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Biomedical subjects

A Grauer

Publications and source records attributed to A Grauer.

At least 19 recordsLinked to original sources
PubMed2001

A case of neuroendocrine oncogenic osteomalacia associated with a PHEX and fibroblast growth factor-23 expressing sinusidal malignant schwannoma.

Oncogenic osteomalacia is a rare paraneoplastic syndrome that is characterized biochemically by hypophosphatemia and low plasma 1,25-dihydroxyvitamin D3, and clinically by osteomalacia, pseudofractures, bone pain, fatigue, and muscle weakness. We present a patient with a malignant schwannoma as the underlying cause of this disorder. A permanent cell line (HMS-97) derived from this tumor showed evidence of neuroendocrine differentiation by immunohistochemistry and of neurosecretory activity by electron microscopy. The cell line did express PHEX (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) and FGF-23 (fibroblast growth factor-23) transcripts on northern hybridization; however, none of the known mutations from the related mendelian disorders of X-linked hypophosphatemic rickets or autosomal-dominant hypophosphatemic rickets could be detected. Tumor cell (HMS-97)-derived conditioned medium did not inhibit phosphate transport in a standard opossum kidney cell assay and in animal experiments. The medium also showed no PTH1- or PTH2-receptor-stimulating bioactivity. HMS-97 cells might be useful for further studies that aim to determine the genetic mechanism that leads to the observed PHEX and FGF-23 expression, both of which might have a direct role in the pathogenesis of oncogenic osteomalacia. In addition, these cells might be a useful tool for the investigation of neuroendocrine Schwann cell function and autoimmune peripheral nerve disease.

Female↗
PubMed2000

Short- and long-term effects of ibandronate treatment on bone turnover in Paget disease of bone.

BACKGROUND: In Paget disease of bone (PD), serum total alkaline phosphatase (TAP) is a valid marker of disease activity. The aim of the present longitudinal study was to compare TAP with new and potentially more specific markers of bone turnover in bisphosphonate-treated patients with PD. METHODS: Twenty patients with active PD were studied before and after treatment with 2 mg of intravenous ibandronate over a period of 12 months. TAP (by colorimetry), serum bone-specific alkaline phosphatase (BAP; by enzyme immunoassay), serum osteocalcin (OC; by ELISA), serum bone sialoprotein (BSP; by RIA), and urinary total pyridinoline (PYD; by HPLC) and deoxypyridinoline (DPD; by HPLC) were measured as markers of bone turnover. RESULTS: Before treatment, TAP, BAP, and BSP were increased in all 20 patients, whereas OC was increased in 10, PYD in 13, and DPD in 15 patients. Three months post treatment, nine patients showed normalized TAP values, and a >/=25% re-increase (i.e. , relapse) was observed in all patients after 12 months. A normalization of BAP was achieved in six patients only. No significant changes were found for OC. BSP was decreased significantly at 24 h, and DPD at 48 h post treatment. A normalization of BSP was found in 8, of PYD in 18, and of DPD in 16 cases. Both PYD and DPD increased significantly from 9 months post treatment onward. CONCLUSIONS: Most markers of bone turnover show similar long-term changes after treatment of active PD with ibandronate. With regard to cost-effectiveness and assay performance, TAP remains the marker of choice in therapeutic monitoring of PD. However, more specific markers may improve the biochemical assessment of PD in certain situations.

Aged↗
PubMed1999

Differential induction of proto-oncogene expression and cell death in ocular tissues following ultraviolet irradiation of the rat eye.

BACKGROUND/AIMS: Ultraviolet (UV) irradiation of mammalian cells in culture evokes the transcriptional activation of different proto-oncogenes, among them members of the fos/jun family which are known to play an important role in cell proliferation and differentiation. To investigate in vivo UV induced proto-oncogene expression of irradiated ocular cells, the expression of JunB, JunD, and Egr-1 was analysed in the cornea, lens, and retina. Furthermore, UV radiation is known to induce pleiotrophic events in irradiated cells which include growth arrest, inflammation, and even cell death. In order to determine the type of cell death--for example, apoptosis versus necrosis, sections of UV irradiated rat eyes were further examined for distinct ultrastructural morphology of cell death and DNA fragmentation. METHODS: Eyes of anaesthetised rats were exposed to 1.5 J/cm2 of ultraviolet radiation (280-380 nm). Animals were perfused 6 and 16 hours after irradiation and tissue sections of enucleated bulbi were processed for light and electron microscopy. RESULTS: Under control conditions, Jun B was constitutively expressed in numerous superficial cells but also in scattered basal cells of the corneal epithelium. After UV exposure JunB expression was massively upregulated in many cells of the basal cell layers of the corneal epithelium, although during the entire experiment, both the corneal stroma and endothelium were JunB negative. In contrast, Egr-1 was expressed exclusively in lens epithelium showing only a faint expression pattern under control conditions. However, Egr-1 expression increased after UV exposure, so that many Egr-1 positive cells of the lens epithelium could be found several hours after UV illumination. JunD was expressed in single cells of both the ganglion cell layer and the inner nuclear layer of the retina, a pattern of expression which did not change after UV exposure. Regarding the type of cell death, features of apoptosis were only occasionally present in scattered superficial cells of the corneal epithelium of control eyes. After UV exposure, however, morphological signs of apoptosis and TUNEL positive cells were visible both in the stroma and epithelium of the rat cornea. In contrast, UV irradiated lens epithelial cells exhibited features typical of necrosis. The corneal endothelium and the retina did not show any indications of morphological changes indicative of cell death after UV irradiation. CONCLUSION: Each proto-oncogene encoded protein was found to be expressed in a tissue specific manner and UV irradiation differentially modulates the expression pattern of these transcriptional regulatory proteins. This temporospatial expression pattern of these proteins is accompanied by two morphologically distinct types of cell death in the cornea and lens after UV irradiation.

Animals↗
PubMed1998

Effect of surgeon expertise on the outcome in primary hyperparathyroidism.

BACKGROUND: Success in surgery for primary hyperparathyroidism (PHPT) is thought to be closely linked to surgical expertise. We investigated the effect of the surgeon's experience on the postoperative outcome in patients with PHPT. DESIGN: Cohort study with retrospective analysis. SETTING: University tertiary care center. PATIENTS: Two hundred thirty consecutive patients with PHPT. We excluded patients with prior cervical surgery, parathyroid carcinoma, multiple endocrine neoplasia types 1 and 2, and renal hyperparathyroidism. INTERVENTIONS: All 230 patients underwent bilateral neck exploration for PHPT. MAIN OUTCOME MEASURES: We registered complication rates, fulfillment of predefined operative concepts, and operative time in 230 cervical revisions for PHPT and compared the results of experienced surgeons (40 or more cervical revisions for PHPT performed before 1988) with those of surgeons still in training. RESULTS: Two surgeons classified as experienced operated on 75 patients. Under supervision of these surgeons, most operative procedures (n=155) were performed by 12 different surgeons classified as less experienced. Complications were observed in 31 patients (13.5%) with no statistical difference between the specialists and the less-experienced surgeons (P=.85). The ability to demonstrate 4 or more parathyroid glands was significantly increased for the specialists (74.7% vs 51.6%; P<.001), who also terminated the operation earlier (average, 15 minutes; P<.001). CONCLUSION: In an analysis of 230 operations for PHPT in patients without prior neck surgery, no effect of the surgeon's experience on postoperative outcome was demonstrated. Under the supervision of experienced endocrine surgeons, less-experienced surgeons perform cervical revisions for PHPT with comparable results, although with longer operating time.

Adolescent↗
PubMed1998

[Biphosphonate therapy in the management of skeletal metastases].

Bisphosphonates are a new theraeutic option in the treatment of bone diseases. They inhibit osteoclastic bone resorption and are established in the treatment of osteoporosis, Paget's disease of bone and especially in tumor bone disease. The effects of pamidronate, clodronate and ibandronate in the treatment of hypercalcemia of malignancy and osteolytic bone disease have been extensively studied. These drugs represent the treatment of choice in hypercalcemia of malignancy. The regular application of bisphosphonates reduces skeletal-related events like pathologic fracture, bone pain or hypercalcemia of malignancy, especially in breast cancer and multiple myeloma. Of great interest are the ongoing studies concerning prophylactic application of bisphosphonates in tumors bearing a high risk for bone metastases, especially since the first results suggest a significant reduction in the development of bone metastases in breast cancer patients.

Bone Neoplasms↗
PubMed1998

Clinical usefulness of a new chemiluminescent two-site immunoassay for human calcitonin.

The introduction of two-site immunoassays has greatly improved the measurement of human calcitonin (CT). But even within the two-site assays differences in sensitivity and ease of performance are noted. We evaluated the clinical usefulness of a new sensitive chemiluminescence two-site immunoassay for CT (Nichols) in comparison to an established two-site elisa (Medgenix). The range of measurement spans from 0.7 to 2500 pg/ml after 4h incubation for the chemiluminescent assay, compared to 2.0 to 1000 pg/ml after overnight incubation for the elisa. We investigated 179 healthy subjects (55 males, 124 females) to assess the upper limit of normal for CT values obtained by the chemiluminescence assay, which was defined as the 95th percentile of the distribution. The values obtained were 6.55 pg/ml for males and 4.13 pg/ml for females (p < 0.0005, Mann Whitney test). After pentagastrin-stimulation of 19 healthy volunteers (9 male, 10 female), the upper limit of normal for pentagastrin-stimulated CT was found at 43.0 pg/ml for males and 36.8 pg/ml for females (p < 0.05, Mann Whitney test). CT values obtained in patients with proven medullary thyroid carcinoma (MTC) or in subjects with suspected familial disease were positively correlated between both two-site assays (rho 0.961, p < 0.0001, Spearman rank correlation). More importantly the results led to the same clinical decision (normal vs. elevated) in 92.5% (37 of 40) patients. In all three patients with discordant results, clinical follow up supported the decision based on the chemiluminescence assay. Pentagastrin stimulation tests in MTC patients and localization studies of occult MTC tissue by selective venous catheterization led to concordant results in both assays. The new Nichols chemiluminescence assay demonstrated advantages in handling, a lower detection limit and a slightly higher sensitivity than the Medgenix elisa. CT values obtained by the chemiluminescence assay were on average 1.4-fold lower, which may be due to a slightly superior specificity of the assay, although this problem was not specifically addressed in this study. The clinical usefulness of both assays is highly satisfactory. In all cases, however, where clinically meaningful differences occurred, follow up proved the results obtained with the chemiluminescence assay to be correct.

Adolescent↗
PubMed1998

Seasonal variation of biochemical indexes of bone turnover: results of a population-based study.

Biochemical markers of bone turnover have been shown to provide valuable information for the diagnosis and monitoring of metabolic bone disease. However, these dynamic indexes are influenced by a number of factors that need to be clearly identified to improve their clinical usefulness. To evaluate the contributions of anthropometric, life style, and environmental variables on bone turnover, biochemical markers of bone metabolism were determined in a population-based sample of 580 adults, aged 50-81 yr (297 men and 283 women). Subjects were recruited during 14 consecutive months within the framework of the European Vertebral Osteoporosis Study. Serum total and bone-specific alkaline phosphatase (S-BAP), serum C-terminal propeptide of type I collagen, and serum osteocalcin (S-OC) were measured as bone formation markers. Urinary total pyridinoline and deoxypyridinoline were included as bone resorption indexes. In females, serum levels of 25-hydroxyvitamin D3 were significantly higher (P < 0.01) in summer (May-September) than in winter (October-April), whereas no significant differences were found in males. In both sexes, no seasonal changes were seen in serum PTH. In males, serum total alkaline phosphatase (P < 0.01), S-BAP (P < 0.001), and S-OC (P < 0.05) were significantly higher in winter than in summer. During the same period, females had higher values of S-BAP (P < 0.05), S-OC (P < 0.01), and urinary pyridinoline and deoxypyridinoline (P < 0.001, respectively). Univariate analyses of the effects of life style habits on markers of bone metabolism revealed that in females, regular alcohol consumption and current smoking led to a suppression of markers of bone turnover, whereas in males, only alcohol intake was associated with such changes. In contrast, physical activity was associated with higher levels of bone formation markers and reduced levels of bone resorption indexes in both sexes. As shown by multivariate regression analyses, seasonal variations accounted for more of the variability in most biomarkers (up to 12%) than any of the other anthropometric or life style factors except age. This effect may be attributed to subclinical vitamin D deficiency during the winter period, which is common in countries of the northern hemisphere. We conclude that seasonal variation contributes significantly to the biological variability of bone turnover and needs consideration when interpreting the results of bone marker measurements.

Aged↗
PubMed1997

[The Wolfram syndrome: diabetes mellitus, hypacusis, optic atrophy and short stature in STH deficiency].

HISTORY AND CLINICAL FINDINGS: A 43-year-old man was known for 3 years to have diabetes mellitus. For 2 months before admission he had symptoms of hyperglycaemia with polyuria, polydipsia, weight loss, as well as impairment of vision and declining fitness. In addition to bilateral deafness he was clearly of normally proportioned short stature (150 cm). INVESTIGATIONS: The levels of blood sugar (221 mg/dl), HbA1c(10.2%), triglycerides (496 mg/dl) and cholesterol (323 mg/dl) were raised, while the concentration of somatotropic hormone was diminished, both before and after arginine administration. Fundoscopy revealed concentric diminution of the visual fields with left amblyopia. Visual evoked potentials and colour sense testing revealed bilateral optical atrophy, and the audiogram demonstrated deafness. These findings provided the diagnosis of Wolfram syndrome, namely insulin-dependent diabetes mellitus, deafness, optical atrophy and small stature with somatotropic hormone deficiency. TREATMENT AND COURSE: On insulin treatment the metabolic state became normal (HbA1c 7.5%, normal lipid profile). It was decided that the deficiency in somatotropic hormone regulation did not require treatment. CONCLUSION: Cardinal symptoms of the autosomally recessive Wolfram syndrome are insulin-dependent diabetes and optic nerve atrophy. Several types of hormonal abnormalities are associated with it, including a deficiency in the somatotropic axis. To obtain early and adequate hormonal substitution requires extensive endocrinological diagnosis of a disease which frequently becomes manifest in childhood or adolescence.

Adult↗
PubMed1996

[Bisphosphonate therapy of Paget's disease of bone with pamidronate].

BACKGROUND: Paget's disease of bone is a disease with massive focal increase of bone turnover. Bisphosphonates like etidronate inhibit of osteoclastic bone resorption and are therefore established in the treatment of Paget's disease. The aminobisphosphonate pamidronate is 100 times more potent than etidronate. To assess the therapeutic potential for Paget's disease, we have investigated the long-term efficacy of two different dosages of pamidronate. PATIENTS AND METHODS: 40 consecutive patients with Paget's disease received a total dose of either 180 mg (n = 21) or 100 mg (n = 19) of pamidronate i.v. over 9 or 5 days respectively in two independent phases of a prospective trial. Efficacy and side effects were monitored for a follow up period of up to two years. RESULTS: For both dosages a significant reduction of urinary 24-h-hydroxyprolin excretion and serum alkaline phosphatase (AP) levels as parameters of disease activity was recorded. AP levels fell to a minimum of 31 +/- 3% (180 mg) and 41 +/- 5% (100 mg) of pretreatment values, respectively. Two years after treatment, a significant reduction of disease activity could still be detected. Side effects, including transient fever, head ache or bone pain occurred in one third of the patients. CONCLUSION: Pamidronate treatment for Paget's disease of bone leads to a sustained inhibition of elevated bone turnover.

Aged↗
PubMed1995

Crucial role of c-myc in 1,25(OH)2D3 control of C-cell-carcinoma proliferation.

1,25(OH)2D3 (1,25D3) enhances DNA synthesis and cell proliferation in the human C-cell carcinoma cell line (TT). These effects are dependent on previous stimulation of c-myc gene expression. Since the TT cell line has lost some characteristic C-cell features, we investigated the rat rMTC 6-23 line to assess whether the 1,25D3 effects on TT cells are representative of C-cell carcinoma cells. Addition of 1,25D3 (10(-7)M) led to a 2.5-fold stimulation of 3H-thymidine incorporation (3H-T) in TT cells, which was preceded by a 2-fold increase in c-myc mRNA. In contrast, in proliferating nonstimulated rMTC 6-23 cells, c-myc mRNA was undetectable. Upon addition of 1,25D3 to these cells, 3-HT decreased to 70% of control, with no change in c-myc expression. Thus, the stimulatory effect of 1,25D3 in TT cells seems to depend, at least in part, on a c-myc-dependent pathway.

Calcitriol↗
PubMed1995

Clinical significance of antibodies against calcitonin.

Calcitonin (CT) inhibits osteoclast-mediated bone resorption and is being used to treat Paget's disease of bone, hypercalcemia of malignancy and postmenopausal osteoporosis. The formation of antibodies against heterologuous calcitonins like salmon calcitonin (sCT) is common and occurs in 40-70% of the patients treated for more than 4 months. Not all of these patients, however, develop a secondary resistance to sCT, therefore the clinical significance of sCT antibodies is discussed controversially. In vivo and in vitro approaches demonstrate a neutralizing effect in 35 to 60% of the patient sera with antibodies against sCT. These neutralizing antibodies appear to explain most cases of clinically relevant secondary resistance to sCT treatment, which occurs in 25-45% of the patients after treatment periods of 6 months and longer. A positive treatment response to human CT after development of secondary resistance to sCT proves the diagnosis of antibody related resistance. Few cases develop secondary resistance in the absence of sCT binding antibodies, the mechanism of this phenomenon is unclear. Antibody related resistance is a significant problem in long term treatment with sCT. Especially in conditions like postmenopausal osteoporosis, where no readily accessable marker of treatment response is available, the development of sCT antibodies and their possible neutralizing effect has to be considered.

Animals↗