Ecological and human health risk assessment of metals in soils and wheat along Sutlej river (India).

Heavy metal (HMs) entry into soil affects the food chain, which is of great worry for human well-being hazards. In order to study the association of HMs in soil-plant system, surface (0-0.15 m) soil and wheat grain samples were collected within five km buffer zone of Sutlej river in Punjab (India). These samples were analysed for total arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), cobalt (Co), iron (Fe), manganese (Mn), nickle (Ni), lead (Pb), and zinc (Zn). Among all the HMs in soil and grain samples, the concentration of total Fe was maximum and As was minimum. The HM contamination of soils was assessed using contamination factor (CF), enrichment factor (EF), potential ecological risk (Er) and modified potential ecological risk (mEr). The CF, EF, Er and mEr were highest for Cd in soils. The bioaccumulation metal factor was highest for Zn and lowest for Ni in wheat grain. There was a significant (p < 0.05) positive relationship between HM concentration in soils and wheat grains indicating the health risk due to consumption of wheat cultivated around the five km buffer of the Sutlej river. The carcinogenic and non-carcinogenic risk due to ingestion of wheat grain were higher from Cd and Pb, respectively. These results are helpful for devising the remediation approaches to decrease the multi-metal contamination in soils and plants, and the epidemiological ways to preclude the human health risk from HM contamination.

A pilot screening study for low bone mass in Singaporean women using years since menopause and BMI.

OBJECTIVE: Current risk assessment tools for osteoporosis have inconsistent performance across different cohorts, making them difficult for clinical practice. This study aimed to evaluate a simple screening index comprising years since menopause (YSM) and body mass index (BMI) that identifies postmenopausal Singaporean women with a greater likelihood of low bone mass. METHODS: The study used data from 188 treatment-naïve postmenopausal women. The associations between low bone mass and different demographic variables, including age, YSM and BMI, were assessed using multivariable logistic regression. Diagnostic performance of the calculated screening index was compared to the Osteoporosis Self-Assessment Tool for Asians (OSTA) and the Fracture Risk Assessment Tool (FRAX®). RESULTS: YSM and BMI were significantly associated with low bone mass. The area under the receiver operating characteristic curves was 0.803 for the screening index, 0.759 for the OSTA, 0.683 for the FRAX® (major osteoporotic fracture probability [MOFP]) and 0.647 for the FRAX® (hip fracture probability [HFP]). Non-parametric Spearman's correlation between the screening index and the other models was 0.857 with the OSTA score, 0.694 with the FRAX® (HFP) and 0.565 with the FRAX® (MOFP) (p < 0.0005). CONCLUSIONS: The diagnostic performance of the screening index comprising YSM and BMI was equivalent to the OSTA and the FRAX®. A risk chart was developed for clinicians to identify and recommend subjects for a further dual-energy X-ray absorptiometry scan. Validation of this model in larger and more diverse cohorts is required.

Antioxidative role of dietary ascorbic acid against arsenic induced haematological, biochemical and histomorphological alterations in Cyprinus carpio.

The current study investigated the antioxidant potential of ascorbic acid to counteract arsenic induced toxic response in Cyprinus carpio. The 96 h LC50 of 107.05 mg L-1 was recorded through acute toxicity test and 1/5th and 1/10th LC50 of arsenic were chosen as sublethal concentrations for assessing toxicity induced through arsenic exposure in fish for a period of 28 days. There were six experimental groups for sublethal toxicity testing viz. negative control (basal feed), positive control (basal feed + 1 g kg-1 diet ascorbic acid), 1/5th LC50 Arsenic, 1/10th LC50 Arsenic, 1/5th LC50 Arsenic with ascorbic acid supplement, 1/10th LC50 Arsenic with ascorbic acid supplement. Following exposure, blood indices, antioxidant enzyme activity and histomorphology of gills, liver and kidney were examined. The results showed decreased total erythrocyte count, haemoglobin, haematocrit and an increased total leukocyte count upon arsenic exposure in fish with an improvement observed in the blood indices in arsenic with ascorbic acid supplementation. The study also analysed the antioxidant enzyme activity of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase which was found to decline in response to arsenic exposure with an increase in their activity recorded in arsenic with ascorbic acid supplemented fish. Furthermore, uptake of arsenic was also found to decrease on ascorbic acid supplementation with improvement in the histoarchitecture of gills, liver and kidney of fish. Collectively, the findings of the present study suggest the effectiveness of ascorbic acid as an ameliorating agent against the deleterious effects of arsenic in fish.

Pre-monsoon spatial distribution of available micronutrients and sulphur in surface soils and their management zones in Indian Indo-Gangetic Plain.

The efficient (site-specific) management of soil nutrients is possible by understanding the spatial variability in distribution of phyto-available nutrients (here after called available nutrients) and identifying the soil management zones (MZs) of agricultural landscapes. There is need for delineating soil MZs of agricultural landscapes of the world for efficient management of soil nutrients in order to obtain sustainability in crop yield. The present study was, therefore, undertaken to understand the spatial distribution pattern of available micronutrients (zinc (Zn), boron (B), iron (Fe), manganese (Mn) and copper (Cu)), available sulphur (S), and soil properties (soil acidity (pH), electrical conductivity (EC) and organic carbon (SOC) content) in soils of intensively cultivated Indo-Gangetic Plain (IGP) of India and to delineate soil MZs for efficient management of soil nutrients. Totally, 55101 soil samples from 0-15 cm depth were obtained from 167 districts of IGP during 2014 to 2017 and were analysed for different soil parameters. Soil pH, EC and SOC content varied from 4.44 to 9.80, 0.02 to 2.13 dS m-1 and 0.10 to 1.99%, respectively. The concentration of available Zn, B, Fe, Mn, Cu and S varied from 0.01 to 3.27, 0.01 to 3.51, 0.19 to 55.7, 0.05 to 49.0, 0.01 to 5.29 and 1.01 to 108 mg kg-1, respectively. Geostatistical analysis resulted in varied distribution pattern of studied soil parameters with moderate to strong spatial dependence. The extent (% area) of nutrient deficiencies in IGP followed the order: S > Zn > B > Mn > Cu > Fe. Principal component analysis and fuzzy c-means clustering produced six distinctly different soil MZs of IGP for implementation of zone-specific soil nutrient management strategies for attaining sustainability in crop yield. The developed MZ maps could also be utilized for prioritization and rationalization of nutrients supply in IGP of India.

Clinical purpura and elastosis and their correlation with skin tears in an aged population.

The previous research reported the results of a prospect cohort study that used logistic regression analysis to construct a risk prediction model for skin tears in individuals aged over 65 years. The model identified three baseline individual characteristics (male gender, history of STs, and history of falls) and two baseline skin manifestations (purpura and elastosis) that predicted the risk of dorsal forearm skin tears. This paper outlines the relationships between baseline skin manifestations and the risk of skin tears. Univariable logistic regression analysis was conducted of all the baseline data collected from the same-study participants to identify variables that significantly predicted purpura and elastosis at baseline. Amongst the 173 participants, 71 (41%) developed one or more skin tears, and in these participants, 52 (73.2%) displayed purpura, 41 (57.8%) had elastosis, and 30 (42.3%) exhibited both manifestations of the dorsal forearm at baseline. Four individual characteristics (age, history of skin tears, history of falls, and antiplatelet therapy) and three skin properties (pH, subepidermal low echogenicity band of the forearms, and skin thickness) were found to predict the risk of purpura. Conversely, three individual variables (age, gender, and smoking), three clinical skin variables (uneven skin pigmentation, cutis rhomboidalis nuchae, and history of actinic keratosis) and one skin property variable (collagen type IV) predicted the risk of skin elastosis. Progressive changes to the skin's structural and mechanical properties from the underlying effects of chronological ageing, and environmental and lifestyle-related influences increased the risk of purpura and elastotic skin manifestations and concomitantly increased risk of skin tears amongst participants.

A small scale honey dehydrator.

A small scale honey dehydrator has been designed, developed, and tested to reduce moisture content of honey below 17 %. Experiments have been conducted for honey dehydration by using drying air at ambient temperature, 30 and 40 °C and water at 35, 40 and 45 °C. In this dehydrator, hot water has been circulated in a water jacket around the honey container to heat honey. The heated honey has been pumped through a sieve to form honey streams through which drying air passes for moisture removal. The honey streams help in increasing the exposed surface area of honey in contact with drying air, thus resulting in faster dehydration of honey. The maximum drying rate per square meter area of honey exposed to drying air was found to be 197.0 g/h-m(2) corresponding to the drying air and water temperature of 40 and 45 °C respectively whereas it was found to be minimum (74.8 g/h-m(2)) corresponding to the drying air at ambient temperature (8-17 °C) and water at 35 °C. The energy cost of honey moisture content reduction from 25.2 to 16.4 % was Rs. 6.20 to Rs. 17.36 (US $ 0.10 to US $ 0.28 (One US $ = 62.00 Indian Rupee on February, 2014) per kilogram of honey.

The epidemic of human papillomavirus and oropharyngeal cancer in a Canadian population.

BACKGROUND: Sexually transmitted infection with the human papillomavirus (hpv) is responsible for a significant burden of human cancers involving the cervix, anogenital tract, and oropharynx. Studies in the United States and Europe have demonstrated an alarming increase in the frequency of hpv-positive oropharyngeal cancer, but the same direct evidence does not exist in Canada. METHODS: Using the London Health Sciences Centre pathology database, we identified tonsillar cancers diagnosed between 1993 and 2011. Real-time polymerase chain reaction was then used on pre-treatment primary-site biopsy samples to test for dna from the high-risk hpv types 16 and 18. The study cohort was divided into three time periods: 1993-1999, 2000-2005, and 2006-2011. RESULTS: Of 160 tumour samples identified, 91 (57%) were positive for hpv 16. The total number of tonsillar cancers significantly increased from 1993-1999 to 2006-2011 (32 vs. 68), and the proportion of cases that were hpv-positive substantially increased (25% vs. 62%, p < 0.002). Those changes were associated with a marked improvement in 5-year overall survival (39% in 1993-1999 vs. 84% in 2006-2011, p < 0.001). When all factors were included in a multivariable model, only hpv status predicted treatment outcome. INTERPRETATION: The present study is the first to provide direct evidence that hpv-related oropharyngeal cancer is increasing in incidence in a Canadian population. Given the long lag time between hpv infection and clinically apparent malignancy, oropharyngeal cancer will be a significant clinical problem for the foreseeable future despite vaccination efforts.

Five-year decline in estimated glomerular filtration rate associated with a higher risk of renal disease and atherosclerotic vascular disease clinical events in elderly women.

BACKGROUND: Estimated glomerular filtration rate (eGFR) has been demonstrated to predict atherosclerotic vascular disease (ASVD)-associated clinical events independent of traditional vascular risk factors. Recent studies have demonstrated that eGFR decline over time may improve prediction of ASVD-associated mortality risk in chronic kidney disease (CKD) patients. AIM: The aim of this study is to evaluate the association between 5-year change in eGFR with renal disease and ASVD-associated clinical events. DESIGN: Prospective observational study. METHODS: A total of 1012 women over the age of 70 years from the Calcium Intake Fracture Outcome Study were included. Baseline characteristics including baseline and 5-year creatinine, participants' comorbidities and complete verified 10-year records for ASVD and renal disease-associated hospitalization and/or mortality were obtained using the Western Australian Data Linkage System. RESULTS: Participants were stratified according to annual rate of eGFR change in quartiles [≤-1.2 (first quartile), >-1.2 to 0.1 (second quartile), >0.1-1.7 (third quartile) and >1.7 ml/min/1.73 m(2)/year (fourth quartile)]. In the adjusted model, compared with participants in the fourth quartile, those in the first and/or second quartiles of annual eGFR change had significantly higher risk of renal disease and/or ASVD-associated clinical events. However, the association with renal clinical events was more pparent in participants with baseline eGFR of <60 ml/min/1.73 m(2). CONCLUSION: The results of this study suggest that the inclusion of long-term eGFR change over time might augment prognostication for renal disease and ASVD-associated clinical events in elderly women.

Pseudoaneurysm of the external carotid artery secondary to subcondylar fracture.

Arterial pseudoaneurysms are rare in oral and maxillofacial surgery, but when they occur, quick recognition and management is necessary to avoid devastating consequences. The authors report a case of a pseudoaneurysm of the external carotid artery that developed after open reduction and internal fixation of a mandibular condyle fracture.

Cocomposting with and without Eisenia fetida for conversion of toxic paper mill sludge to a soil conditioner.

Present study was envisaged for fast bioremediation of toxic paper mill sludge into a soil ameliorating agent. Although a rich source of organic carbon this sludge cannot be directly applied in fields and is recycled very slowly in landfills as it is deficient in other nutrients. Therefore it was mixed with cattle dung in various proportions and subjected to aerobic cocomposting (without worms) and vermicocomposting (with Eisenia fetida). It was observed that mixing cattle dung with the sludge improved physico-chemical characteristics (with transition metals in the permissible range for manures) of the products of both the processes and enhanced its acceptability for worms. Higher decline in organic carbon and higher content of nitrogen and phosphorous along with lower electrical conductivity and higher pH of the products of vermicomposting indicated that E. fetida helped in fast conversion of toxic paper mill sludge into a soil conditioner in 100days.

Effects of a 1-year randomized controlled trial of resistance training on lower limb bone and muscle structure and function in older men.

SUMMARY: A 1-year randomized controlled trial of resistance training compared with a control group was undertaken in 143 men aged 55-80 years. Although hip bone mineral density, lean body mass, and function increased in both groups, lean body mass and function but not bone density increased more in the resistance group. INTRODUCTION: Previous studies have demonstrated a positive effect of resistance training on bone mineral density (BMD) in postmenopausal women, but the effect in men is unclear. The aim was to examine the effect of a 1-year resistance training program on bone and lean body mass in 143 men aged 55-80 years, randomized to either resistance training or active control. METHODS: Resistance exercises were selected to provide loading at the hips. Measurements were taken at 0, 6, and 12 months for BMD (whole body, hip, and spine), lean body mass, strength, and functional fitness. RESULTS: The intervention showed a significant increase in total hip BMD for both groups at 12 months (active control, 1,014-1,050 mg/cm(2); resistance, 1,045-1,054 mg/cm(2), p < 0.05) with no increased effect of resistance training compared to active control. However, compared to the active control group, the resistance group increased their lean body mass (active control, 0.1 +/- 2.1%; resistance, 1.5 +/- 2.7%, p < 0.05), fitness (active control, 4.6 +/- 11.1%; resistance, 13.0 +/- 13.4%, p < 0.05), and lower limb muscle strength (active control, 14.3 +/- 16.8%; resistance, 39.4 +/- 30.87%, p < 0.05). CONCLUSIONS: In contrast to previous findings in older women, in older men, a resistance training program does not increase hip bone mass more than walking 30 min three times a week.

The acute effects of psyllium on postprandial lipaemia and thermogenesis in overweight and obese men.

Overweight and obesity is one of the risk factors for developing CVD. At present, very little is known about the acute effects of dietary fibre on lipids, glucose and insulin, resting energy expenditure and diet-induced thermogenesis in overweight and obese individuals. This study examined the postprandial metabolic effects of dietary fibre in overweight and obese men. Ten overweight and obese men consumed a mixed meal accompanied by either a high-fibre or low-fibre supplement on two separate visits, in a random order, 1 week apart. Two isoenergetic breakfast meals with similar composition were consumed by ten overweight/obese men. The meals contained either a low (3 g) or high (15 g) amount of fibre, low-fibre meal (LFM) and high-fibre meal (HFM) respectively. Analysis was carried out using paired t test and ANOVA. Serum TAG incremental area under the curve during 6 h of the postprandial period was significantly lower after the consumption of HFM compared with LFM. At the first hour of the postprandial period, plasma apo B48 concentration after consumption of HFM was significantly lower compared with LFM. The resting energy expenditure and diet-induced thermogenesis after both meals was similar during 6 h of the postprandial period. Collectively, these findings suggest that a single acute dose of dietary fibre in the form of psyllium supplement can decrease arterial exposure to TAG and modify chylomicron responses in the postprandial period.

Membrane type-1 matrix metalloproteinase is induced following cyclic compression of in vitro grown bovine chondrocytes.

OBJECTIVE: To determine if membrane type-1 matrix metalloproteinase (MT1-MMP) will respond to cyclic compression of chondrocytes grown in vitro and the regulatory mechanisms underlying this response. METHODS: Cyclic compression (30min, 1kPa, 1Hz) was applied to bovine chondrocytes (6-9-month-old animals) grown on top of a biodegradable substrate within 3 days of initiating culture. Luciferase assays using bovine articular chondrocytes were undertaken to demonstrate the mechanosensitivity of MT1-MMP. Semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) and western blot analysis were used to establish the time course of gene and protein upregulation in response to cyclic compression. The regulation of MT1-MMP was assessed by electrophoretic mobility shift assays, RT-PCR and western blot analysis. As well, an MT1-MMP decoy oligonucleotide and an extracellular signal-regulated kinase 1/2 (ERK1/2) pharmacological inhibitor were utilized to further characterize MT1-MMP regulation. RESULTS: After cyclic compression, MT1-MMP showed a rapid and transient increase in gene expression. Elevated protein levels were detected within 2h of stimulation which returned to baseline by 6h. During cyclic compression, phosphorylation of the mitogen activated protein kinase ERK1/2 increased significantly. This was followed by increased gene and protein expression of the transcription factor; early growth factor-1 (Egr-1) and Egr-1 binding to the MT1-MMP promoter. Blocking Egr-1 DNA binding with a decoy MT1-MMP oligonucleotide, downregulated MT1-MMP gene expression. The ERK1/2 inhibitor U0126 also reduced Egr-1 DNA binding activity to MT1-MMP promoter sequences and subsequent transcription of MT1-MMP. CONCLUSIONS: These data suggest that cyclic compression of chondrocytes in vitro upregulates MT1-MMP via ERK1/2 dependent activation of Egr-1 binding. Delineation of the regulatory pathways activated by mechanical stimulation will further our understating of the mechanisms influencing tissue remodeling.

A cohort study of the effect of endogenous estrogen on spine fracture risk and bone structure in elderly women and an assessment of its diagnostic usefulness.

The decline in endogenous estrogen concentration after menopause is associated with accelerated bone loss. However, effects in older women remain controversial and the usefulness of estrogen status as a predictor of spine fracture has not been assessed. Therefore, we undertook a prospective cohort study of 1350 women mean age 75 years in order to study the role of endogenous estrogen concentration on the risk of morphometric X-ray absorptiometry (MXA)-defined vertebral deformity and atraumatic clinical spine fracture and the association of endogenous estrogen with bone structure. At 5 years 70 patients (5.2%) had sustained > or = 1 incident spine fracture. The fracture group had significantly lower concentrations of baseline free estradiol index (FEI) median (IQ range) (0.38 (0.22-0.60) vs. 0.49 (0.29-0.84) pmol/nmol, p=0.009). The patients in the lowest tertile of FEI (FEI <0.35) had twice the risk of sustaining a clinical vertebral fracture compared to those subjects in the highest tertile (FEI >0.68) (HR 2.18: 95% CI 1.11-4.28). A low FEI was associated with an increased risk of a vertebral deformity over the 5-year study (OR 1.77: 95% CI 1.02-3.07) for the lowest compared to highest tertile. A low baseline FEI was associated with lower baseline QUS heel bone structure and DXA hip bone structure at 12 months and with deterioration in QUS heel bone structure 5 years later. The effect size of the FEI in predicting spine fracture was similar to the effect size for DXA BMD and heel QUS, probably because of the beneficial effect of the FEI on bone structure. The data suggest that the estrogen effect on reducing spine fracture is at least in part due to an effect on bone structure and its measurement does not significantly improve fracture prediction.

Preferred clinical measures of central obesity for predicting mortality.

OBJECTIVE: To define the clinical measures of obesity that best predict all cause mortality and cardiovascular disease (CVD) mortality. DESIGN AND SETTING: Eleven-year mortality follow-up of an Australian urban population sample of 9309 adults aged 20-69 years in 1989. Baseline measures of obesity included body mass index (BMI), waist circumference (WC), waist-to-stature ratio and the waist-to-hip ratio. The age-standardized hazard ratios for mortality were calculated for 1 s.d. above the mean for each measure of obesity using Cox regression analysis. We constructed receiver operator characteristic (ROC) curves to assess sensitivity and specificity of the measures and to identify approximate cut-points for the prediction of risk. RESULTS: Waist-to-hip ratio was superior by magnitude and significance in predicting all cause mortality (male hazard ratio 1.25, P=0.003, female hazard ratio 1.24, P=0.003) and CVD mortality (male hazard ratio 1.62, P<0.001, female hazard ratio 1.59, P<0.001). Waist-to-stature ratio and WC were highly significant but less powerful predictors for CVD mortality. ROC analysis showed higher 'area under the curve' values for waist-related measures in males, with similar less marked trends in females. The ROC cut-points yielded values that corresponded to current promulgated criteria. CONCLUSIONS: The waist-to-hip ratio is the preferred clinical measure of obesity for predicting all cause and CVD mortality. WC is a practical alternative. Waist-to-stature ratio is not more useful than WC alone.

Cyclic compressive mechanical stimulation induces sequential catabolic and anabolic gene changes in chondrocytes resulting in increased extracellular matrix accumulation.

Overcoming the limited ability of articular cartilage to self-repair may be possible through tissue engineering. However, bioengineered cartilage formed using current methods does not match the physical properties of native cartilage. In previous studies we demonstrated that mechanical stimulation improved cartilage tissue formation. This study examines the mechanisms by which this occurs. Application of uniaxial, cyclic compression (1 kPa, 1 Hz, 30 min) significantly increased matrix metalloprotease (MMP)-3 and MMP-13 gene expression at 2 h compared to unstimulated cells. These returned to constitutive levels by 6 h. Increased MMP-13 protein levels, both pro- and active forms, were detected at 6 h and these decreased by 24 h. This was associated with tissue degradation as more proteoglycans and collagen had been released into the culture media at 6 h when compared to the unstimulated cells. This catabolic change was followed by a significant increase in type II collagen and aggrecan gene expression at 12 h post-stimulation and increased synthesis and accumulation of these matrix molecules at 24 h. Mechanical stimulation activated the MAP kinase pathway as there was increased phosphorylation of ERK1/2 and JNK as well as increased AP-1 binding. Mechanical stimulation in the presence of the JNK inhibitor, SP600125, blocked AP-1 binding preventing the increased gene expression of MMP-3 and -13 at 2 h and type II collagen and aggrecan at 12 h as well as the increased matrix synthesis and accumulation. Given the sequence of changes, cyclic compressive loading appears to initiate a remodelling effect involving MAPK and AP-1 signalling resulting in improved in vitro formation of cartilage.

Prediction of incident osteoporotic fractures in elderly women using the free estradiol index.

A decline in postmenopausal estrogen concentration accelerates postmenopausal bone loss. We have examined the predictive power of endogenous estrogen production, DXA hip bone density (BMD), and heel quantitative ultrasound (QUS) on incident clinical fracture in a prospective 3-year population based, randomised controlled trial of calcium supplementation. Baseline blood testing on 1499 women mean (SD) age 75 (3) years for estradiol and sex hormone binding globulin measurements and ankle QUS measurements (Lunar Achilles) was undertaken. Bone density was measured using DXA (Hologic 4500A) at 1 year. Incident clinical fractures were confirmed by X-ray. At 3 years, 10% had sustained more than one incident fracture. The fracture group had significantly lower levels of free estradiol index (FEI) (0.40+/-0.44 versus 0.49+/-0.54 pmol/nmol), hip BMD (0.776+/-0.129 versus 0.815+/-0.124 g/cm(2)) and measures of QUS (BUA 98+/-8 versus 101+/-8 db/Hz, SOS 1504+/-22 versus 1514 +/-26 m/s; stiffness 67+/-11 versus 71+/-11 % mean young adult), respectively, than the non-fracture group. After adjustment for age, weight, use of topical estrogen, calcium supplementation and prevalent fracture, incident fracture was predicted by free estradiol index (HR per SD: 1.43:95%CI: 1.08-1.91, P=0.013). After adjustment for BMD, SOS or stiffness, the free estradiol index no longer predicted fracture. When examined separately, the presence of a vertebral or an appendicular fracture was associated with an 18% lower free estradiol index compared with no fracture. The risk of vertebral fracture increased with decreased free estradiol index (HR per SD reduction: 1.63:95% CI: 0.91-2.92); the risk of appendicular fracture also increased with decreased free estradiol index (HR per SD reduction: 1.45:95% CI: 1.05-2.01) after adjustment for age, weight, use of topical estrogen, calcium supplementation and prevalent fracture. After further adjustment for hip BMD or QUS measures, the effect of free estradiol index was no longer significant for vertebral or appendicular fractures. Therefore, a low free estradiol index increases the probability of having an incident fracture as a result of decreased BMD. These data confirm the importance of postmenopausal estrogen concentration in the pathogenesis of osteoporosis in elderly women.

A randomized clinical trial comparing oral alendronate and intravenous pamidronate for the treatment of Paget's disease of bone.

Second and third generation bisphosphonates are the treatment of choice for Paget's disease of bone. These drugs are more effective than calcitonin and etidronate, but there have been no head to head, randomized controlled trials comparing potent bisphosphonates. We conducted a 2-year, randomized, open-label trial comparing oral alendronate and intravenous pamidronate in 72 subjects with Paget's disease. Randomization was stratified according to baseline plasma total alkaline phosphatase (ALP) and previous bisphosphonate treatment (yes or no). All previously treated patients had received pamidronate but not alendronate. Assigned treatments were pamidronate (60 mg) every 3 months as a single infusion or alendronate (40 mg) daily in 3-month blocks, continued until biochemical remission (defined as both ALP and urine deoxypyridinoline (DPD)/creatinine ratio in the reference range) or a clear plateau effect was observed. At 1 year, nonresponders to pamidronate were crossed over to alendronate treatment. At 1 year, 31/36 (86%) subjects randomized to alendronate achieved biochemical remission compared with 21/36 (56%) for pamidronate (P = 0.017). There was a significantly greater reduction in ALP (P < 0.001) and DPD/creatinine ratio (P < 0.001) for alendronate compared with pamidronate treatment. In previously untreated patients, alendronate resulted in remission in 20/22 (91%) subjects compared with 19/22 (86%) of pamidronate-treated subjects, which was not significantly different; however, alendronate resulted in a significantly greater reduction in ALP (P = 0.014) and DPD/creatinine ratio (P < 0.001). In previously treated patients, alendronate resulted in remission in 11/14 (79%) subjects compared with 2/14 (14%) for pamidronate (P < 0.001), with a significantly (P < 0.001) greater reduction in both ALP and DPD/creatinine ratio. Of subjects crossed over from pamidronate to alendronate, 10/14 (71%) achieved remission, including 9/11 (82%) previously treated patients. We conclude that, in patients with previously untreated Paget's disease of bone, alendronate and pamidronate have similar efficacy in achieving biochemical remission. In patients previously treated with pamidronate, alendronate is more effective.

Calcium-sensing receptor gene polymorphism A986S does not predict serum calcium level, bone mineral density, calcaneal ultrasound indices, or fracture rate in a large cohort of elderly women.

Postmenopausal osteoporosis is a complex and heterogeneous disease influenced by multiple factors and related to peak bone mass achieved in early adult life, followed by a subsequent continuous bone loss. Genetic variance and polymorphisms have been shown to be of clinical significance for osteoporotic fragility fractures. Previous studies have related variations in the calcium sensor receptor (CASR) gene to circulating Ca levels and bone mass in young women and adolescent girls. The aim of this study was to investigate the impact of the A986S polymorphism of the CASR gene on calcium homeostasis and bone metabolism in elderly women. We studied the distribution of the A986S polymorphism in a large cohort of 1252 ambulatory Australian women in relation to biochemical markers of bone metabolism, bone mass evaluated by quantitative ultrasound measurements (QUS) and DXA of the hip, prevalent and 36-month incident fracture data. No effect of the polymorphism was found on circulating calcium level, renal Ca excretion, or biochemical markers of bone turnover. Moreover, A986S was not associated with bone mass or prevalent or incident fractures. Power calculations revealed that a difference in circulating calcium levels of 0.05 mmol/l, a difference in DXA bone density of 24 mg, and a 1.6-fold difference in fracture rate could have been detected with a power of 80%. In conclusion, in a large cohort of elderly women the A986S polymorphism of the CASR gene was not found to be significant for calcium homeostasis or bone mass. It is questioned whether the polymorphism has any clinical significance for postmenopausal osteoporosis.

The T869C TGF beta polymorphism is associated with fracture, bone mineral density, and calcaneal quantitative ultrasound in elderly women.

Osteoporosis is a disease that is strongly genetically determined and polymorphisms present in a range of candidate genes may be involved. A number of previous studies have shown an association between the T869C functional polymorphism of the gene for transforming growth factor beta (TGF beta) and bone mineral density (BMD) and fracture, but these studies have been limited to relatively small studies of selected subjects. In a population-based study of 1337 white women over age 70 we examined the TGF beta T869 polymorphism in relation to BMD, calcaneal quantitative ultrasound (QUS), and prevalent and incident fracture. The TGF beta C allele was observed in 50% of the subjects and was associated with reduced hip BMD at all sites (2.8% total hip, 2.4% femoral neck, 2.6% intertrochanter, and 3.4% trochanter) compared to the TGF beta TT genotype. The TGF beta C allele was also associated with a reduction in the QUS parameters BUA, SOS, and stiffness of 0.87%, 0.26%, and 2.4%, respectively, compared to the TGF beta TT genotype. After adjustment for body mass index in an analysis of variance model, the effect of the TGF beta C allele remained significant at the total hip, the femoral neck, and the trochanter, and for the QUS SOS and stiffness parameters. The TGF beta C allele was associated with an increase in osteoporosis [T score < or =-2.5 SD; odds ratio (OR) 2.07; 95% confidence interval (CI) 1.19-3.60] and prevalent fracture (1.37; 95% CI 1.06-1.75). After adjustment for BMD and QUS stiffness, the association of the TGF beta C allele with prevalent fracture was still present (OR 1.40; 95% CI 1.04-1.89), suggesting that the effect of the C allele on fracture was independent of a reduction in BMD and QUS stiffness. Subjects with normal BMD and a TGF beta C allele had an increased risk of incident fracture over 3 years compared to subjects with normal BMD and a TGF beta TT genotype (relative risk 3.95; 95% CI 1.52-10.29). This association was not found in osteopenic or in osteoporotic subjects, indicating a BMD-TGF beta C allele interaction in relation to the association of the TGF beta C allele with fracture risk. These findings are of potential clinical usefulness, as the TGF beta T869C genotype could be used, in conjunction with other genetic and clinical information, to determine an individual's risk of osteoporosis.