Segmental allergen challenge enhances chitinase activity and levels of CCL18 in mild atopic asthma.

BACKGROUND: Allergic airway inflammation contributes to the airway remodelling that has been linked to increased obstruction and morbidity in asthma. However, the mechanisms by which allergens contribute to airway remodelling in humans are not fully established. CCL18, chitotriosidase (CHIT1) and YKL-40 are readily detectable in the lungs and contribute to remodelling in other fibrotic diseases, but their involvement in allergic asthma is unclear. OBJECTIVE: We hypothesized that CCL18, YKL-40 and CHIT1 bioactivity are enhanced in allergic asthma subjects after segmental allergen challenge and are related to increased pro-fibrotic and Th2-associated mediators in the lungs. METHODS: Levels of CCL18 and YKL-40 protein and chitotriosidase (CHIT1) bioactivity in bronchoalveolar lavage (BAL) fluid, as well as CCL18, YKL-40 and CHIT1 mRNA levels in BAL cells were evaluated in patients with asthma at baseline and 48 h after segmental allergen challenge. We also examined the correlation between CCL18 and YKL-40 levels and CHIT1 activity with the levels of other pro-fibrotic factors and chemokines previously shown to be up-regulated after allergen challenge. RESULTS: Chitotriosidase activity and YKL-40 and CCL18 levels were elevated after segmental allergen challenge and these levels correlated with those of other pro-fibrotic factors, T cell chemokines, and inflammatory cells after allergen challenge. CCL18 and YKL-40 mRNA levels also increased in BAL cells after allergen challenge. CONCLUSIONS AND CLINICAL RELEVANCE: Our results suggest that CCL18 and YKL-40 levels and CHIT1 activity are enhanced in allergic airway inflammation and thus may contribute to airway remodelling in asthma.

Transitional hypothermia in preterm newborns.

Hypothermia remains a significant challenge in the initial care of premature infants. Although a number of prevention strategies have been identified, hypothermia is still a common event, especially in extremely low birth weight infants. Using data from four centers, we documented an incidence of hypothermia on admission to the neonatal intensive care unit from the delivery room of 31-78% for infants < 1500 g birth weight. Increased efforts will be necessary to prevent early hypothermia in very preterm infants, especially with respect to the environmental conditions of the delivery room itself. Journal of Perinatology (2007) 27, S45-S47. doi:10.1038/sj.jp.7211842.

Determinants of 25-hydroxyvitamin D levels in African-American and Caucasian male veterans.

SUMMARY: Among 307 males seen in VA Medical Center, independent determinants (p < 0.01 for all) of serum 25-hydroxyvitamin D [25(OH)D] levels included race, vitamin D supplements, BMI, dietary calcium intake and smoking, but not age. Negative association between 25(OH)D and parathyroid hormone (PTH) was similar for Caucasian and African-American men. INTRODUCTION: In this prospective cohort study, we examined determinants of serum 25-hydroxyvitamin D [25(OH)D] levels and the relationship between 25(OH)D and PTH levels and body mass index (BMI). METHODS: Male veterans (n = 307) were recruited at a VA Medical Center. Serum levels of PTH and 25(OH)D were obtained. Surveys and chart reviews were completed. Vitamin D insufficiency was defined as 25(OH)D <30 ng/ml. Univariate and multivariate regression analyses were performed. RESULTS: Among 232 African-American (AA) men (mean +/- SD), 25(OH)D level (21.4 +/- 10.4 ng/ml) was lower and prevalence of insufficiency (80%) was higher than among 75 Caucasians (C; 28.5 +/- 11.1 ng/ml and 53%, respectively, p < 0.01 for both). In multivariate regression analysis, independent determinants (p < 0.01 for all) of 25(OH)D levels included AA race, vitamin D supplements, BMI, dietary calcium intake, and smoking. Despite lower 25(OH)D levels in African-Americans, PTH levels were similar to those seen in Caucasians. There was a significant (p < 0.02) negative linear association between 25(OH)D and PTH in African-American (r(2) = 0.05) and Caucasian (r(2) = 0.08) men, and there was no difference between the slopes of the relationship. CONCLUSIONS: 25(OH)D levels are determined by modifiable risk factors such as vitamin D supplementation in both AA and C males. The negative association between 25(OH)D and PTH is similar between the two races.

Effects of vitamin D insufficiency on bone mineral density in African American men.

UNLABELLED: In African American men serum, 25-hydroxyvitamin D (25-OHD) was below 30 ng/ml in 89% of subjects. In overall group, there was no correlation between 25-OHD and bone mineral density (BMD). A subgroup analysis of subjects with 25-OHD

Transitional hypothermia in preterm newborns.

Hypothermia remains a significant challenge in the initial care of premature infants. Although a number of prevention strategies have been identified, hypothermia is still a common event, especially in extremely low birth weight infants. Using data from four centers, we documented an incidence of hypothermia on admission to the neonatal intensive care unit from the delivery room of 31-78% for infants <1500 g birth weight. Increased efforts will be necessary to prevent early hypothermia in very preterm infants, especially with respect to the environmental conditions of the delivery room itself.

The prevalence of emotional abuse in gynaecology patients and its association with gynaecological symptoms.

AIM: To determine the lifetime prevalence of emotional abuse in a population of women attending a gynaecology outpatient clinic and also to investigate whether women who reported emotional abuse were more likely to complain of certain gynaecological symptoms. SETTING: A gynaecology outpatient clinic in a North of England Hospital. METHODS: Anonymous confidential questionnaire given to women. RESULTS: Nine hundred and twenty consecutive women were included, 825 questionnaires were returned (90% response rate). The prevalence of emotional abuse was 24% (198/825). Emotional abuse is four times less common in women over 50 years old. Of the fifteen presenting symptoms reported by the women, referral for termination of pregnancy, cervical smear abnormality, worry about cancer and urinary incontinence were significantly more common in the group who reported emotional abuse. The women with emotional abuse also had significantly more consultations; however, the duration of their symptoms was not significantly different. CONCLUSION: The prevalence of emotional abuse in a group of women attending the gynaecology outpatient clinic in a North of England Hospital was 24%. Women who are subjected to emotional abuse tend to have more consultations and are more likely to complain of certain symptoms.

Utility of screening tools for the prediction of low bone mass in African American men.

INTRODUCTION: Osteoporosis remains under-diagnosed, particularly in African American men, despite the availability of reliable diagnostic tests. In women, several screening tools, including heel ultrasound and clinical assessment tools, reliably predict low bone mass, however the usefulness of these screening tools in African American men is unknown. The aim of this study was to determine the utility of screening tools, namely heel ultrasound, the osteoporosis self-assessment tool (OST), weight-based criterion (WBC) and body mass index (BMI), in screening for low bone mass in African American men. MATERIALS AND METHODS: African American men 35 years of age and older were invited to participate. The OST risk index is a score based on age and weight [(weight in kilograms--age in years)x0.2]. Bone mineral density (BMD) of the heel was measured by heel ultrasound, and BMD of both the lumbar spine and hip were determined by dual energy X-ray absorptometry (DXA). One hundred and twenty-eight men fulfilled the inclusion criteria for our study. RESULTS: The population prevalence of osteopenia and osteoporosis were 39% and 7%, respectively. Using a heel ultrasound T-score cut-off value of -1 or less, we predicted low bone mass (T-score of -2 or less at the hip) with a sensitivity of 83%, a specificity of 71% and an area under the curve (AUC) of 0.80. Using an OST cut-off value of 4, we predicted low bone mass with a sensitivity of 83%, a specificity of 57% and an AUC of 0.83. The OST risk index ranged from 18.1 to -6.1, based on which we categorized risk as: low, 5 or greater; moderate, 0-4; high, -1 or less. Of the men with a high-risk OST score, 87% had either osteopenia or osteoporosis based on World Health Organization (WHO) criteria. Using the WBC alone with a cut-off value of 85 kg, we predicted low bone mass with a sensitivity of 74%, a specificity of 50% and an AUC of 0.70. A BMI cut-off value of 30 or greater yielded a sensitivity of 83%, a specificity of 43% and an AUC of 0.70 for the diagnosis of low bone mass. DISCUSSION: The prevalence of osteopenia and osteoporosis were unexpectedly high in outpatient African American male veterans, who are considered to be at low risk for low bone mass. Heel ultrasound was able to predict low bone mass with sufficiently high sensitivity and specificity for use as a screening tool. Surprisingly, WBC and BMI proved ineffective in predicting low bone mass with adequate sensitivity and specificity. The OST, a clinical formula based on weight and age, appeared to be an easy and reliable screening tool for identifying men at high risk for low bone mass.

Domestic violence: prevalence and association with gynaecological symptoms.

OBJECTIVE: To determine the prevalence of domestic violence in a population of women attending a gynaecology outpatient clinic in the United Kingdom and also to investigate whether women who reported domestic violence were more likely to complain of certain gynaecological symptoms. DESIGN: Questionnaire survey. SETTING: A gynaecology outpatient clinic in a North of England Hospital. SAMPLE: Nine hundred and twenty consecutive clinic attenders. METHODS: Anonymous confidential questionnaire given to women. MAIN OUTCOME MEASURES: Disclosure of a past history of domestic violence and gynaecological complaints. RESULTS: Nine hundred and twenty consecutive women were included and 825 questionnaires were returned (90% response rate). The prevalence of physical abuse was 21% (171/825). Thirty-four (4%) had experienced violence in the past year. Domestic violence is three times less common in women over 50 years old. Ex-husbands (32%) and ex-boyfriends (29%) were the main perpetrators. Forty-eight percent women who had experienced physical violence also had forced sexual activity. Of the 15 presenting symptoms reported by the women, lower abdominal pain, dysmenorrhoea, dyspareunia, smear abnormalities, cancer worries and bowel symptoms were significantly more common complaints in the group who reported domestic violence. The women with domestic violence also had significantly more consultations; however, the duration of their symptoms was not significantly different. CONCLUSION: The prevalence of domestic violence in a cohort of women who attended the gynaecology outpatient clinic in a North of England Hospital was 21%. Women who are subjected to domestic violence tend to have more consultations and are more likely to complain of certain symptoms.

Effect of parathyroid hormone related protein, and dihydrotestosterone on proliferation and ornithine decarboxylase mRNA in human prostate cancer cell lines.

OBJECTIVES: Parathyroid hormone related protein (PTHrP) has been identified as the major hormone responsible for the syndrome of humoral hypercalcemia of malignancy (HHM). Recent studies have shown that a large number of prostate tumors demonstrate the presence of PTHrP despite the fact that prostate cancer is rarely associated with the HHM syndrome. Other studies have indicated that PTHrP behaves as an early response gene, which stimulates ornithine decarboxylase (ODC) enzyme activity, an enzyme, involved in the biosynthesis of polyamines. It is therefore possible that PTHrP regulates prostate tumor cell proliferation via ODC gene expression. METHODS: In the present study, we evaluated the effects of PTHrP and/or dihydrotestosterone (DHT) treatment on DNA synthesis by thymidine incorporation in androgen-dependent (LnCaP) and androgen-independent (PC3) human prostate adenocarcinoma cell lines. In addition, we utilized Northern blot analysis to investigate the effect of PTHrP [1-34] alone or in combination with DHT on ODC mRNA. RESULTS: PTHrP [1-34] treatment resulted in an increase in thymidine uptake in PC3 cells by 50%, whereas no such increase was seen in LnCaP cells. However, in the LnCaP cells, in the presence of DHT, PTHrP stimulated DNA synthesis to a level greater than that seen with DHT alone. DHT (10 nM) treatment resulted in an induction of PTHrP as well as ODC mRNAs in the androgen-dependent (LnCaP) but not in androgen-independent (PC3) cell line. PTHrP [1-34] treatment resulted in induction of ODC mRNA in the LnCaP cells. Addition of DHT resulted in a further increase in the ODC mRNA expression. CONCLUSIONS: These data suggest that PTHrP may play a role in prostate cancer cell proliferation and the increased ODC gene expression may be one possible mechanisms responsible for this phenomenon.

The synthetic phytoestrogen, ipriflavone, and estrogen prevent bone loss by different mechanisms.

Ipriflavone (IP), a synthetic isoflavone has been reported to prevent bone loss in both postmenopausal women and ovariectomized (ovx) rats. The purpose of this study was to compare and contrast some of the bone protective mechanisms of IP to those of 17beta-estradiol (E(2)) in ovarian hormone deficiency. Forty-eight 95-day-old Sprague-Dawley rats were assigned to four groups: sham, ovx, ovx+IP, and ovx+E(2). The doses of IP and E(2) were 100 mg and 10 microg/kg body weight per day, respectively. Rats were fed a diet that contained 0.4% calcium, 0.3% phosphorus, and 0.195 nmol vitamin D(3)/g diet. After sacrifice, left femoral bone densities were measured and bone histomorphometry was performed on the proximal tibial metaphysis. Ipriflavone as well as E(2) treatment completely prevented the ovx-induced femoral bone density loss. However, in contrast to E(2), IP did not lower the ovx-induced rise in serum alkaline phosphatase (ALP) activity or insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 concentrations. On histomorphometry analysis, the ovariectomy-induced increase (P < 0. 09) in bone formation rate (BFR) was significantly (P < 0.05) suppressed by E(2) treatment, whereas this higher BFR was maintained in IP-treated animals. These findings indicate that IP is effective in preventing the ovx-associated bone loss. The bone protective mechanisms of IP in ovarian hormone deficiency may be different from those of E(2) and may involve increased rates of bone formation.

Lifestyle and biologic contributors to proximal femur bone mineral density and hip axis length in two distinct ethnic groups of premenopausal women.

Although relatively little is known about osteoporotic risk factors in women from the Indian subcontinent, osteoporotic fractures usually occur 10-20 years earlier in Indian men and women compared with their western Caucasian counterparts. The primary purpose of this cross-sectional study was to determine the relative contributions of ethnicity, reproductive history, body size (height, weight) and composition, bone turnover, serum 25(OH)vitamin D(3) [25(OH)D(3)], dietary intake (of calcium, fiber and alcohol) and energy expenditure to femoral bone mineral density (BMD) in Indian and Pakistani (Indian/Pakistani; n = 47) versus American (n = 47) Caucasians. We also contrasted femoral BMD and hip axis length in these two distinct groups of premenopausal females living in the USA. The Indian/Pakistani (0.875 +/- 0.096) women had lower (p = 0.0014) femoral BMD (g/cm(2)) than their American (0.937 +/- 0.088) counterparts, placing them at greater osteoporotic risk. However, the shorter (p = 0.0002) hip axis length (cm) of the Indian/Pakistani (10.54 +/- 0.57) versus American (11.11 +/- 0.78) Caucasians might attenuate hip fracture risk in the former group. Significant contributors to proximal femur BMD were maximum non-pregnant lifetime weight, age at menarche, ratio of summation sigma central-to-peripheral skinfold thicknesses, calcium intake from milk and usual alcohol intake. Although serum 25(OH)D(3) and urinary N-telopeptide concentrations did not contribute to femoral BMD in the regression models, the lower (p<0.0001) serum 25(OH)D(3) (33.1 +/- 16.5 vs 64.0 +/- 22.0 nmol/l) and higher (p = 0.0004) urinary N-telopeptide (45.9 +/- 43.3 vs 18.9 +/- 18.7 nmol BCE/mmol) values in Indian/Pakistani versus American Caucasians, respectively, coupled with their lower BMD, places the Indian/Pakistani women at greater osteoporotic risk. These results suggest that a clinical trial to increase BMD and reduce osteoporotic risk is warranted in this ethnic group of premenopausal women.

Role of soy protein with normal or reduced isoflavone content in reversing bone loss induced by ovarian hormone deficiency in rats.

Soy protein, a rich source of isoflavones, fed immediately after an ovariectomy prevents bone loss in rats. Reports of the effectiveness of natural and synthetic isoflavones in preventing or treating osteoporosis led us to examine the effect of soy protein in reversing established bone loss. Seventy-two 95-d-old female Sprague-Dawley rats were assigned to 6 groups. The rats were either sham operated (SHAM; 2 groups) or ovariectomized (OVX; 4 groups) and then fed a casein-based, semipurified diet. Thirty-five days after surgery, 1 SHAM and 1 OVX group were killed to examine the occurrence of bone loss. Thereafter, the other SHAM and 1 OVX groups continued to receive the casein-based diet. Whereas the remaining 2 OVX groups received diets in which casein was replaced by soy protein with normal (OVX+SOY) or reduced (OVX+SOY-) isoflavone content for 65 days. The OVX control group had significantly lower femoral and fourth lumbar vertebral bone densities than the SHAM group. Femoral density of rats fed SOY or SOY- diets were not significantly different from SHAM or OVX controls. This suggests a slight reversal of cortical bone loss that may be partially due to higher femoral insulin-like growth factor I mRNA transcripts resulting from both the SOY and SOY- diets. The ovariectomy-induced increases in indexes of bone turnover were not ameliorated by either of the soy diets, suggesting that any positive effect of soy was achieved through enhanced bone formation rather than slowed bone resorption. Long-term consumption of soy or its isoflavones may be needed to produce small but continued increments in bone mass.

Bone-sparing effect of soy protein in ovarian hormone-deficient rats is related to its isoflavone content.

Our previous studies showed that a soy-protein diet prevents ovariectomy-induced bone loss. The purpose of this study was to determine whether isoflavones in soy protein are responsible for this bone-protective effect. Forty-eight 95-d-old Sprague-Dawley rats were divided into 4 groups: sham-operated fed a casein-based diet (SHAM), ovariectomized fed a casein-based diet (OVX+CASEIN), ovariectomized fed soy protein with normal isoflavone content (OVX+SOY), and ovariectomized fed soy protein with reduced isoflavone content (OVX+SOY-). The OVX+SOY group had significantly greater femoral bone density (in g/cm3 bone vol) than the OVX+CASEIN group, whereas OVX+SOY- was similar to OVX+CASEIN (mean +/- SD; SHAM, 1.522 +/- 0.041; OVX+CASEIN, 1.449 +/- 0.044; OVX+SOY, 1.497 +/- 0.030; OVX+SOY-, 1.452 +/- 0.030). Ovariectomy resulted in greater bone turnover as indicated by higher serum alkaline phosphatase activity, serum insulin-like growth factor I and insulin-like growth factor binding protein 3 concentrations, and urinary hydroxyproline. These increases were not affected by soy with either normal or reduced isoflavone content. Similarly, histomorphometry revealed a greater bone formation rate with ovariectomy, and this was not altered by the soy diets. The findings of this study suggest that isoflavones in soy protein are responsible for its bone-sparing effects. Further studies to evaluate the mechanism of action of isoflavones on bone are warranted.

Osteoporosis and coronary atherosclerosis in asymptomatic postmenopausal women.

Estrogen deficiency is a risk factor for osteoporosis and coronary artery disease. Osteoporosis can be evaluated by measuring bone mineral density (BMD). Coronary atherosclerotic burden can be evaluated by measuring coronary calcium using electron beam computed tomography (EBT) of the heart. We compared coronary calcium scores in 45 asymptomatic postmenopausal women with normal and low BMD. BMD of the lumbar spine and proximal femur was measured by dual X-ray absorptiometry (DXA), and coronary calcium was measured quantitatively by EBT. Women were divided into control, osteopenia, and osteoporosis groups based on the T score of the lumbar spine. Women were similar in age, years since menopause, height, weight, and body mass index (BMI). BMD +/- SD (g/cm2) of L1-L4 was 0.96 +/- 0.11, 0.83 +/- 0.03, and 0.73 +/- 0.05, in control, osteopenia, and osteoporosis group, respectively. The total coronary calcium score +/- SD (relative units) was 41.9 +/- 83.1, 115.1 +/- 181.9, and 221.7 +/- 355.4 for control, osteopenia, and osteoporosis group, respectively; the score was significantly higher in the osteoporosis than in the control group. This study provides initial data suggesting that women with osteoporosis may have a higher risk of developing coronary atherosclerosis.

Enhanced expression of parathyroid hormone-related protein in prostate cancer as compared with benign prostatic hyperplasia.

Parathyroid hormone-related protein (PTHrP) has been shown to be the primary factor responsible for humoral hypercalcemia of malignancy. Recently PTHrP has been shown to be an early-response gene that may be involved in cellular proliferation or differentiation. In addition, PTHrP has been implicated in the pathogenesis of bone metastases. Bone metastases are a significant complication in patients with prostate cancer. We compared the expression of PTHrP by immunohistochemical staining using a monoclonal antibody directed against epitope between amino acids [53-64] in benign prostatic hyperplasia (BPH) with that in various stages of prostate cancer. Tissue sections were obtained on formalin-fixed paraffin-embedded blocks from BPH, well-differentiated prostate cancer, poorly differentiated prostate cancer, lymph node metastases (n = 15 each), and normal prostate (n = 2). In the normal prostate tissue there was no staining observed. In BPH, 13 of 15 tissue samples were positive for PTHrP immunoreactivity. An average of 33% of the cells stained positive with 1+ intensity. All samples from prostate cancer stained positive for PTHrP. In the samples from well-differentiated prostate cancer, an average of 87% of cells stained positive for PTHrP, whereas 100% of cells were positive in poorly differentiated and metastatic tumors. The intensity of staining was 3+ in well-differentiated tumors and 4+ in poorly differentiated tumors. Therefore, the expression of PTHrP is enhanced in prostate cancer as compared with BPH and is greater in poorly differentiated carcinoma as compared with the well-differentiated tumors. The role of PTHrP in the pathogenesis of prostate cancer deserves further study.

Effects of progesterone on serum levels of IGF-1 and on femur IGF-1 mRNA in ovariectomized rats.

Local and systemic insulin-like growth factors (IGFs) may be involved in the regulation of bone formation by sex hormones. The present studies describe the in vivo effects of estradiol, progesterone, or both on IGF-1 mRNA abundance in bone, serum IGF-1 levels, and bone formation. Rats were sham-operated (SHAM) or ovariectomized (OVX) at 12 weeks of age and used a week later in three experiments. First, OVX rats were treated with vehicle, estradiol, and/or medroxyprogesterone (MPA) for 3 weeks, and bone formation was assessed in the tibial metaphysis. Second, OVX rats were treated in the same manner and serum IGF-1 levels measured. Third, OVX rats were treated with an injection of vehicle, estradiol, and/or progesterone, and 24 h later, levels of IGF-1 mRNA in the femur were analyzed. The mineralized surface, mineral opposition rate, and bone formation rate (BFR) were higher in OVX than in SHAM rats. The BFR was decreased in estrogen-treated but increased in MPA-treated rats compared with vehicle-treated OVX rats. Circulating levels of IGF-1 were higher in OVX than in SHAM rats but were not affected by sex hormones in a 3-week experiment, whereas these levels were not different among groups in a 24-h experiment. Northern analysis detected 7.5 and 0.8 kb IGF-1 mRNA transcripts. The abundance of IGF-1 mRNA was higher in OVX than in SHAM rats. IGF-1 transcripts 7.5 and 0.8 kb were decreased by 72 and 29%, respectively, in estrogen-treated and increased by 44 and 43%, respectively, in progesterone-treated rats compared with vehicle-treated OVX rats. We conclude that in the short term, estrogen lowers and progesterone raises bone IGF-1 mRNA and these changes are followed by coordinated changes in bone formation rate.

Parathyroid hormone-related protein expression in the human colon: immunohistochemical evaluation.

Parathyroid hormone-related protein (PTHrP) has been shown to be the primary factor responsible for humoral hypercalcemia of malignancy. In addition to its hypercalcemic action, PTHrP has been implicated as an autocrine modulator of growth and differentiation, as well as an early response gene in some tissues. Several different types of tumors have been evaluated for the presence of PTHrP immunoreactivity. In the present study, we evaluated the expression of PTHrP by immunohistochemical staining in tissue samples from normal colorectal mucosa, polyps, and colorectal carcinoma removed from the same patients (n = 10 each). We have used a commercially available monoclonal antibody directed against epitopes between amino acids [53-64] which share no homology to parathyroid hormone (PTH). In normal colon, 94.3 per cent of the tissue samples were negative for PTHrP immunoreactivity. In polyps of the colon, only 22.6 per cent of the cells showed positive immunostaining, whereas 91.5 per cent of the samples from colon cancer stained positive for PTHrP. In the case of polyps, the intensity of staining was 1-3+; however, all of the samples from adenocarcinoma stained with 4+ intensity. In the positive samples, the immunoreactivity was present throughout the cytoplasm of the glandular epithelium. Omission of primary antibody, as well as substitution of the primary antibody by a negative control monoclonal antibody or non-immune rabbit serum, resulted in a negative reaction. All analyses were performed in duplicate, and the data have been presented as mean +/- SEM. Differences in normal polyps, carcinoma of the colon, and PTHrP expression were tested for statistical significance by student's t test. Our results show the expression of PTHrP is enhanced in colon cancer tissue as compared to normal colorectal mucosa and polyps. In addition, the expression appears to be greater in polyp than in normal colon. The role of PTHrP in the pathogenesis of colon cancer deserves further study.

Transactivation of the PTHrP gene in squamous carcinomas predicts the occurrence of hypercalcemia in athymic mice.

Humoral hypercalcemia of malignancy (HHM) is caused by the secretion of parathyroid hormone-related protein (PTHrP) by tumor cells, and tumors of squamous histology are the ones most commonly complicated by HHM. To determine why some squamous tumors cause HHM and others do not, we quantitated the levels of PTHrP mRNA expression and PTHrP secretion in a series of eight squamous tumor lines. As anticipated, we found that the level of PTHrP mRNA expression in individual lines correlated with their PTHrP secretion rates. However, PTHrP mRNA levels varied widely in individual lines, and only those tumor lines with the highest levels of PTHrP gene expression were able to cause hypercalcemia in athymic mice. We found that a specific segment of the PTHrP promoter could reproduce the relative pattern of PTHrP gene expression when cloned in front of a chloramphenicol acetyltransferase reporter gene and transiently transfected into these squamous lines. Deletional analysis confirmed that specific sequences within the PTHrP gene promoter appeared to be involved in the transactivation of the gene in tumor lines expressing high levels of PTHrP mRNA. These data suggest that the ability of a given squamous tumor to cause HHM is ultimately a function of its level of PTHrP gene expression, which in turn appears to be a function of the ability of specific transcription factors to transactivate PTHrP gene expression.

Dietary soybean protein prevents bone loss in an ovariectomized rat model of osteoporosis.

The purpose of this study was to examine whether soybean protein isolate prevents bone loss induced by ovarian hormone deficiency. Thirty-two 95-d-old Sprague-Dawley rats were randomly assigned to four treatment groups [sham-operated (sham); ovariectomized (ovx); ovx+soybean; ovx + 17 beta-estradiol (E2)] and killed after 30 d. Rats in the sham, ovx and ovx + 17 beta-estradiol groups were fed a casein-based diet, and the soybean group was fed soybean protein isolate instead of casein; the diets were otherwise comparable. Rats in the ovx group had significantly lower densities of the right femur (P < 0.001) and the fourth lumbar vertebra (P < 0.05) than rats in the sham group. These lower bone densities were not observed in animals receiving 17 beta-estradiol or fed soybean. The ovx group also had significantly (P < 0.01) greater serum concentrations of 1,25-dihydroxycholecalciferol than the other three groups. Our findings suggest that dietary soybean protein is effective in preventing bone loss due to ovarian hormone deficiency. Because serum activities of both alkaline phosphatase and tartrate-resistant acid phosphatase were significantly greater in the ovx group and in the ovx + soybean group but not in the group receiving 17 beta-estradiol, compared with sham animals, this confirms that ovariectomy enhances and 17 beta-estradiol suppresses the rate of bone turnover. Despite the higher rate of bone turnover in the soybean-fed animals, the vertebral and femoral bone densities of these rats were significantly greater than those of rats in the ovx group, suggesting that formation exceeded resorption. Further studies are needed to clarify whether this protective effect on bone is due to the protein itself or to the presence of isoflavones in soybean protein.