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Biomedical subjects

D M Black

Publications and source records attributed to D M Black.

At least 19 recordsLinked to original sources
PubMed2006

Short-term changes in bone turnover markers and bone mineral density response to parathyroid hormone in postmenopausal women with osteoporosis.

CONTEXT: Treatment of osteoporotic women with PTH increases biochemical markers of bone turnover, increases axial bone mineral density (BMD), and reduces fracture risk. OBJECTIVE: Our objective was to determine the relationship between levels of baseline turnover before PTH therapy and short-term changes in turnover during PTH therapy and subsequent changes in areal and volumetric BMD. DESIGN AND SETTING: We conducted a randomized, placebo-controlled trial at four academic centers. PATIENTS: Patients included 238 postmenopausal women with low hip or spine BMD. INTERVENTION: Subjects were randomized to sc PTH (1-84), 100 mug/d (119 women), for 1 yr. MAIN OUTCOME MEASURE: Bone turnover markers were measured in fasting blood samples collected before therapy and after 1 and 3 months. Areal and volumetric BMD at the spine and hip were assessed by dual-energy x-ray absorptiometry and quantitative computed tomography (QCT) after 1 yr of therapy. RESULTS: Among women treated with PTH alone, the relationships between baseline turnover and 1-yr changes in dual-energy x-ray absorptiometry and QCT BMD were inconsistent. Greater 1- and 3-month increases in turnover, particularly the formation marker N-propeptide of type I collagen, were associated with greater increases in areal BMD. When volumetric hip and spine BMD were assessed by QCT, greater short-term increases in turnover were even more positively associated with 1-yr increases in BMD. Each sd increase in the 3-month change of N-propeptide of type I collagen was associated with an a 21% greater increase in QCT spine trabecular BMD. CONCLUSIONS: Greater short-term changes in turnover with PTH therapy are associated with greater 1-yr increases in spine and hip BMD among postmenopausal osteoporotic women.

Absorptiometry, Photon↗
PubMed2003

A role for BRCA1 in sporadic breast cancer.

To test the hypothesis that altered expression of BRCA1 protein may play an important role in sporadic breast cancer development, 50 randomly selected primary breast cancers (frozen sections, 5 years' median follow-up) were immunolabelled with two monoclonal BRCA1 antibodies (MS110 and MS13). MS110 labelling was exclusively nuclear showing no relation to outcome or tumour pathology. Western blotting demonstrated crossreactivity, suggesting antibody nonspecificity. MS13 labelling was predominantly cytoplasmic. Intense labelling predicted decreased overall survival (P=0.012), disease-free survival (P=0.029), oestrogen receptor negativity (P=0.0004) and c-erbB-2 overexpression (P=0.006). Western blotting detected a 110 kDa molecule consistent with BRCA1 delta11b splice variant. BRCA1 protein is postulated to function as a tumour suppressor. We demonstrate cytoplasmic localisation in sporadic breast cancer suggesting excess delta11b splice variant production, reduced production of full-length BRCA1 and thus postulate reduced tumour suppressor activity. BRCA1 protein appears to have a significant role in both sporadic and hereditary breast cancers.

Adult↗
PubMed2002

Digital X-ray radiogrammetry predicts hip, wrist and vertebral fracture risk in elderly women: a prospective analysis from the study of osteoporotic fractures.

Digital X-ray radiogrammetry (DXR) is a technique that uses automated image analysis of standard hand radiographs to estimate bone mineral density (DXR-BMD). Previous studies have shown that DXR-BMD measurements have high precision, are strongly correlated with forearm BMD and are lower in individuals with prevalent fractures. To determine whether DXR-BMD measurements predict wrist, hip and vertebral fracture risk we conducted a case-cohort study within a prospective study of 9704 community-dwelling elderly women (the Study of Osteoporotic Fractures). We compared DXR-BMD, and BMD of the radius (proximal and distal), calcaneus, femoral neck and posteroanterior lumbar spine in women who subsequently suffered a wrist (n = 192), hip (n = 195), or vertebral fracture (n = 193) with randomly selected controls from the same cohort (n = 392-398). DXR-BMD was estimated from hand radiographs acquired at the baseline visit. The radiographs were digitized and the Pronosco X-posure System was used to compute DXR-BMD from the second through fourth metacarpals. Wrist fractures were confirmed by radiographic reports and hip fractures were confirmed by radiographs. Vertebral fractures were defined using morphometric analysis of lateral spine radiographs acquired at baseline and an average of 3.7 years later. Age-adjusted odds ratio (OR, vertebral fracture) or relative hazard (RH, wrist and hip fracture) for a 1 SD decrease in BMD were computed. All BMD measurements were similar for prediction of wrist (RH = 1.5-2.1) and vertebral fracture (OR = 1.8-2.5). Femoral neck BMD best predicted hip fracture (RH = 3.0), while the relative hazards for all other BMD measurements were similar (RH = 1.5-1.9). These prospective data indicate that DXR-BMD performs as well as other peripheral BMD measurements for prediction of wrist, hip and vertebral fractures. Therefore, DXR-BMD may be useful for prediction of fracture risk in clinical settings where hip BMD is not available.

Absorptiometry, Photon↗
PubMed2001

Detection of the isoflavone aglycones genistein and daidzein in urine using solid-phase microextraction-high-performance liquid chromatography-electrospray ionization mass spectrometry.

An improved method of detection of the isoflavone aglycones, genistein and daidzein, is reported using solid-phase microextraction-high-performance liquid chromatography-electrospray ionization mass spectrometry (SPME-HPLC-ESI-MS). Extraction of the isoflavonoids from urine using SPME with a Carbowax-templated resin fiber coating allows rapid preconcentration of the analytes without the usual sample preparation required by other methods. Detection of the analytes is accomplished by HPLC-ESI-MS. Analysis of spiked samples of urine resulted in a linear range of 0.25 to 250 ng/ml for daidzein and 0.27 to 27.0 ng/ml for genistein. Limits of detection of daidzein and genistein were measured at 25.4 pg/ml for daidzein and 2.70 pg/ml for genistein. Daidzein and genistein were detected in urine following consumption of a soy drink.

Chromatography, High Pressure Liquid↗
PubMed2001

Effect of niacin and atorvastatin on lipoprotein subclasses in patients with atherogenic dyslipidemia.

This study was conducted to determine the efficacy of atorvastatin and niacin on lipoprotein subfractions in patients with atherogenic dyslipidemia. This was a multicenter, randomized, open-label, parallel-design study of patients with total cholesterol >200 mg/dl, triglycerides between 200 and 800 mg/dl, and apolipoprotein B >110 mg/dl. Patients were randomly assigned to atorvastatin 10 mg or immediate release niacin 3,000 mg daily for 12 weeks following a low-fat diet stabilization period. Lipoprotein subclasses were measured by nuclear magnetic resonance spectroscopy. Atorvastatin and niacin both significantly reduced the concentrations of very low-density lipoprotein (VLDL) particles (-31% and -29%, respectively) and small low-density lipoprotein (LDL) particles (-44% and -35%, respectively). Niacin increased the concentration of large LDL (+75%). Atrovastatin reduced the number of LDL particles more than niacin (31% vs 14%). In patients with atherogenic dyslipidemia, both drugs had important effects on lipoprotein subfractions, which contributed to a reduction in coronary heart disease risk. The drugs equally reduced VLDL subclass levels. Niacin shifted the LDL subclass distribution toward the larger particles, more effectively converted patients from LDL phenotype B to phenotype A, and increased levels of the larger and perhaps more cardioprotective high-density lipoprotein particles. In contrast, atorvastatin preferentially lowered the concentration of small LDL particles without increasing levels of large LDL, and more effectively, reduced LDL particle numbers. Atorvastatin had a preferred LDL effect, whereas niacin had a preferred high-density lipoprotein effect.

Anticholesteremic Agents↗
PubMed2001

The TES gene at 7q31.1 is methylated in tumours and encodes a novel growth-suppressing LIM domain protein.

Many studies suggest that a multi-tissue tumour suppressor gene is located at human chromosome 7q31.1. We have cloned and characterized a novel gene at this locus. The TES gene lies within the minimal region of overlap of several LOH studies and appears to possess the properties of a tumour suppressor. TES is widely expressed and is predicted to encode a protein of 421 amino acids, with three C-terminal LIM domains. Mutation analysis of the coding TES exons in 21 human tumour-derived cell lines revealed the presence of a frameshift mutation in one allele in the breast cancer cell line ZR-75. Methylation of the CpG island at the 5' end of TES appears to be a remarkably frequent finding, occurring in seven out of 10 ovarian carcinomas and in each of the 30 tumour-derived cell lines tested. Moreover, forced expression of TES in HeLa or OVCAR5 cells, resulted in a profound reduction in growth potential, as determined by the colony formation assay. We believe that TES is a tumour suppressor gene that is inactivated primarily by transcriptional silencing resulting from CpG island methylation.

Base Sequence↗
PubMed2001

Effects of hormone replacement therapy on clinical fractures and height loss: The Heart and Estrogen/Progestin Replacement Study (HERS).

PURPOSE: To determine if estrogen plus progestin reduces the incidence of fractures or height loss in postmenopausal women with coronary disease. SUBJECTS AND METHODS: We enrolled 2,763 postmenopausal women with coronary disease and with an intact uterus into the Heart Estrogen/progestin Replacement Study, a randomized double-blind, placebo-controlled secondary prevention trial of cardiovascular disease. Radiographically documented clinical fractures were a prespecified secondary endpoint. Height loss was used as a surrogate for vertebral fractures. The average age of the women was 66.7 +/- 6.7 years, and fewer than 15% of the women had osteoporosis based on their bone density. Women were randomly assigned to either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n = 1,380) or placebo (n = 1,383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 64% at the end of the study. RESULTS: During 10,554 person years of follow-up, 286 women experienced a fracture: 138 in the treatment group (26.3 per 1,000 person years) and 148 in the placebo group (28.0 per 1,000 person years); relative hazard, 0.94; 95% confidence interval 0.8 to 1.2, P = 0.61). These included 58 wrist fractures (1.01; 0.6 to 1.7); 27 hip fractures (1.09; 0.5 to 2.3); 32 spine fractures (0.69; 0.3 to 1.4), and 192 other fractures (0.91; 0.7 to 1.2). There was no difference in average height loss between the treatment and placebo groups or in the percent of women who lost more than 2 cm in height: 10.6% in the treatment group and 12.1% in the placebo group. CONCLUSIONS: There was no evidence of a reduction in the incidence of fractures or rate of height loss in older women not selected for osteoporosis. Randomized studies are needed to clarify the effect of hormone replacement therapy on fracture risk among women with and without osteoporosis.

Aged↗
PubMed2001

Challenges for model-based economic evaluations of postmenopausal osteoporosis interventions.

Assessing the cost-effectiveness of long-term treatment for osteoporosis requires use of mathematical models to estimate health effects and costs for competing interventions. The primary motivations for model-based analyses include the lack of long-term clinical trial outcome data and the lack of data comparing all relevant treatments within randomized clinical trials. We report on specific modeling challenges that arose in the development of a model of the natural history of postmenopausal osteoporosis that is suitable for assessing the cost-effectiveness of osteoporosis interventions among various population subgroups in diverse countries. These include choice of modeling changes in bone mineral density (BMD) or in fracture rate, definition of health states, modeling mortality and costs of long-term care following fracture, incorporation of health utility, and model validation. This report should facilitate future postmenopausal osteoporosis model development and provide insight for decision-makers who must evaluate model-based economic analyses of postmenopausal osteoporosis interventions.

Aged↗
PubMed2001

The effect of alendronate on fracture-related healthcare utilization and costs: the fracture intervention trial.

The Vertebral Fracture Arm (VFA) of the Fracture Intervention Trial (FIT) study demonstrated that alendronate reduced the incidence of spine, forearm and hip fractures in women with low bone mass and existing vertebral fractures by about 50%. The objective of the present study was to determine the effects of alendronate therapy versus placebo on fracture-related healthcare utilization and costs. Participants were randomly assigned to double-masked treatment with alendronate (5 mg/day for 2 years and then 10 mg/day for 1 year) or placebo for 3 years. For each patient experiencing a clinical fracture, we determined whether treatment in an emergency room, hospital, nursing home and/or rehabilitation hospital was a consequence of the fracture. The VFA of the FIT Study enrolled 2027 women aged 55-81 years with low bone mass and pre-existing vertebral fractures from population-based listings in 11 metropolitan areas of the United States. We measured (1) the proportion of patients who had any fracture-related healthcare event and (2) the estimated cost of fracture-related healthcare services. Alendronate significantly reduced the proportion of patients utilizing fracture-related healthcare (emergency room, hospital, rehabilitation hospital or nursing home) by 25% (p = 0.038). Alendronate significantly reduced the costs associated with hip-fracture-related care by 58%, or $181 per patient randomized (p = 0.036). The reduction in fracture-related total costs was 35% ($190 per patient randomized) in the alendronate group relative to the placebo group (p = 0.114). Alendronate thus not only reduces the incidence of clinical fractures and associated morbidity, but reduces the proportion of patients utilizing the associated healthcare resources.

Aged↗
PubMed2001

An assessment tool for predicting fracture risk in postmenopausal women.

Due to the magnitude of the morbidity and mortality associated with untreated osteoporosis, it is essential that high-risk individuals be identified so that they can receive appropriate evaluation and treatment. The objective of this investigation was to develop a simple clinical assessment tool based on a small number of risk factors that could be used by women or their clinicians to assess their risk of fractures. Using data from the Study of Osteoporotic Fractures (SOF), a total of 7782 women age 65 years and older with bone mineral density (BMD) measurements and baseline risk factors were included in the analysis. A model with and without BMD T-scores was developed by identifying variables that could be easily assessed in either clinical practice or by self-administration. The assessment tool, called the FRACTURE Index, is comprised of a set of seven variables that include age; BMD T-score, fracture after age 50 years, maternal hip fracture after age 50, weight less than or equal to 125 pounds (57 kg), smoking status, and use of arms to stand up from a chair. The FRACTURE Index was shown to be predictive of hip fracture, as well as vertebral and nonvertebral fractures. In addition, this index was validated using the EPIDOS fracture study. The FRACTURE Index can be used either with or without BMD testing by older postmenopausal women or their clinicians to assess the 5-year risk of hip and other osteoporotic fractures, and could be useful in helping to determine the need for further evaluation and treatment of these women.

Aged↗
PubMed2001

Statins in children: what do we know and what do we need to do?

Children have been tested and treated for hypercholesterolemia for more than 30 years. Although most treatment regimens have been limited to dietary intervention, statin use is increasing. Statins have been used in children since 1987, but published sources have only reported on small numbers of children with severe hypercholesterolemia. The available data indicates that statins can be useful and well tolerated. New data will be available in the next few years that will lead to the wider use of these drugs. Although statin drugs have proven to be safe in the adult population, physicians will be obliged to follow pediatric patients closely when these agents are widely used in the first few years. The use of highly effective safe drugs such as statins will allow for the assessment of the best time to initiate therapy in younger populations and what benefits may be found over the long term.

Atorvastatin↗
PubMed2001

Apolipoprotein E genotype affects plasma lipid response to atorvastatin in a gender specific manner.

The response to therapy with hypolipidemic agents shows considerable individual variation. These differences may be due to the interaction of environmental and genetic factors that affect drug bioavailability, receptor function or ligand structure. Our objective was to assess the effect of apolipoprotein (apo) E genotype and gender on lipid-lowering response to the HMG CoA reductase inhibitor, atorvastatin. Genotyping was carried out on DNA from 328 male and female subjects who participated in a multicentric, double-blind clinical trial, and received 10 mg/day of atorvastatin. Our data demonstrate no significant gender differences for LDL cholesterol levels at baseline. Moreover, mean LDL-C lowering was similar in men (-36.2%, range -2.7 to -57.8%) and in women (-38.1%, range -9.5 to -58.5%) as compared to baseline. However, men carrying the epsilon2 allele had a significantly higher mean LDL-C response (-44%) than epsilon3 homozygotes (-37%) and epsilon4 carriers (-34%); P=0.01 for apoE group by treatment interaction. No such gene/treatment interactions were noted in women, with those carrying the epsilon2 allele showing a similar mean response (-34%) as epsilon3 homozygotes (-39%) and epsilon4 carriers (-34%). Mean plasma triglyceride lowering with atorvastatin was 17%. A significant apoE group by treatment interaction (P=0.010) was also observed in men, with epsilon2 carriers being more responsive (-27%) than epsilon3/3 (-13%) and epsilon4 (-22%). This interaction was not observed in women. In summary, atorvastatin treatment had similar effects on plasma lipid levels in both men and women; however, the apoE gene locus was a significant predictor of LDL-C and TG responses to atorvastatin therapy in men, but not in women.

Anticholesteremic Agents↗
PubMed2001

Older women with diabetes have an increased risk of fracture: a prospective study.

To determine whether type 2 diabetes is associated with fracture in older women, we analyzed data from 9654 women, age 65 yr or older, in the Study of Osteoporotic Fractures. Diabetes with age at onset 40 yr or older was reported by 657 women, of whom 106 used insulin. A total of 2624 women experienced at least one nonvertebral fracture during an average follow-up of 9.4 yr, and 388 had at least one vertebral fracture during an average interval of 3.7 yr. Although diabetes was associated with higher bone mineral density, it was also associated with a higher risk of specific fractures. Compared with nondiabetics, women with diabetes who were not using insulin had an increased risk of hip [relative risk (RR), 1.82; 95% confidence interval (CI), 1.24-2.69] and proximal humerus (RR, 1.94; 95% CI, 1.24-3.02) fractures in multivariate models controlling for age, body mass index, bone density, and other factors associated with fractures and diabetes. Insulin-treated diabetics had more than double the risk of foot (multivariate adjusted RR, 2.66; 95% CI, 1.18-6.02) fractures compared with nondiabetics. This study indicates that diabetes is a risk factor for hip, proximal humerus, and foot fractures among older women, suggesting that fracture prevention efforts should be a consideration in the treatment of diabetes.

Aged↗
PubMed2001

A normative reference database study for Pronosco X-posure System.

Cortical width from radiographs has been used for more than 40 yr as a means of estimating bone strength. In the last 5-10 yr, increased availability of computers and the development of automated algorithms for image assessment have led to an increased interest in radiogrammetry. In this study, we examined a new radiogrammetry device, the Pronosco X-posure System, which estimates bone mineral density (BMD) from forearm/hand radiographs. We obtained hand and forearm radiographs and performed dual X-ray absorptiometry (DXA) at the wrist and hip on 832 women ages 20-79 at four clinical centers across the United States. We then used the X-posure System to estimate BMD (DXR-BMD). The goal of the study was to establish reference ranges for the method and to compare the measurement to DXA measurements of BMD at the wrist and hip. Using statistical models, we estimated that the peak value for DXR-BMD occurred at age 38 (mean = 0.598 g/cm2, standard deviation = 0.034 g/cm2). The correlation between DXR-BMD and DXA was 0.90 at the wrist and 0.61 at the hip. The relationship of DXR-BMD to reported history of fracture was of similar magnitude to that for DXA at the wrist and hip. The strong correlation of DXR-BMD from the X-posure System with DXA at the wrist from the Hologic machine suggests that the X-posure System may be an alternative to DXA at the wrist for the assessment of osteoporosis.

Absorptiometry, Photon↗
PubMed2000

Effect of atorvastatin on hemorheologic-hemostatic parameters and serum fibrinogen levels in hyperlipidemic patients.

Plasma fibrinogen and hemorheologic-hemostatic factors contribute to dyslipidemia-induced morbidity. Some of these parameters can be favorably affected when abnormal serum lipoprotein levels are corrected. Thus, we investigated whether treatment with atorvastatin would result in changes in plasma viscosity and other hemorheologic and hemostatic parameters. Twenty-two hyperlipidemic men at a university lipid clinic were treated single-blinded with atorvastatin 80 mg/day for 12 weeks to determine hemostatic-hemorheologic parameters including blood viscosity, fibrinogen levels, whole blood platelet aggregation, tissue plasminogen activator antigen, hematocrit, plasminogen activator inhibitor activity, factor VII activity, red blood cell (RBC) deformity and lipid ratio, sedimentation rate, and fasting serum lipoprotein levels. Atorvastatin treatment provided significant lowering of serum lipoprotein levels: low-density lipoprotein -53% (p = 0.0001), very low density lipoprotein -43% (p = 0.0001), and triglycerides -35% (p < 0.0001). These effects were accompanied by changes in plasma viscosity -10% (p = 0.0007), arachidonic acid-induced whole blood platelet aggregation -11% (p = 0.006), factor VII -8% (p = 0.001), RBC lipid composition +5% (p = 0.0003), and RBC sedimentation -33% (p = 0.0002). Plasma fibrinogen levels were not affected. Thus, atorvastatin 80 mg/day produced marked reductions in serum low-density lipoprotein cholesterol (-53%), very low density lipoprotein cholesterol (-43%), and triglycerides levels (-35%), and significant changes in plasma viscosity as well as other hemorheologic-hemostatic parameters, but no changes in plasma fibrinogen levels.

Adult↗
PubMed2000

Effect of alendronate on limited-activity days and bed-disability days caused by back pain in postmenopausal women with existing vertebral fractures. Fracture Intervention Trial Research Group.

BACKGROUND: Women with new vertebral fractures have an increased risk of back pain and functional limitation because of back pain. Alendronate sodium treatment reduces the risk of new vertebral fracture by 50% in postmenopausal women with osteoporosis. OBJECTIVE: To determine the effect of alendronate therapy on days affected by back pain in postmenopausal women with existing vertebral fractures. DESIGN: Three-year, placebo-controlled, randomized, double-blind study. SETTING: Fifteen university-based research clinics in the United States. PARTICIPANTS: A total of 2027 postmenopausal women aged 55 to 81 years with low femoral neck bone density and a preexisting vertebral fracture. INTERVENTION: Alendronate sodium (5 mg/d for 2 years and 10 mg/d for the third year) or placebo. MAIN OUTCOME MEASURES: Occurrence and severity of back pain, number of days with back pain, and number of days of bed rest or limited activity because of back pain during 3 years of follow-up. RESULTS: Irrespective of treatment assignment, women with new, clinically recognized vertebral fractures during follow-up had an increased risk of days of bed disability and days of limited activity because of back pain after the fracture. Women receiving alendronate reported an average of 3.2 fewer days of bed rest (P = .001) and 11.4 fewer days of limited activity (not including days of bed rest) because of back pain (P = .04) during follow-up than those receiving placebo. In the alendronate group, relative to the placebo group, there was a reduced risk of 1 or more bed-rest days (relative risk, 0.68; 95% confidence interval, 0.53-0.87), of 7 or more bed-rest days (0.44; 0.30-0.64), and of 7 or more limited-activity days (0.87; 0.76-0.99). There were no statistically significant differences between treatment groups in the frequency of days of back pain or increases in back-related disability between baseline and study end. CONCLUSION: In postmenopausal women with preexisting vertebral fracture, alendronate therapy for 3 years reduced the number of days of bed disability and days of limited activity caused by back pain.

Activities of Daily Living↗