor [P = 0.92]), and hypercoagulability (P-selectin [P = 0.33]; prothrombin fragment 1 and 2 [P = 0.81]; D-dimer [P = 0.88]) among patients assigned vitamin therapy compared with placebo despite a 3.7-mumol/L (95% CI, 2.7 to 4.7) reduction in total homocysteine (tHcy). Conclusions - Lowering tHcy by 3.7 mumol/L with folic acid-based multivitamin therapy does not significantly reduce blood concentrations of the biomarkers of inflammation, endothelial dysfunction, or hypercoagulability measured in our study. The possible explanations for our findings are: ( 1) these biomarkers are not sensitive to the effects of lowering tHcy (eg, multiple risk factor interventions may be required); ( 2) elevated tHcy causes cardiovascular disease by mechanisms other than the biomarkers measured; or ( 3) elevated tHcy is a noncausal marker of increased vascular risk.

Changes in inflammatory mediators following eccentric exercise of the elbow flexors

The aims of this study were to examine the plasma concentrations of inflammatory mediators including cytokines induced by a single bout of eccentric exercise and again 4 weeks later by a second bout of eccentric exercise of the same muscle group. Ten untrained male subjects performed two bouts of the eccentric exercise involving the elbow flexors (6 sets of 5 repetitions) separated by four weeks. Changes in muscle soreness, swelling, and function following exercise were compared between the bouts. Blood was sampled before, immediately after, 1 h, 3 h, 6 h, 24 h (1 d), 48 h (2 d), 72 h (3 d), 96 h (4 d) following exercise bout to measure plasma creatine kinase (CK) activity, plasma concentrations of myoglobin (Mb), interleukin (IL)-1 beta, IL-1 receptor antagonist (IL-1ra), IL-4, IL-6, IL-8, IL-10, IL-12p40, tumor necrosis factor (TNF)-alpha, granulocyte colony-stimulating factor (G-CSF), myeloperoxidase (MPO), prostaglandin E-2 (PGE(2)), heat shock protein (HSP) 60 and 70. After the first bout, muscle soreness increased significantly, and there was also significant increase in upper arm circumference; muscle function decreased and plasma CK activity and Mb concentration increased significantly. These changes were significantly smaller after the second bout compared to the first bout, indicating muscle adaptation to the repeated bouts of the eccentric exercise. Despite the evidence of greater muscle damage after the first bout, the changes in cytokines and other inflammatory mediators were quite minor, and considerably smaller than that following endurance exercise. These results suggest that eccentric exercise-induced muscle damage is not associated with the significant release of cytokines into the systemic circulation. After the first bout, plasma G-CSF concentration showed a small but significant increase, whereas TNF-alpha and IL-8 showed significant decreases compared to the pre-exercise values. After the second bout, there was a significant increase in IL-10, and a significant decrease in IL-8. In conclusion, although there was evidence of severe muscle damage after the eccentric exercise, this muscle damage was not accompanied by any large changes in plasma cytokine concentrations. The minor changes in systemic cytokine concentration found in this study might reflect more rapid clearance from the circulation, or a lack of any significant metabolic or oxidative demands during this particular mode of exercise. In relation to the adaptation to the muscle damage, the anti-inflammatory cytokine IL-10 might work as one of the underlying mechanisms of action.

Composition of pecan cultivars Wichita and Western Schley [Carya illinoinensis (Wangenh.) K. Koh] grown in Australia

Pecans from the cultivars Wichita and Western Schley [Carya illinoinensis (Wangenh.) K. Koch] collected over three years were analyzed for the following constituents: total lipid content; fatty acid profiles; sucrose content; protein; total dietary fiber; the minerals magnesium, calcium, potassium, sulfur, phosphorus, boron, copper, iron, manganese, sodium, zinc, and aluminum; vitamin C; and lipase; and lipoxygenase activities. Year of harvest and cultivar had little effect on the composition of the pecans. Overall, protein content was the only constituent that differed between pecans grown in Australia and those grown in the United States. This difference is probably related to differences in growing location and horticultural practices between the two countries.

A field trial of the effect of improved piglet management on smallholder sow productivity in the Philippines

We conducted a randomised, controlled field trial during 1998/1999 to evaluate the hypothesis that improved piglet management would improve the reproductive performance of smallholder sows. Simple changes were introduced into the treatment herds including the construction of a heated piglet-separation pen, vitamin injections, creep feeding and early weaning. The control herds were unchanged. Data were collected from all sows in each enrolled herd over two farrowings. We enrolled 176 sows, including 170 (96 treatment and 74 control) sows that remained throughout the study period. Significant differences in the reproductive performance of treatment and control sows were recorded for interfarrowing interval (median 176 versus 220 days), average number liveborn over 2 litters (11 versus 12), and average preweaning mortality over 2 litters (0 versus 37%). Based on a discount rate of 17%, the benefit-cost ratio of the treatment was 11.1 and 12.1 over 3 and 5 years, respectively. (C) 2001 Elsevier Science B.V. All rights reserved.

Maintaining muscle mass during extended disuse: Aestivating frogs as a model species

Prolonged muscle disuse in vertebrates can lead to a pathological change resulting in muscle wasting and a loss of muscle strength. In this paper, we review muscle disuse atrophy in the vertebrates and examine the factors that influence the magnitude of the atrophic response during extended periods of inactivity, both artificially imposed (e.g. limb immobilisation) and naturally occurring, such as the quiescence associated with dormancy (e.g. hibernation and aestivation). The severity of muscle atrophy is positively correlated with mass-specific metabolic rate, and the metabolic depression that occurs during dormancy would appear to have a protective role, reducing or preventing muscle atrophy despite periods of inactivity lasting 6-9 months. In the light of these findings, the role of reactive oxygen species and antioxidants during muscle disuse is emphasised.

Long-term trends in sunshine duration and its association with schizophrenia birth rates and age at first registration - data from Australia and the Netherlands

Back ground. Based on the well-described excess of schizophrenia births in winter and spring, we hypothesised that individuals with schizophrenia (a) would be more likely to be born during periods of decreased perinatal sunshine, and (b) those born during periods of less sunshine would have an earlier age of first registration. Methods. We undertook an ecological analysis of long-term trends in perinatal sunshine duration and schizophrenia birth rates based on two mental health registers (Queensland. Australia n = 6630; The Netherlands n = 24, 474). For each of the 480 months between 1931 and 1970, the agreement between slopes of the trends in psychosis and long-term sunshine duration series were assessed. Age at first registration was assessed by quartiles of long-term trends in perinatal sunshine duration, Males and females were assessed separately. Results. Both the Dutch and Australian data showed a statistically significant association between falling long-term trends in sunshine duration around the time of birth and rising schizophrenia birth rates for males only. In both the Dutch and Australian data there were significant associations between earlier age of first registration and reduced long-term trends in sunshine duration around the time of birth for both males and females, Conclusions. A measure of long-term trends in perinatal sunshine duration was associated with two epidemiological features of schizophrenia in two separate data sets. Exposures related to sunshine duration warrant further consideration in schizophrenia research. (C) 2002 Elsevier Science B.V. All rights reserved.

Transcriptional regulation of the sodium-sulfate cotransporter NaSi-1 gene

Inorganic sulfate is one of the most abundant anions in mammalian plasma and is essential for proper cell growth and development, as well as detoxification and activation of many biological compounds. To date, little is understood how physiological levels of sulfate are maintained in the body. Our studies, and of others, have identified the NAS(i)-1 protein to be a functional sulfate transporter in the kidney and intestine, and due to this localization, constitutes a strong candidate gene for maintaining body sulfate homeostasis. Several factors, including hormones and metabolic conditions, have been shown to alter NAS(i)-1 mRNA and protein levels in vivo. In this study, we describe the transcriptional regulation of NaSi-1, with a focus on the mouse NaSi-1 gene (Nas1) that was recently cloned in our laboratory. Vitamin D (1,25-(OH)(2)D-3) and thyroid hormone (T-3) led to an increase in Nas1 promoter activity in OK cells. Mutational analysis of the Nas1 promoter resulted in identification of a direct repeat 6-type vitamin-D-responsive element (DR6 VDRE) at -525 to -508 and an imperfect inverted repeat 0-type T-3 responsive element (IRO T3RE) at -426 to -425 which conferred 1,25-(OH)(2)D-3 and T-3 responsiveness respectively. These findings suggest for vitamin D and thyroid hormone regulation of NaSi-1, may provide important clues to the physiological control of sulfate homeostasis.

Diagnosis and management of unusual dental abscesses in children

Although the majority of dental abscesses in children originate from dental caries or trauma, a few are associated with unusual conditions which challenge diagnosis and management. Recent research findings have shed light on these unusual entities and greatly improved understanding of their clinical implications. These conditions include developmental abnormalities such as dens invaginatus in which there is an invagination of dental tissues into the pulp chamber and dens evaginatus in which a tubercle containing pulp is found on the external surface of a tooth crown. In addition, inherited conditions which show abnormal dentine such as dentine dysplasia, dentinogenesis imperfecta, and osteogenesis imperfecta predispose the dentition to abscess formation. Furthermore, 'spontaneous' dental abscesses are frequently encountered in familial hypophosphataemia, also known as vitamin D-resistant rickets, in which there is hypomineralization of dentine and enlargement of the pulp. In addition to developmental conditions, there are also acquired conditions which may cause unusual dental abscesses,. These include pre-eruptive intracoronal resorption which was previously known as 'pre-eruptive caries' or the 'fluoride bomb'. In addition, some undiagnosed infections associated with developing teeth are now thought to be the mandibular infected buccal cysts which originate from infection of the developing dental follicles. In the present paper, these relatively unknown entities Which cause unusual abscesses in children are reviewed with the aim of updating the general practitioner in their diagnosis and management.

Biochemical characterization of two mutants of human pyruvate dehydrogenase, F205L and T231A of the E1 alpha subunit

Mutations in the E1alpha subunit of the pyruvate dehydrogenase multienzyme complex may result in congenital lactic acidosis, but little is known about the consequences of these mutations at the enzymatic level. Here we characterize two mutants (F205L and T231A) of human pyruvate dehydrogenase in vitro, using the enzyme expressed in Escherichia coli. Wild-type and mutant proteins were purified successfully and their kinetic parameters were measured. F205L shows impaired binding of the thiamin diphosphate cofactor, which may explain why patients carrying this mutation respond to high-dose vitamin B-1 therapy. T231A has very low activity and a greatly elevated K-m for pyruvate, and this combination of effects would be expected to result in severe lactic acidosis. The results lead to a better understanding of the consequences of these mutations on the functional and structural properties of the enzyme, which may lead to improved therapies for patients carrying these mutations.

Dietary influences on survival after ovarian cancer

We evaluated the effects of various food groups and micronutrients in the diet on survival among women who originally participated in a population-based case-control study of ovarian cancer conducted across 3 Australian states between 1990 and 1993. This analysis included 609 women with invasive epithelial ovarian cancer, primarily because there was negligible mortality in women with borderline tumors. The women's usual diet was assessed using a validated food frequency questionnaire. Deaths in the cohort were identified using state-based cancer registries and the Australian National Death Index (NDI). Crude 5-year survival probabilities were estimated using the Kaplan-Meier technique, and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained from Cox regression models. After adjusting for important confounding factors, a survival advantage was observed for those who reported higher intake of vegetables in general (HR = 0.75, 95% CI = 0.57-0.99, p-value trend 0.01 for the highest third, compared to the lowest third), and cruciferous vegetables in particular (HR = 0.75, 95% CI = 0.57-0.98, p-value trend 0.03), and among women in the upper third of intake of vitamin E (HR = 0.76, 95% CI = 0.58-1.01, p-value trend 0.04). Inverse associations were also seen with protein (p-value trend 0.09), red meat (p-value trend 0.06) and white meat (p-value trend 0.07), and modest positive trends (maximum 30% excess) with lactose (p-value trend 0.04), calcium and dairy products. Although much remains to be learned about the influence of nutritional factors after a diagnosis of ovarian cancer, our study suggests the possibility that a diet high in vegetable intake may help improve survival. (C) 2003 Wiley-Liss, Inc.