Biomedical subjects

L A Fitzpatrick

Publications and source records attributed to L A Fitzpatrick.

At least 73 records · Page 4Linked to original sources

PubMed1997

Expression and function of recombinant endothelial NO synthase in coronary artery smooth muscle cells.

Smooth muscle cells (SMCs) play a key role in the pathogenesis of vascular diseases. The objectives of this study were to determine whether transfer of recombinant endothelial nitric oxide synthase (eNOS) gene to porcine coronary artery smooth muscle cell (CSMCs) would result in expression of a functional enzyme and to assess the effect of expression of eNOS on cell proliferation. CSMCs were transduced in vitro with adenoviral vectors encoding cDNA for eNOS (AdeNOS) and beta-galactosidase (Ad beta Gal). In contrast to Ad beta Gal- or sham-transduced cells, CSMCs transduced with AdeNOS stained positive with the NADPH-diaphorase stain, acquired calcium-dependent NOS activity (measured by the conversion of [3H]L-arginine to [3H]L-citrulline), had increasing cyclic 3',5' cGMP levels with increasing concentrations of the vector, and produced increased amounts of nitrite. cGMP production by AdeNOS-transduced cells was augmented by increasing intracellular levels of the eNOS cofactor tetrahydrobiopterin. CSMCs transduced with AdeNOS showed diminished serum-stimulated DNA synthesis as measured by thymidine uptake. Cell proliferation was diminished in AdeNOS-transduced CSMCs as assessed by cell counts 3 and 6 days after serum stimulation of quiescent CSMCs. The present study demonstrates that adenovirus-mediated gene transfer of eNOS to CSMCs results in the expression of a functional enzyme whose activity can be augmented by increasing intracellular levels of tetrahydrobiopterin. Expression of recombinant eNOS in CSMCs results in inhibition of serum-stimulated DNA synthesis and cell proliferation. These findings imply that eNOS gene transfer to SMCs may be a unique mode of increasing local NO production in the arterial wall.

Adenoviridae↗

PubMed1997

The effects of growth factors associated with osteoblasts on prostate carcinoma proliferation and chemotaxis: implications for the development of metastatic disease.

The extensive mortality and morbidity associated with prostate cancer is caused by the high prevalence of metastatic disease at the time of diagnosis. The area most frequently involved in metastatic prostate cancer is the skeleton. Unlike other cancers, which metastasize to bone and destroy the bone matrix, prostate cancer is unique in that it is osteogenic, resulting in the formation of dense, sclerotic bone with high levels of osteoblastic activity. We proposed that factors produced by bone cells may be responsible for the development of prostate carcinoma metastasis. We studied the effects of these growth factors on prostate cell proliferation by [3H]thymidine incorporation and chemotaxis by the double-filter chamber method. Three prostate carcinoma cell lines were studied, LNCaP (androgen responsive) and PC-3 and DU-145 (androgen unresponsive). The bone-associated growth factors tested were: insulin-like growth factors I and II (IGF-I, IGF-II), transforming growth factor beta, interleukin (IL)-1 beta, IL-6, and tumor necrosis factor alpha (TNF-alpha), IGF-I and IGF-II significantly increased proliferation in all three cell lines, whereas IL-6, TNF-alpha, and IL-1 beta significantly decreased proliferation. Transforming growth factor beta induced a biphasic response in proliferation in DU-145 and PC-3 cells and produced no response on LNCaP cells. Increased cell chemotaxis occurred in the presence of IGF-I and IGF-II, and decreased cell chemotaxis occurred with the addition of TNF-alpha and IL-1 beta. These data indicate that growth factors produced by bone cells alter prostate carcinoma cell proliferation and chemotaxis and suggest that modulations of the production of these factors may be a potential therapeutic intervention in deterring the metastasis of prostate carcinoma to bone.

Carcinoma↗

PubMed1997

Evidence of a correlation of estrogen receptor level and avian osteoclast estrogen responsiveness.

Isolated osteoclasts from 5-week-old chickens respond to estradiol treatment in vitro with decreased resorption activity, increased nuclear proto-oncogene expression, and decreased lysosomal enzyme secretion. This study examines osteoclasts from embryonic chickens and egg-laying hens for evidence of estrogen responsiveness. Although osteoclasts from both of these sources express estrogen receptor mRNA and protein, estradiol treatment had no effect on resorption activity. In contrast to the lack of effect on resorption, estradiol treatment for 30 minutes resulted in steady-state mRNA levels of c-fos and c-jun increasing in osteoclasts from embryonic chickens and decreasing in osteoclasts from egg-laying hens. These data suggest that a nuclear proto-oncogene response may not be involved in estradiol-mediated decreased osteoclast resorption activity. To examine the influence of circulating estrogen on osteoclast estrogen responsiveness, 5-week-old chickens were injected with estrogen for 4 days prior to sacrifice. Estradiol treatment of osteoclasts from these chickens did not decrease resorption activity in vitro. Transfection of an estrogen receptor expression vector into osteoclasts from the estradiol-injected chickens and egg-laying hens restored estrogen responsiveness. Osteoclasts from 5-week-old chickens and estradiol treated 5-week-old chickens transfected with the estrogen receptor expression vector contained significantly higher levels of estrogen receptor protein and responded to estradiol treatment by decreasing secretion of cathepsins B and L and tartrate-resistant acid phosphatase. In contrast, osteoclasts from embryonic chickens, egg-laying hens, and estradiol-treated 5-week-old chickens either untransfected or transfected with an empty expression vector did not respond similarly. These data suggest that modulation of osteoclast estrogen responsiveness may be controlled by changes in the osteoclast estrogen receptor levels.

Aging↗

PubMed1996

Gender-related differences in the development of atherosclerosis: studies at the cellular level.

1. Calcified arteriosclerotic lesions have been recognized early in life as abnormalities in coronary arteries. 2. We examined coronary arterial plaques as an undecalcified tissue and revealed widespread mineralization within the plaque. Non-collagenous proteins that regulate calcification, such as osteopontin, have been identified within the atherosclerotic plaque. In vitro, smooth muscle cells derived from porcine coronary arteries express non-collagenous proteins and type I collagen. 3. We have demonstrated that oestrogen regulates the proliferation of smooth muscle cells obtained from the coronary arteries of sexually mature pigs. The inhibition of proliferation by beta-estradiol occurred in coronary smooth muscle cells (VSMC) obtained from female animals and no proliferation was noted in VSMC isolated from intact male animals after exposure to beta-estradiol. 4. The dynamic changes in matrix composition and cellular proliferation in atherosclerotic vessels may be responsible for the calcification associated with the atherosclerotic plaque.

Animals↗

PubMed1996

Endothelin receptors are modulated in association with endogenous fluctuations in estrogen.

Experiments were designed to determine whether endogenous physiological fluctuations in sex steroid hormones affect expression or functional responses of endothelin receptors. Coronary arteries from sexually mature male, female, and ovariectomized pigs were prepared either for receptor binding or measurement of isometric force in organ chambers. Competitive binding of 125I-labeled endothelin-1 was significant for a one-site model with unlabeled endothelin-1 and a two-site model with unlabeled endothelin-3 and sarafotoxin S6c in all pigs. The total number of binding sites for all endothelin ligands was not different between male and female pigs. Binding affinities for the high-affinity binding site for both endothelin-3 and sarafotoxin S6c were significantly greater (lower inhibition constant) in membranes prepared from female pigs with high endogenous estrogen. In organ chamber experiments, contractions to endothelin-1 but not endothelin-3 or sarafotoxin S6c were significantly greater in coronary arterial rings from female compared with male pigs and were not affected significantly by removal of the endothelium or by treatment of the rings with either indomethacin (10(-5) mol/l) or the combination of indomethacin and NG-monomethyl-L-arginine (10(-4) mol/l). These results suggest endogenous fluctuations in estrogen are associated with an increase in affinity of a high-affinity endothelin receptor in coronary arterial smooth muscle of female pigs. In addition, independent of endogenous estrogen status, coronary arteries from female pigs generate significantly greater contractions to endothelin-1 compared with male pigs. This phenomenon occurs at the level of smooth muscle and is not dependent on the endothelium or synthesis of nitric oxide or prostaglandins.

Animals↗

PubMed1996

Differential response in cell proliferation to beta estradiol in coronary arterial vascular smooth muscle cells obtained from mature female versus male animals.

Although the cardioprotective effect of estrogen is well recognized, the mechanisms by which this sex steroid provides a reduction in coronary artery disease are not fully understood. Vascular smooth muscle cells (VSMC) are present in early atherosclerosis and become the dominant cell type. VSMC contain estrogen receptors and may have specific responses to estrogen. We studied the effect of beta-estradiol on the proliferation of coronary VSMC obtained from sexually mature male, female, and oophorectomized pigs. Alpha-estradiol, an inactive isomer of estradiol, had no effect on cells obtained from male or female animals. In vascular smooth muscle cells obtained from sexually mature female animals, significant inhibition of proliferation of coronary vascular smooth muscle cells was noted at physiologic concentrations of beta-estradiol. Progesterone inhibited VSMC proliferation at concentrations of 10(-9)M. In contrast, beta-estradiol did not alter proliferation in porcine coronary vascular smooth muscle cells obtained from sexually mature male or from oophorectomized female animals. This study is the first to indicate, in an animal model, specific gender-related differences in cell proliferation in response to sex steroid hormones.

Analysis of Variance↗

PubMed1996

Type I procollagen production and cell proliferation is mediated by transforming growth factor-beta in a model of hepatic fibrosis.

Fibrosis is a significant component of advanced chronic inflammatory liver diseases and is caused by the accumulation of extracellular matrix, including type I procollagen. The mechanism by which fibrosis develops in liver tissue remains unknown. We tested the effects of transforming growth factor beta 1 (TGF-beta), a cytokine that alters cell differentiation and proliferation, and bleomycin, a cytotoxic glycopeptide antibiotic, on cultured isolated rat hepatocytes. TGF-beta (1 ng/ml) inhibited radiolabeled thymidine incorporation 39% at 24 h and 69% at 48 h. Inhibition of hepatocyte proliferation was dose dependent. Bleomycin (1 microgram/ml) significantly inhibited radiolabeled thymidine incorporation at 48 h (44%). Neutralizing antibody to thymidine incorporation at 48 h (44%). Neutralizing antibody to TGF-beta (TGF-beta-Ab) attenuated the inhibition of proliferation by TGF-beta and bleomycin in a concentration-dependent manner. The addition of either TGF-beta or bleomycin increased immunostaining of type I procollagen in hepatocytes. The addition of TGF-beta-Ab alone increased cell proliferation, suggesting that neutralization of endogenous TGF-beta may attenuate the inhibition of hepatocyte proliferation. These data suggest that the hepatocyte contains type I procollagen and, under some conditions, produces TGF-beta. We propose that procollagen production in rat hepatocytes is induced by TGF-beta and may be related to endogenous production of this cytokine in response to cell injury. The cytotoxic effect of bleomycin is mediated by TGF-beta and inhibition of TGF-beta and bleomycin with TGF-beta-Ab attenuates the additive effects of those compounds on isolated rat hepatocytes. These data provide a model of collagen expression in isolated rat hepatocytes.

Animals↗

PubMed1996

Paget's disease is associated with changes in the immunohistochemical distribution of noncollagenous matrix proteins in bone.

Paget's disease of bone is characterized histologically by abnormal architecture of bone matrix. Extensive areas of woven bone and numerous scalloped cement lines occur as a result of increased irregular remodeling. Noncollagenous proteins (NCP) play an important role in the organization and mineralization of bone matrix and promote distinct cell-matrix interactions necessary for normal remodeling. To gain insight into the pathological changes in the biochemical composition of Pagetic bone, the distribution of NCPs in the calcified matrix of bone from patients with known Paget's disease was compared to that of bone from normal healthy volunteers. Undecalcified plastic-embedded sections of bone were stained immunohistochemically using antibodies generated against several NCPs. In Pagetic and normal bone a similar distribution of osteopontin was observed at cement (reversal) lines, whereas significant differences were observed in the distribution of osteopontin in the matrix immediately adjacent to Haversian canals, where initial osteoclast recruitment and attachment occur. The differences in osteopontin distribution appeared to be related to the state and severity of the disease. Site-specific differences in the distribution of osteonectin, osteocalcin, and decorin were also observed between normal bone and cortical and periosteal de novo Pagetic bone, whereas the distribution of other matrix proteins, such as biglycan, was unchanged. We conclude that these site-specific changes in the biochemical distribution of NCPs in Pagetic bone probably reflect abnormal production and/or incorporation during bone remodeling and may lead to disorganized matrix assembly and mineralization as well as have profound effects on bone cell functions.

Adult↗

PubMed1996

Changes in quantitative bone histomorphometry in aging healthy men.

Changes in bone mineral metabolism with aging in healthy men and the roles of various factors in the pathogenesis of age-related changes in quantitative bone histomorphometry in men are poorly defined. To clarify these changes and factors, serum and urinary biochemical parameters and iliac crest bone biopsies were evaluated in 43 healthy men, aged 20-80 yr. The static histomorphometric parameters, cancellous bone volume and osteoblast-osteoid interface, decreased by 40.0% and 19.2%, respectively, between 20-80 yr of age. The dynamic histomorphometric parameters, double and single labeled osteoid, also decreased by 18.6% and 18.0%, respectively, over this period. None of the other static or dynamic histomorphometric parameters changed with age in this population sample of healthy men. Univariate analysis of static bone histomorphometric parameters and biochemical parameters revealed significant correlations between osteoid surface and intact PTH (r = 0.37; P = 0.015); osteoclast surface and serum total testosterone (r = 0.36; P = 0.016), estradiol (r = 0.40; P = 0.009), and FSH (r = 0.49; P = 0.001); osteoblast-osteoid interface and serum phosphate (r = 0.31; P = 0.046); and cortical thickness and serum total calcium (r = 0.38; P = 0.013). Univariate analysis of dynamic bone histomorphometric parameters and biochemical parameters revealed correlations between mineral apposition rate and serum total testosterone (r = 0.32; P = 0.037); total volume-referent bone formation rate and serum osteocalcin (r = 0.43; P = 0.004), total testosterone (r = 0.47; P = 0.001), estradiol (r = 0.35; P = 0.023), and dehydroepinadrosterone sulfate (r = 0.31; P = 0.045); and mean wall thickness and serum total calcium (r = 0.36; P = 0.019) and creatinine clearance (r = 0.42; P = 010). Mineralization lag time and serum phosphate (r = -0.39; P = 0.012) and urinary total pyridinoline (r = 0.36; P = 0.023), and mean wall thickness and urinary total pyridinoline (r = -0.38; P = 0.013), were inversely correlated. Multiple regression analysis using all-subset analysis comparing cancellous bone volume to serum and urinary biochemical parameters in these men indicated that the log free androgen index and body weight best predicted the age-related decline in iliac crest cancellous bone volume (r2 = 0.19; P = 0.015). Multiple regression analysis by the same method, comparing bone density at different skeletal sites to bone histomorphometric parameters, indicated that lumbar spine bone mineral density (BMD) was best predicted by cancellous bone volume and mineral apposition rate (r2 = 0.31; P = 0.001), femoral neck BMD by cancellous bone volume and osteoid surface (r2 = 0.19; P = 0.020), femoral greater trochanter BMD by cortical thickness and single labeled osteoid surface (r2 = 0.13; P = 0.060), and total body BMD by cancellous bone volume and surface-based bone formation rate (r2 = 0.31; P = 0.001). In summary, cancellous bone volume, osteoblast-osteoid interface, and double and single labeled osteoid decreased with age in this sample of healthy men. The lack of detectable change in bone density at some skeletal sites in these men may be due to the small sample size or other confounding factors. Multivariate analysis suggests that different combinations of histomorphometric parameters predict bone density at different skeletal sites, and that cancellous bone volume predicts bone density at the lumbar spine, femoral neck, and total body, but not at the femoral greater trochanter. We conclude that alterations in several biochemical parameters are important in the pathogenesis of age-related bone loss in healthy men.

Adult↗

PubMed1996

Electron beam computed tomography and coronary artery disease: scanning for coronary artery calcification.

OBJECTIVE: To review the association of coronary artery calcification with coronary atherosclerosis and its potential clinical application as detected on electron beam computed tomography (EBCT). DESIGN: A literature review of coronary artery calcification, coronary artery disease, and EBCT is presented, and clinical applications of EBCT are discussed. RESULTS: Recent studies have confirmed that arterial calcification is an active process intimately associated with atherosclerotic plaque evolution. Clinical investigations with use of EBCT have shown that a scan "negative" for coronary calcification is common in patients with normal or near-normal findings on coronary angiography, whereas patients with severe obstructive disease most commonly have "positive" scans--greater amounts of coronary artery calcium are associated with more severe luminal disease. Coronary artery calcium as evaluated on EBCT follows patterns that reflect the development of coronary atheromatous disease as a function of age and gender. Although histologic studies have confirmed that not all atherosclerotic segments have detectable calcification, the area of coronary artery calcification quantified on EBCT has a direct, positive relationship with the histopathologic coronary plaque area. CONCLUSION: The long-held notion of "degenerative" calcification of the coronary arteries with aging is incorrect. Although the incidence of coronary artery calcification increases with patient age, this relationship simply parallels the increased incidence of coronary atherosclerosis with advancing age. Data suggest that EBCT is a highly sensitive and specific test for coronary atherosclerosis and provide a basis for clinical applications when EBCT is viewed as a noninvasive method to estimate human coronary atherosclerotic involvement and "plaque burden."

Adult↗

PubMed1995

Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study.

BACKGROUND: Coronary calcium identified by electron-beam computed tomography (EBCT) correlates poorly with luminal atherosclerotic narrowing, but calcium, an intimate part of coronary plaque, may be more directly related to atheromatous plaque area. METHODS AND RESULTS: Thirty-eight coronary arteries from 13 autopsy hearts were dissected, straightened, and scanned with EBCT in 3-mm contiguous increments. Coronary calcium area was defined as one or more pixels with a density > 130 Hounsfield units (0.18 mm2/pixel). Each artery was divided into corresponding 3-mm segments, representative histological sections were stained, and atherosclerotic plaque area per segment (mm2) was quantified. Coronary artery calcium and coronary artery plaque areas were correlated for the hearts as a whole, for individual coronary arteries, and for individual coronary artery segments. The sums of histological plaque areas versus the sums of calcium areas were highly correlated for each heart and for each coronary artery. However, coronary plaque area was on the order of five times greater than calcium area. Furthermore, minimal diffuse segmental coronary plaque could be present despite the absence of coronary calcium detectable by EBCT. CONCLUSIONS: This histopathologic study confirms an intimate relation between whole heart, coronary artery, and segmental coronary atherosclerotic plaque area and EBCT coronary calcium area but suggests that there is a threshold value for plaque area below which coronary calcium is either absent or not detectable by this methodology.

Adult↗

PubMed1995

Antithetic effects of ryanodine and ruthenium red on osteoclast-mediated bone resorption and intracellular calcium concentrations.

In the process of bone remodeling, osteoclasts are responsible for resorption of bone. High levels of intracellular calcium decrease the bone resorbing activity of osteoclasts and increase detachment of osteoclasts from the bone surface. The regulatory role of intracellular calcium in bone resorption is not clearly understood. To understand this phenomenon, we studied the effects of the intracellular calcium modulators ryanodine and ruthenium red on bone resorption using the disaggregated osteoclast pit assay. Changes in intracellular calcium concentrations after treatment with these compounds were detected with the fluoroprobe fura2. With ryanodine, a significant, dose-dependent decrease in bone resorption was detected. This inhibition of bone resorption was reversible upon the removal of ryanodine. Ryanodine increased intracellular calcium concentrations, suggesting that the mechanism of inhibition by ryanodine was via alterations in intracellular stores of calcium. After treatment with ruthenium red, osteoclasts resorbed significantly more bone compared to vehicle-treated cells. This increase in bone resorption correlated with a decrease in intracellular calcium concentrations. The addition of parathyroid hormone or ruthenium red to osteoclast cultures containing ryanodine did not attenuate the decrease in bone resorption caused by ryanodine, suggesting that the mechanism of ryanodine inhibition of bone resorption may involve the "locking" of a calcium channel in an open position.

Analysis of Variance↗

PubMed1995

Matrix proteins associated with bone calcification are present in human vascular smooth muscle cells grown in vitro.

Atherosclerotic lesions are composed of cellular elements that have migrated from the vessel lumen and wall to form the cellular component of the developing plaque. The cellular elements are influenced by various growth-regulatory molecules, cytokines, chemoattractants, and vasoregulatory molecules that regulate the synthesis of the extracellular matrix composing the plaque. Because vascular smooth muscle cells (VSMC) constitute the major cellular elements of the atherosclerotic plaque and are thought to be responsible for the extracellular matrix that becomes calcified in mature plaques, immunostaining for collagenous and noncollagenous proteins typically associated with bone matrix was conducted on VSMC grown in vitro. VSMC obtained from human aorta were grown in chambers on glass slides and immunostained for procollagen type I, bone sialoprotein, osteonectin, osteocalcin, osteopontin, decorin, and biglycan. VSMC demonstrated an intense staining for procollagen type I, and a moderately intense staining for the noncollagenous proteins, bone sialoprotein and osteonectin, two proteins closely associated with bone mineralization. Minimal immunostaining was noted for osteocalcin, osteopontin, decorin, and biglycan. The presence in VSMC of collagenous and noncollagenous proteins associated with bone mineralization suggest that the smooth muscle cells in the developing atherosclerotic plaque play an important role in the deposition of the extracellular matrix involved in calcification of developing lesions.

Biglycan↗

PubMed1995

Role of calcium channels in parathyroid hormone secretion.

Experimental evidence exists for the presence of parathyroid cell membrane calcium channels that respond to plasma calcium. In previous reports, the effects of various calcium channel agents on PTH secretion have revealed conflicting results. To resolve some of these inconsistencies, we have compared the pure calcium channel agonist, (+)202-791, and its antagonistic enantiomer (-)202-791 with other calcium channel agents--verapamil, nifedipine, and (+)Bay-K-8644. The agonist (+)202-791 enhanced 45Ca+2 uptake and decreased PTH secretion, while the antagonist (-)202-791 decreased 45Ca+2 uptake and increased PTH secretion. The calcium channel appears coupled to a G-protein as indicated by pertussis toxin treatment of the cells. The enantiomers (+/-)202-791 had little effect on intracellular cAMP production suggesting that the calcium channel may not be responsible for the previously observed calcium-mediated changes in cAMP. The antagonist (-)202-791 increased the phosphorylation of a 60-kd protein. The enantiomers (+/-)202-791 did not alter the effect of depolarizing concentrations of potassium on PTH secretion. Our results suggest that calcium channels provide a pathway for the movement of calcium across the plasma membrane and that this pool of calcium regulates, at least in part, PTH secretion.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1995

The importance of bone biopsy in managing renal osteodystrophy.

A case is presented in which bone biopsy results helped to resolve not only difficult issues in the clinical management of the patient's renal osteodystrophy but also disruptive psychosocial problems surrounding her clinical course. The outcome was a satisfactory resolution based on rational medical treatment and directed supportive care. The presentation highlights important principles in the procurement, processing, and interpretation of the bone biopsy, while also addressing the importance of accurate diagnosis in facilitating the overall long-term management by the entire renal team.

Aged↗

PubMed1995

Nifedipine, but not verapamil, acutely elevates parathyroid hormone levels in premenopausal women.

BACKGROUND: Calcium channel antagonist therapy in humans has been associated with changes in anterior pituitary, thyroid and adrenal hormone secretion. Human studies assessing effects of calcium channel antagonists on calciotropic hormones have been few and typically involved small numbers of subjects studied for short periods of time. Few of these previously published studies have included women. The endocrine effects of calcium channel antagonists in women have become increasingly important as more women are taking these agents for diseases such as hypertension, angina, Raynaud's phenomenon and migraine. OBJECTIVE: To assess both acute and chronic effects of calcium channel antagonists on calciotropic hormones in women. DESIGN: A four-week prospective, randomized trial. SUBJECTS: Twenty-nine premenopausal women, randomly assigned to receive either 240 mg of sustained release verapamil or 30 mg of sustained release nifedipine daily. LABORATORY END-POINTS: Total and ionized serum calcium, phosphate, creatinine, parathyroid hormone (PTH), parathyroid hormone-related protein (PTHrP) and calcitonin, measured at baseline, after 24 hours, and 28 days of treatment. RESULTS: Total and ionized calcium, phosphate, creatinine, PTHrP and calcitonin levels were not altered significantly after 24 hours or 28 days in any of the subjects, when compared to baseline. There were no significant differences in PTH levels after 24 hours or 28 days of verapamil treatment. There was a significant increase in serum PTH levels after 24 hours of nifedipine therapy; however, these differences were not evident after 28 days of therapy. CONCLUSIONS: The short-term administration of nifedipine results in increased release of parathyroid hormone; however, long-term administration has no significant effect on the concentrations of calciotropic hormones.

Adult↗

PubMed1995

Osteomalacia associated with adult Fanconi's syndrome: clinical and diagnostic features.

OBJECTIVE: Osteomalacia associated with adult acquired Fanconi's syndrome is thought to result from hypophosphataemia and relative 1,25-dihydroxyvitamin D deficiency. We have followed the clinical and diagnostic features of patients with osteomalacia associated with adult Fanconi's syndrome, with particular emphasis on their responses to treatment with calcium, phosphate and vitamin D. DESIGN: Retrospective Mayo Clinic case-note review from 1975 to 1994 and prospective follow-up study, combined with literature review. PATIENTS: Eleven patients (7 male, 4 female) were identified who satisfied criteria for diagnosis of osteomalacia and adult Fanconi's syndrome. Twenty-five additional patients were identified in a literature review from 1954 to the present. METHODS: Clinical history and physical examination, serum and urine bone and mineral parameter, X-ray radiography and iliac crest bone histomorphometry. RESULTS: All patients presented with typical symptoms of osteomalacia, including lower extremity or low back bone pain, and all had fractures, pseudofractures, and/or bone demineralization on X-ray radiography. Osteomalacia and Fanconi's syndrome were diagnosed concurrently in 10 patients, whereas osteomalacia preceded diagnosis of Fanconi's syndrome by 5 years in one patient. Pre-treatment bone biopsies in 9 of the 11 patients demonstrated increased osteoid surface, volume and width. In the one patient labelled with tetracycline prior to biopsy, mineralization lag time was prolonged at 111 days (normal 19.2 +/- 1.0 days). Hypophosphataemia, inappropriately low 1,25-dihydroxyvitamin D levels, renal insufficiency, and chronic acidosis due to bicarbonate leak and uraemia, contributed to the osteomalacia in these patients. Secondary hyperparathyroidism was present in two patients. Eight of the 11 patients with osteomalacia associated with Fanconi's syndrome had monoclonal disorders, including multiple myeloma or lymphoma, many of them manifest by light-chain proteinuria. Over a mean patient follow-up period of 46 months (range 1-239 months), patients responded symptomatically to calcium, phosphate, and vitamin D replacement typically within 1-6 months. In 8 patients in whom follow-up data were available, post-treatment serum phosphate and 1,25-dihydroxyvitamin D levels improved in the setting of stable mild renal insufficiency; only one patient developed end-stage renal failure after 20 years, suggesting that these patients do not invariably progress rapidly to renal failure. CONCLUSIONS: Regardless of the underlying cause, osteomalacia associated with adult acquired Fanconi's syndrome appears to respond well to calcium, phosphate, and vitamin D replacement. These patients do not appear to necessarily require 1,25-dihydroxyvitamin D replacement.

Adult↗

PubMed1995

Artificial insemination of Bos indicus heifers: the effects of body weight, condition score, ovarian cyclic status and insemination regimen on pregnancy rate.

Effects of body weight, condition score, ovarian cyclic status and insemination regimen on pregnancy rates were investigated in 164 Bos indicus heifers synchronised with norgestomet-oestradiol and pregnant mare serum gonadotrophin (PMSG). Oestrus detection techniques were also compared. Heifers were inseminated at either a fixed time (group 1, n = 83) of 48.0 +/- 0.2 h (mean +/- SEM) after implant removal or at 8.9 +/- 0.5 h after oestrus was detected (group 2, n = 81). Group 2 heifers that were not detected in oestrus by 72 h after implant removal were inseminated at that time. Oestrus was detected for the purpose of insemination using heatmount detectors. Tail-paint and oestrogen treated, chin-ball harnessed steers were used to compare the efficiency of oestrus detection. The probability of ovarian cyclicity increased with increasing body weight and condition score (P < 0.001). A higher proportion of heifers that were acyclic at the commencement of treatment, compared with cyclic heifers, were detected in oestrus at the time of insemination in the fixed-time inseminated group (P < 0.01). Analysis of covariance revealed that intervals from implant removal to oestrus were influenced by ovarian cyclic status (P < 0.01) and insemination group (P < 0.05). A higher pregnancy rate (% +/- SEM) was obtained in acyclic compared with cyclic heifers in the group 1 heifers (50.0 +/- 10 vs 28.1 +/- 6; P = 0.055) but not among the group 2 heifers (45.8 +/- 10 vs 49.1 +/- 7; P = 0.787). The probability of pregnancy was found to be associated negatively with body weight (P = 0.01) while a higher pregnancy rate was obtained in the group 2 compared with group 1 heifers (48.2% vs 34.9%; P = 0.093). The efficiency of oestrus detection was highest using heatmount detectors compared with tail-paint and chin-ball harnessed steers (90.7% vs 37.0% and 23.5%, respectively; P < 0.0001). We conclude that pregnancy rates can be increased in extensive environments when insemination follows oestrus detection using heatmount detectors compared with a fixed-time insemination. The fertility of heifers inseminated at a fixed time is influenced by ovarian cyclic status due to its influence on oestrus-to-insemination intervals.

Analysis of Variance↗