Vitamin D receptor genotypes and bone mineral density.
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Biomedical subjects
Publications and source records attributed to E Alhava.
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Several prospective studies have shown that the bone mineral density (BMD) measured in the appendicular or axial skeleton has an inverse relationship with the risk of subsequent fractures. However, most of these studies have concentrated on relatively old age groups, and the usefulness of measuring BMD at the time of menopause has not been established. In the present study, BMD was measured at the lumbar spine and femoral neck by dual X-ray absorptiometry (DXA) in a random stratified population sample of 3222 perimenopausal women (mean age 53.4 years, range 47-59 years). These women were followed for fractures over a period of 2 years. The fractures reported by a postal inquiry were verified from medical records. Fractures sustained in motor vehicle accidents were excluded from the analyses. During a mean follow-up of 2.4 years, 183 fractures occurred in 168 women. Wrist (n = 47), ankle (n = 31), and rib (n = 28) were the most common sites of a fracture. Women in the lowest quartile of spinal BMD had a 2.9 times greater risk of fracture than those in the highest quartile. The respective risk increased 2.2 times from the lowest to the highest quartile of femoral BMD, respectively. The relative risk for suffering from any fracture per one SD decrease in BMD was 1.50 (95% CI; 1.27-1.76) for the spine and 1.41 (1.21-1.64) for the femoral neck. The present study demonstrates that bone mass is important in the pathogenesis of fractures even in perimenopausal women. We conclude that the axial BMD measurement at the time of menopause can be of use in predicting subsequent fracture risk.
OBJECTIVE: To evaluate the effects of intra-abdominal surgical emergency on breathing pattern and gas exchange and compare it with the changes induced by elective abdominal surgery. DESIGN: Prospective clinical study. SETTING: Abdominal surgical departments in a university hospital. PATIENTS: Patients operated for intra-abdominal emergency (n = 10, EAS), elective upper abdominal (n = 19, UAS). MEASUREMENTS AND RESULTS: Breathing pattern and gas exchange were measured with a respiratory inductive plethysmograph and a gas exchange monitor. EAS patients had pre-operatively a classical rapid shallow breathing pattern and increased ventilatory demand due to increased energy expenditure. The operation improved the breathing to normal pattern (frequency, 26 +/- 5/min and 17 +/- 3/min, p < 0.01; tidal volume, 439 +/- 128 ml and 541 +/- 165 ml, NS., before and after surgery, respectively). Sighing was absent before and after EAS and strictly reduced after elective surgery (p < 0.01 for UAS). The operation restricted the abdominal-diaphragmatic breathing movement which was reflected as increased contribution of the rib cage to VT (%RC: from 37% +/- 15 to 57% +/- 15 for UAS p < 0.001; from 47% +/- 16 to 61% +/- 14 for EAS NS.). After EAS and UAS hypoxemia was common (p < 0.001) with frequent radiological pathology. We conclude that intra-abdominal surgical emergencies increase the ventilatory demand and challenge the respiratory system to marked adaptive changes both pre- and post-operatively.
The relationship between gynecological history and bone mineral density (BMD) of the lumbar spine and femoral neck was studied in 3126 perimenopausal women. The study population was a random, stratified sample of participants, selected from the Kuopio Osteoporosis Study, which consisted primarily of all 14,220 women aged 47-56 years in Kuopio Province in 1989. After exclusion of 1521 women reporting past or present hormonal replacement therapy (HRT), 1605 women formed the final study population. Present HRT users had significantly higher lumbar BMD but not femoral BMD, than non-hormone users. Postmenopausal status, late menarche, and bilateral oophorectomy were risk factors for low BMD. Protective factors against low BMD were increased body weight, increased number of pregnancies, as well as hysterectomy without bilateral oophorectomy. The majority (43.8%) of these operations had been performed due to the presence of leiomyomas. No significant correlation was found between nulliparity, breast-feeding or amenorrhea before the age of 30 and BMD. In the multiple regression analysis, gynecological variables could account for only 18.4-26.8% of the variance in BMD, while time since last periods, age, age at menarche, weight and hysterectomy were the most significant variables. We conclude that reproductive history gives rise to some special risk groups, to whom BMD measurements and osteoporosis prevention efforts should be directed. However, it is impossible to predict BMD by gynecological characteristics.
The relationship between past fractures and current bone density (BMD) was analyzed in a population sample of 3222 women aged 48-58. BMD was determined with dual X-ray absorptiometry (DXA) at the spine and femoral neck. 702 women reported fractures. Wrist and ankle were the most common fracture sites. Fracture history increased the risk [OR (95% CI)] of low spinal BMD (of more than 1 SD below the study population mean) by 1.75 (1.41; 2.18). The sensitivity and specificity of fracture history to detect a low spinal BMD were 31 and 80%, respectively. One SD decreases of spinal and femoral BMD equalled to respective overall fracture risks (adjusted ORs) of 1.36 (1.24; 1.50) and 1.38 (1.25; 1.51). Both BMDs related more strongly to wrist fracture [1.73 (1.47; 2.05)/1.69 (1.43; 1.99)] than to all nonwrist fractures combined [1.24 (1.11; 1.37)/1.27 (1.14; 1.42)]. Ankle and rib fractures related only to spinal [1.21 (1.00; 1.46)/1.45 (1.12; 1.87)] but tibia and foot bone fractures only to femoral [2.04 (1.37; 3.04)/2.20 (1.42; 3.41)] BMD. Spinal BMD related more strongly to fractures due to falls on same level than to fractures due to all other trauma combined. Fracture history poorly screens out low perimenopausal BMD. The results suggest that pre- and perimenopausal fractures relate to low axial bone density and that the magnitude of this relation depends on the sites of fracture and densitometry as well as on the type of trauma.
1. Pilocarpine is a cholinomimetic natural alkaloid. Its interactions with testosterone hydroxylations, coumarin 7-hydroxylase (COH), dimethylnitrosamine N-demethylase (DMNA), pentoxyresorufin O-dealkylase (PROD) and 7-ethoxyresorufin O-deethylase (EROD), which are indicative of the activities of cytochrome P4502A5 (CYP2A5) or 6, 2E1, 2B, 1A, were examined in mouse and human liver microsomes. 2. In mouse liver microsomes the IC50 values of pilocarpine were 6 microM for COH and testosterone 15 alpha-hydroxylase (T15 alpha OH) activities, 4 microM for PROD, approximately 100 microM for DMNA and testosterone 6 beta-hydroxylase (T6 beta OH) activities and > 1 mM for EROD activity. 3. In human liver microsomes, the IC50 value for COH was 6 microM and for DMNA 10 microM; T15 alpha OH and PROD activities were not detectable but T6 beta OH and testosterone 16 beta/2 beta-hydroxylase activities were moderately inhibited (IC50 70 microM). 4. These results suggest that pilocarpine has (i) a high affinity towards phenobarbitone-inducible CYP2A4/5 and CYP2B activities in mouse liver, (ii) a high affinity towards CYP2A6 in human liver microsomes and (iii) a moderate affinity towards CYP3A enzyme(s) in both microsomal preparations. 5. The low IC50 concentrations in vitro indicate potential metabolic interactions between pilocarpine and several P450 enzymes.
OBJECTIVE: To examine the associations between potential risk factors and fractures in perimenopausal women. SUBJECTS: A total of 3,140 women (mean age 53.4 +/- 2.8 (s.d.) years) were followed-up for 2.4 years after axial bone densitometry (lumbar spine and femoral neck) with regard to the occurrence of fractures. RESULTS: In all, 5.6% of the women sustained a fracture. There were 169 low energy fractures (falling on a level surface) in 157 women after the exclusion of 18 fractures caused by a high energy trauma. The wrist was the most frequent site of fracture (n = 46). Lumbar bone mineral density was 5.8% lower and femoral bone mineral density 4.6% lower among fracture cases compared with non-fracture cases (p < 0.0001). History of a fracture during 1980-1989 elevated the risk of all fractures 2.83-fold (95% confidence interval (CI) 1.95-4.10) and the risk of a first wrist fracture 2.25-fold (95% CI 1.10-4.62). The amount of weekly alcohol intake was higher among fracture cases than among non-fracture cases yielding an age-adjusted odds ratio (OR) of 1.45 (95% CI 1.05-2.02). Past or present use of hormone replacement therapy was protective against fractures (age-adjusted OR 0.70, 95% CI 0.50-0.96). If bilateral oophorectomy had been carried out under the age of 45 years, the risk of fracture was 3.64-fold (95% CI 1.01-13.04) compared with women operated upon after the age of 45 years. Age at menarche, parity, lactation and smoking history did not differ between the fracture and non-fracture groups. CONCLUSIONS: A former history of fractures, low baseline bone mineral density (BMD) and use of alcohol are predisposing factors associated with perimenopausal fractures, while hormone replacement therapy is protective in this respect.
A prospective study of 62 patients with colorectal cancer was carried out to evaluate the value of tumour-associated trypsin inhibitor (TATI) in the diagnosis and staging of this disease. The reference group consisted of 97 patients with benign gastrointestinal disease. Increased serum TATI levels were detected in 46 patients with colorectal cancer (sensitivity 74%), and the highest mean values were measured in the patients with stage II cancer. The frequency of elevated values was not affected by the stage of the disease, however. There were altogether 64 false positives (specificity 34%). In comparison to CEA and CA 242, TATI showed higher sensitivity at low (< 40%) specificity levels, but it was less sensitive at high (70-95%) specificity levels. The performance of the CA 50 test was poorest both at high and low specificity levels. The various combinations of TATI and other markers (two tests positive) did not offer any further advantage as compared to CEA alone. A marginally significant positive correlation (p = 0.07) was found between serum TATI and CEA values in colorectal cancer patients. The results suggest that TATI is a very sensitive marker in colorectal cancer, but its utility is limited because of its low specificity in symptomatic patients. Concomitant measurement of TATI and other markers does not seem to give any further benefit, and nor does TATI seem to have any significant value in staging of the disease. Our results also indicate that CEA is probably the best current test in colorectal cancer.
We determined broadband ultrasound attenuation (BUA) of the calcaneus, and bone mineral density (BMD) of the spine, proximal femur and radius in 137 healthy subjects (79 women and 58 men) and in 56 women with Colles' fracture. The repeated measurements on 9 healthy subjects indicated a short-term reproducibility (coefficient of variation) of 4 percent for BUA. There was a small (7 percent) but significant difference in BUA between normal men and women. The age-dependence in normal subjects was weak. When all the study subjects were pooled, modest correlations between BUA of the calcaneus and BMD at all measured skeletal sites were found (rs values 0.3-0.4). However, it was not possible to make an accurate prediction of the axial BMD, using BUA. BUA values were 13 percent lower in the wrist fracture patients than in the age-matched normals. In general, BUA could discriminate the fracture patients from normals as effectively as BMD. As suggested by the physical theory of ultrasound attenuation, our results support the idea that BUA reflects not only the bone density but also other factors related to the structural properties of bone.
OBJECTIVE: To evaluate the contribution to peak bone mass of exercise, smoking, and calcium intake in adolescents and young adults. DESIGN: Prospective cohort study with end point measurement (bone mineral density) after 11 years' follow up for lifestyle. SETTING: Five university hospital clinics. SUBJECTS: 264 (153 females, 111 males) subjects aged 9 to 18 years at the beginning of the follow up and 20 to 29 years at the time of measurement of bone mineral density. MAIN OUTCOME MEASURE: Bone mineral density of lumbar spine and femoral neck by dual energy x ray absorptiometry; measures of physical activity and smoking and estimates of calcium intake repeated three times during follow up. RESULTS: In the groups with the lowest and highest levels of exercise the femoral bone mineral densities (adjusted for age and weight) were 0.918 and 0.988 g/cm2 for women (P = 0.015, analysis of covariance) and 0.943 and 1.042 g/cm2 for men (P = 0.005), respectively; at the lumbar spine the respective values were 1.045 and 1.131 (P = 0.005) for men. In men the femoral bone mineral densities (adjusted for age, weight, and exercise) were 1.022 and 0.923 g/cm2 for the groups with the lowest and highest values of smoking index (P = 0.054, analysis of covariance). In women the adjusted femoral bone mineral density increased by 4.7% together with increasing calcium intake (P = 0.089, analysis of covariance). In multiple regression analysis on bone mineral density of the femoral neck, weight, exercise, age, and smoking were independent predictors for men; with weight, exercise, and age for women. These predictors together explained 38% of the variance in bone mineral density in women and 46% in men. At the lumbar spine, weight, smoking, and exercise were predictors for men; and only weight for women. CONCLUSIONS: Regular exercise and not smoking is important in achieving maximal peak bone mass in adolescents and young adults.
Population-based epidemiological studies on osteoporosis are few. Our study evaluated the effects of menopause and certain putative behavioural risk factors on bone mineral density (BMD). Spinal and femoral neck BMD were measured with dual X-ray absorptiometry (DXA) from 1600 perimenopausal women aged 48-59 years (mean 53.2 years) with no diseases or medications known to affect bone metabolism. These women were a selected sample of the Kuopio Osteoporosis Risk Factor and Prevention Study population (n = 14,220). There was a wide variation of BMD among perimenopausal women. Menopause had a major effect on BMD. Postmenopausal women had significantly lower BMD in both spine (-6.2%) and femoral neck (-3.9%) as compared with premenopausal women. Multiple regression analysis showed that weight, menopausal status, age, and grip strength were significant independent predictors of both spinal and femoral BMD. Additionally, physical activity was found to be a significant predictor of femoral BMD, and alcohol consumption was a significant predictor of spinal BMD. However, current anthropometric and lifestyle factors explained only 18.7-25.4% of the variability of BMD. Therefore, the estimation of the risk factor status at menopause is not an adequate substitute for bone densitometry. However, our results may in part help clinicians to identify the risk groups at which to direct bone density measurements.
The bone mineral density (BMD) of the lumbar vertebrae L2-4 and femoral neck was determined by dual-energy X-ray absorptiometry (DXA) in 3222 perimenopausal women-a random stratified sample of the population-based Kuopio Osteoporosis Study (OSTPRE). The mean age of the women was 53.4 years (range 47.9-59.6 years). Twenty-nine percent of the women were past users of oral contraceptives (OC) containing 50 micrograms or less of ethinyl estradiol and 7.4% (n = 250) of the women reported OC use for more than 6 years. There was a slight but statistically significant difference between OC users (n = 939) and non-users (n = 2283) in lumbar BMD (1.134 +/- 0.155 g/cm2 v 1.123 +/- 0.161 g/cm2, p = 0.014). A statistically significant difference was recorded also after adjustment for years since menopause, duration of hormonal replacement therapy (HRT) and present weight (p = 0.044). When the analysis was performed among women who had never used oestrogen replacement therapy (n = 1427) and among premenopausal women (n = 387), no differences in BMD were found between OC users and non-users. Similarly, femoral neck BMD did not differ between the groups. This population-based study demonstrated a slightly higher lumbar BMD among past OC users. However, OC users and non-users differed from each other in many behavioral characteristics. Thus, the differences in BMD may be accounted for more by other factors than by past OC use itself. The low-dosage estrogen OCs used today would not be expected to have any positive bone effects among future perimenopausal women.
Biogenic amines play an important role in regulating cell proliferation in the normal and neoplastic colon. Elevated histidine decarboxylase (HDC) activity has been measured in human colorectal tumors. H2 antagonists can suppress the growth of colorectal cancer and their inclusion in human therapy has been proposed. We studied the effects of histamine, cimetidine, mepyramine and alpha-fluoromethylhistidine (FMH) on the growth of colorectal tumors in ten patients in the 6-day mouse subrenal capsule assay (SRCA). The effect of the Hic antagonist DPPE was tested in two assays. In summary, a reduction of tumor size was achieved with histamine and DPPE. In addition, significant inhibition of tumor growth was seen in the FMH-treated animals. When pooled by their growth potential, as assessed by the growth of saline-treated controls, FMH and DPPE caused distinct tumor reduction in rapidly growing tumors. In the moderately growing tumors, histamine and mepyramine were the most effective.
Bone mineral density (BMD) of the spine and femoral neck was measured in a random stratified sample of 3222 perimenopausal women aged 47-59 years. A total of 969 women had used fluoridated drinking water (1.0-1.2 mg/l) for over 10 years. These women were compared with 2253 women with low levels of fluoride in drinking water (< 0.3 mg/l). BMD of the spine was significantly higher in the fluoride group than in the non-fluoride group (1.138 +/- 0.165 vs. 1.123 +/- 0.156 g/cm2, P = 0.026). Femoral neck BMDs did not differ between the groups. When the BMD values were adjusted for confounding factors (age, weight, menopausal status, calcium intake, physical activity level, deliveries, alcohol consumption and estrogen use), the differences between the groups increased (P < 0.001 for the spine and P = 0.004 for the femoral neck, respectively). There was no significant difference between the groups in the prevalence of self-reported fractures sustained during 1980-1989. We propose that the fluoridation of drinking water has a slight increasing effect on axial BMD in women in low fluoride areas.
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BACKGROUND: The aim of this study was to determine whether the number of argyrophilic nucleolar organizer regions (AgNORs) could be of diagnostic significance in differentiating between chronic pancreatitis and pancreatic ductal adenocarcinoma. METHODS: The number of AgNORs was enumerated in biopsy specimens of normal pancreas, chronic pancreatitis, and pancreatic ductal adenocarcinoma. RESULTS: The number of AgNORs was lower in patients with normal pancreas than in patients with chronic pancreatitis or pancreatic adenocarcinoma. In addition, the number of AgNORs was significantly lower in chronic pancreatitis than in pancreatic ductal adenocarcinoma (p < 0.001). CONCLUSIONS: The diagnosis of pancreatic adenocarcinoma is usually clear. Difficulties can be encountered, however, in cases of chronic pancreatitis, specially when biopsy material is small. Our results suggest that the number of AgNORs may help in distinguishing between chronic pancreatitis and pancreatic ductal adenocarcinoma, especially in diagnostically difficult specimens.
We investigated the effect of clodronate on immobilization osteopenia (IO) induced by sciatic neurectomy in rats. 100 Wistar female rats were divided into 5 groups of 20 animals each: 1) sham-operated, control group, 2) IO+saline control group, 3) IO+clodronate 3 mg/kg/day, 4) IO+clodronate 10 mg/kg/day, and 5) IO+clodronate 30 mg/kg/day. Clodronate was administered subcutaneously beginning on the day after nerve sectioning. After 7 weeks, the animals were killed and both tibiae were removed. Bone mineral density, ash weight and calcium, phosphorus and magnesium contents of the ash of the tibiae were analyzed. The weight of the rats did not differ between the groups during the experiment. The ash weight of the tibiae decreased by 6.6 percent and the mineral density decreased by 5.1 percent after neurectomy. Clodronate reduced IO in a dose-dependent manner and the highest dose neutralized the effect of neurectomy. The calcium content of the ash decreased after neurectomy as compared to the sham-operated group, and clodronate increased it to the sham-operated level. The bone Ca/P ratio remained normal.
Periarticular osteoporosis is a common feature of rheumatoid arthritis. However, the cellular basis and the aetiology of periarticular bone loss have not been established. We studied periarticular bone samples obtained from metatarsal resections (n = 18) and total knee arthroplasties (n = 9) by histomorphometry. Autopsy material (n = 10) and patients with osteoarthrosis (n = 11) served as controls. Histomorphometrically, there was reduced trabecular bone volume and increased resorption surfaces in rheumatoid arthritis patients in most of the measured areas. The indices of bone turnover were most markedly increased in the vicinity of inflammatory cells and rheumatoid granulation tissue. Trabecular bone volume and the degree of inflammation as measured by the erythrocyte sedimentation rate (ESR) had a negative correlation. In addition, an elevated ESR was associated with increased osteoid parameters in periarticular bone. We conclude that periarticular bone loss in rheumatoid arthritis is due to increased bone resorption. Local inflammatory mediators might account for the increased bone turnover.