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Biomedical subjects

R Lindsay

Publications and source records attributed to R Lindsay.

At least 91 records · Page 5Linked to original sources
PubMed1996

Selective toxic effects of tamoxifen on osteoclasts: comparison with the effects of oestrogen.

We investigated the actions of the trans- and cis-isomers of tamoxifen on the function of neonatal rat osteoclasts in vitro. Both compounds inhibited resorption pit formation by osteoclast-containing mixed bone cell cultures incubated for 24 h on cortical bone slices. Cell counts revealed that the inhibition was closely related to a cytotoxic effect, to which osteoclasts appeared particularly sensitive. Partial inhibition of resorption was seen in the presence of 2 microM trans-tamoxifen, whereas complete abolition of resorption and osteoclast viability occurred with 10 microM trans-tamoxifen; survival of mononuclear cells was unimpaired at either concentration. Cis-tamoxifen appeared to be slightly more toxic, with significant inhibitions of osteoclast viability and thus resorption pit formation at a concentration of 2 microM, and also of mononuclear cell numbers at 10 microM. Time-lapse video observations indicated that osteoclast death occurred rapidly (within 2-3 h) following exposure to 10 microM of either trans-tamoxifen or cis-tamoxifen. The morphological appearance of the dying cells was consistent with apoptosis. These results may help to explain the anti-resorptive action of tamoxifen seen in vivo in rats and humans. In contrast, oestradiol-17 beta consistently exerted no significant effects on resorption pit formation by rat osteoclasts over 24 h, even at grossly supraphysiological concentrations (up to 10 microM).

Animals↗
PubMed1995

Combination therapy with colestipol and psyllium mucilloid in patients with hyperlipidemia.

OBJECTIVE: To test whether combining psyllium mucilloid with half the usual dose of colestipol reduces the adverse effects associated with colestipol and maintains or increases its efficacy in the treatment of hyperlipidemia. This strategy might make bile acid sequestrants, which are seldom used because they cause adverse effects such as bloating and constipation, more tolerable and less expensive. DESIGN: A randomized, parallel-group, double-blind, controlled trial. SETTING: An outpatient clinic in a tertiary care hospital. PATIENTS: 121 patients who had moderate primary hypercholesterolemia (total cholesterol level > 6 mmol/L and < 8 mmol/L; triglyceride level < 3 mmol/L) after following a low-fat diet for 1 year (National Cholesterol Education Program Step Two diet). INTERVENTION: 5 g of cellulose placebo; 5 g of colestipol; 2.5 g of colestipol plus 2.5 g of psyllium; or 5 g of psyllium three times daily before meals for 10 weeks. MAIN OUTCOME MEASURES: At baseline and at weeks 4 and 10, fasting blood lipid levels and apoprotein concentrations were measured and a quality-of-life instrument was completed. RESULTS: A combination of 2.5 g of psyllium and 2.5 g of colestipol was better tolerated than and as effective as either 5 g of colestipol alone or 5 g of psyllium alone. The combination therapy and colestipol alone did not differ significantly with respect to changes in individual lipid values. The ratio of total cholesterol to high-density lipoprotein cholesterol (HDL) was reduced by 18.2% (95% CI, 12.3% to 24%) with the combination therapy; by 10.6% (CI, 2.0% to 15.4%) with colestipol alone; by 6.1% (CI, 1.5% to 10.6%) with psyllium alone; and by 0.1% (CI, -4.8% to 7%) with placebo (P = 0.0002). Combination therapy reduced the ratio of total cholesterol to HDL significantly more than did colestipol alone or psyllium alone (P < 0.05). CONCLUSIONS: These findings suggest that adding psyllium to half the usual dose of bile acid sequestrant resins maintains the efficacy and improves the tolerability of these resins.

Adult↗
PubMed1995

Effect of growth factors on substance P mRNA expression in axotomized dorsal root ganglia.

The effects of NGF, BDNF, NT-3, BDNF plus NT-3 and LIF on substance P (SP) mRNA levels were analysed in axotomized dorsal root ganglia (DRGs) in vivo by quantitative in situ hybridization. The growth factors were applied on to the transected sciatic nerve. SP mRNA levels were decreased significantly 3 days after axotomy. NGF (1 microgram) fully counteracted the down-regulation of SP mRNA. Neither BDNF (10 micrograms) nor NT-3 (10 micrograms) alone had any effect. However, co-administration of BDNF together with NT-3 (10 micrograms) distinctly reversed the decrease in SP mRNA. A similar effect was seen with a high (1.5 micrograms) but not a low dose of LIF (0.15 microgram). Our data suggest that the present method of delivering growth factors to the transected sciatic nerve is a valid way to study in vivo effects of growth factors on peptide expression in DRGs. Moreover, SP expression is regulated by several growth factors in vivo such as NGF, BDNF plus NT-3 as well as the neuroimmune factor LIF.

Animals↗
PubMed1995

The burden of osteoporosis: cost.

Osteoporotic fractures are generally assumed to be a major public health problem in the western world. Cost calculations are based primarily on hip fractures, which are easy to count since most require hospital admission and surgical intervention. The estimates of cost, which are $10-20 billion annually in the United States to $0.3 billion in England and Wales are therefore likely to be underestimates of the total cost of the disease. As populations age throughout the world, the costs worldwide can only increase, and estimates are staggering. Within 50 years the cost of hip fracture alone in the United States may exceed $240 billion. In some countries there appears also an age-specific increase in incidence that will only compound the problem. It is not clear to what extent therapeutic interventions can control the possible epidemic of fractures in the next century.

Fractures, Bone↗
PubMed1995

Teenage and current calcium intake are related to bone mineral density of the hip and forearm in women aged 30-39 years.

The relation between diet and bone mineral density in premenopausal women was evaluated in a cross-sectional study of 139 women aged 30-39 years. The population consisted of volunteers recruited in Rockland County, New York, between September 1988 and August 1992. A food frequency questionnaire was used to determine nutrient intake for both the year prior to bone density measurement and for ages 13-17 years. Physical measurements included height, weight, grip strength, and percent body fat. Bone mineral density was measured in the lumbar spine, hip, and forearm. Multiple regression equations were used to relate nutrient intake to bone density while controlling for age, height, weight, and grip strength. There were no relations between lumbar spine or distal forearm bone density and any nutrient studied from either the current or teenage diet. Current dietary calcium intake was modestly related to hip bone density (beta = 0.077; p = 0.074). When fiber intake was added to the multiple regression model, the association between calcium and hip bone density was strengthened (beta = 0.101; p = 0.037); this would be expected, because fiber interferes with calcium absorption. In the teenage diet, phosphorus and calcium intake were related to hip bone density. A higher lifetime calcium intake was associated with a higher hip bone density compared with low lifetime calcium intake. An increase in teenage calcium intake from 800 to 1,200 mg per day is estimated to increase hip bone density by 6 percent.

Adolescent↗
PubMed1995

Oral 1,25-dihydroxyvitamin D administration in osteoporotic women: effects of estrogen therapy.

Estrogen has been shown to modify calcium and skeletal homeostasis. In this study, we tested the ability of estrogen to influence the effects of short-term 1,25(OH)2D administration on biochemical indices of bone formation and resorption in a cross-sectional analysis of untreated (n = 10) and estrogen-treated (n = 14) osteoporotic women. Patients were given oral 1,25(OH)2D (Rocaltrol) 0.5 microgram twice a day for 5 days. Serum and urine were sampled at baseline and then 1 h after the first daily Rocaltrol dose for the 5 days of the study. 1,25(OH)2D levels rose similarly in both groups with plateaus reached by the third day of the investigation. Serum PTH levels decreased by the first sampling period (1 h after first Rocaltrol dose; p < 0.008 both groups) and continued to fall gradually in both groups. There were no changes in serum calcium but serum phosphorus rose by the second day (p < 0.05 both groups) and remained elevated throughout the remainder of the protocol. Serum bone Gla protein increased approximately 40% (p < 0.05) with no group differences. In contrast, total alkaline phosphatase and carboxy-terminal propeptide of type I collagen did not increase in either group. Furthermore, there were no significant increments in any bone resorption indicators, including serum tartrate-resistant acid phosphatase and cross-linked carboxy-terminal telopeptide of type I collagen, as well as urine hydroxyproline and pyridinoline. Serum IGF-1 levels also remained unchanged in both groups. We conclude that oral 1,25(OH)2D administration decreased 1-84PTH levels, probably due to a suppression of parathyroid production, and did not stimulate bone resorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗
PubMed1995

Postmenopausal osteoporosis: patient choices and outcomes.

OBJECTIVE: Only two medications, estrogen and injectable salmon calcitonin, are currently approved by the FDA for the treatment of osteoporosis. Oral etidronate has been investigated but not approved for osteoporosis therapy. We compared the three available anti-resorptive medications in untreated osteoporotic women. DESIGN: A nonrandomized, open label trial. After baseline biochemistry and bone mineral density (BMD) determinations, subjects self-selected therapy based on descriptions of the three drugs which were similar for all patients. Bone densitometry of the lumbar spine, femoral neck and distal and proximal forearm sites was repeated every 6 months. RESULTS: Twenty-one patients chose estrogen, 20 chose etidronate and 11 chose calcitonin. Fear of breast cancer was the most common reason given for not choosing estrogen therapy. Mean age was slightly lower and spine and hip bone densities slightly higher in the estrogen group compared with both the etidronate and calcitonin groups. In the lumbar spine, all three agents resulted in similar small increments (mean increments 1.2-4.4% at 2 years). In the estrogen group, there was no change in femoral neck density while there were significant losses in both calcitonin and etidronate groups (3.1-4.9%). In the forearm, there was either no change (distal site) or an increment (proximal site) in the estrogen group, while both etidronate and calcitonin groups demonstrated a mean loss at both sites over the 2-year observation period. CONCLUSIONS: These preliminary results suggest that all three agents appear equally effective at maintaining or increasing BMD of the lumbar spine, while estrogen appeared more effective at maintaining or increasing BMD of the appendicular skeleton. This study underscores the need for an alternative to estrogen therapy which is equally effective and can be given orally for those in whom estrogen is either contraindicated or undesirable.

Aged↗
PubMed1995

Effects of reciprocal treatment with estrogen and estrogen plus parathyroid hormone on bone structure and strength in ovariectomized rats.

Intermittent administration of PTH has been found to be an effective anabolic agent in cancellous bone. We have reported previously that combined treatment with PTH and estrogen in estrogen-deficient rats was beneficial in correcting established osteopenia. To determine if the beneficial effects of PTH therapy can be preserved by estrogen alone and whether PTH therapy can be effective in treating osteopenic subjects stabilized with estrogen, we have undertaken a "crossover" study in the rat model of estrogen-deficiency induced osteopenia. Six-month-old female rats were ovariectomized and after 5 wk treated for 8 wk with vehicle, 30 micrograms/kg per day of rPTH(1-34) plus 15 micrograms/kg per day of 17 beta-estradiol or 17 beta-estradiol alone. One group from each treatment regimen was then sacrificed and for an additional 8 weeks the remaining rats were (a) maintained on their previous treatment; (b) "crossed over" to their reciprocal treatment; or (c) administered vehicle only. At the end of this second 8-wk treatment period all rats were sacrificed. Bone mineral density of the distal femur, histomorphometric measurements of the proximal tibia and mechanical testing of the distal femur and selected vertebral bodies were performed. Our results demonstrated that (a) the gains in bone mass, trabecular connectivity and mechanical strength induced by PTH can be maintained by estrogen alone, but are reversed when both agents are withdrawn; and (b) rats with established osteopenia, maintained on estrogen treatment alone, can derive the full beneficial effects from the addition of PTH to the treatment at a later date. These data indicate that combined and/or sequential use of antiresorptive and anabolic agents may be a promising approach to the treatment of osteoporosis.

Animals↗
PubMed1995

Estradiol and tamoxifen interactions with thyroid hormone in the ovariectomized-thyroidectomized rat.

Receptors for estrogens and thyroid hormone (T3) have related DNA-binding domains that interact with closely related DNA target sequences which enable transcriptional control. In vitro molecular studies have raised the possibility that estrogen and T3 receptors may compete for binding to certain DNA target sites (cross-talk). However, there have been no physiological studies evaluating the abilities of estrogens or T3 to mimic or inhibit each other in vivo in a manner consistent with a mechanism involving receptor cross-talk. To address this issue, the effects of estradiol, tamoxifen (an antiestrogen), and T3 were studied in an ovariectomized-thyroidectomized rat model designed to minimize hormone interplay occurring via neuroendocrine or pharmacokinetic mechanisms. The T3 responses examined included induction of GH, somatic growth, and hepatic malic enzyme, and suppression of TSH secretion. The estrogen responses examined included induction of pituitary kallikrein, PRL, and uterine weight; increases in serum triglycerides; and suppression of LH secretion. Estradiol and tamoxifen acted as partial T3 agonists on GH induction, with agonist or antagonist effects depending upon T3's presence. Estradiol and tamoxifen acted as pure T3 antagonists on T3 induction of somatic growth and malic enzyme. Similarly, estradiol blocked T3-evoked decreases in bone mineral density and had no effect on bone in T3's absence. In contrast, estradiol or tamoxifen did not alter T3 feedback inhibition of TSH release or T3 induction of PRL. T3 partially mimicked estrogen actions to suppress LH, but did not mimic or inhibit other estrogen responses. Interestingly, the effect of estradiol and tamoxifen to increase serum triglycerides was totally T3 dependent even though T3 tended to decrease triglyceride levels. The results indicate that physiological effects of estrogens on GH, somatic growth, bone, malic enzyme, and serum triglycerides exhibit properties suggestive of a mechanism involving cross-talk with T3 receptors. Tamoxifen fully mimicked the effects of estradiol arising by an apparent antagonism of T3 actions, but acted as an antiestrogen in other responses.

Animals↗
PubMed1995

Short-term changes in histomorphometric and biochemical turnover markers and bone mineral density in estrogen-and/or dietary calcium-deficient rats.

Both estrogen and dietary calcium deficiencies are important risk factors in the pathogenesis of osteoporosis. We used an animal model of postmenopausal osteoporosis to study histomorphometric and bone turnover markers and bone mineral changes induced by short-term (1 month) estrogen and/or dietary calcium deficiency in the mature rat. Seven groups of rats were studied: 1) basal; 2) sham, fed a calcium-deficient diet (0.1% Ca, Sham-LoCa); 3) sham, fed a regular-calcium diet (1.0% Ca, Sham-RCa); 4) ovariectomy (ovx), on a calcium-deficient diet (Ovx-LoCa); 5) ovx, on a regular-calcium diet (Ovx-RCa); 6) ovx, on a calcium-deficient diet with estrogen replacement (Ovx-LoCa-Est); and 7) ovx, on a regular-calcium diet with estrogen replacement (Ovx-RCa-Est). When compared with sham-operated animals on a regular calcium diet (Sham-RCa), either deficiency alone elevated the turnover markers osteocalcin (BGP) (Sham-LoCa 24.5%; Ovx-RCa 54.7%) and pyridinoline (Sham-LoCa 48.3%, Ovx-RCa 112.3%). Reductions in cancellous bone mass (Cn-BV/TV, Sham-LoCa -26.5%, Ovx-RCa -41.1%) and trabecular connectivity (Node.Node, Sham-LoCa -54.5%, Ovx-RCa -62.6%) were observed. Combined deficiencies (Ovx-LoCa) showed a greater change (BGP, +66.0%; pyridinoline +117.7%; Cn-BV/TV -64.4%; Nd.Nd -95.6%). Estrogen treatment was effective in preventing bone loss from both estrogen and calcium deficiencies.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1995

Temporal changes in cancellous bone structure of rats immediately after ovariectomy.

To understand the structural changes accompanying estrogen deficiency-induced bone loss, we examined the temporal changes in cancellous bone structure in an animal model of postmenopausal osteoporosis. Matured rats were subjected to bilateral ovariectomy, and groups of eight animals were sacrificed at 5-day intervals. Histomorphometric and trabecular strut analyses of the excised proximal tibia, and bone mineral density measurement of the distal femur, were used to investigate cancellous bone loss as a result of estrogen deficiency. There was an immediate increase in bone turnover after ovariectomy, as evidenced by rapid increases in osteoclast surface (400%) and bone formation rate (270%). The resultant time-dependent decrease in cancellous bone volume was highly related to a decrease in trabecular plate number and connectivity parameters, but was not related to the thickness of the remaining cancellous plates. Our results suggest that cancellous bone loss due to estrogen deficiency is the result of decreased connectivity, likely due to osteoclast perforation of trabecular plates, followed by complete removal of the plate without prior generalized thinning.

Animals↗
PubMed1994

Milk and bones.

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Animals↗
PubMed1994

Hereditary hyperphosphatasia: 20 year follow-up and response to disodium etidronate.

We provide a 20 year follow-up of a family with three siblings affected by hereditary hyperphosphatasia (HH). An iliac crest bone biopsy was performed on one of the siblings following double-tetracycline labeling, with results reported quantitatively in a standard histomorphometric format. Biochemical parameters of disease activity were monitored in the patient before and after treatment with oral etidronate disodium, 20 mg/kg/day taken for 5 weeks. Biochemical evidence of intense disease activity continued 20 years after the initial diagnosis of HH in the sibling studied. His bone biopsy specimen also revealed extremely high bone turnover but low cancellous bone volume and osteoclasts unlike those found in Paget's disease. Treatment with etidronate disodium resulted in a temporary 40% reduction in serum alkaline phosphatase and 24 h urine hydroxyproline excretion, with reduction in serum osteocalcin from two times the upper limit of normal to a subnormal level. We conclude that disease activity in HH can continue unabated for two decades. Our bone biopsy finding of low cancellous bone volume, the consistent lack of pagetic-looking osteoclasts in our and other studies, plus the clinical features of HH (childhood onset and extremely diffuse disease with gross skeletal deformation) serve to distinguish HH from Paget's disease. Bisphosphonates may be of value in treating HH.

Adult↗