[Incidental hypo- or hypercalcemia finding. Parathyroid hormone is the key to diagnosis].
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Diagnosis, Differential↗
Biomedical subjects
J Pfeilschifter
Publications and source records attributed to J Pfeilschifter.
[Postmenopausal and steroid-induced osteoporosis guideline-orientated prevention and treatment].
Prevention of osteoporosis and osteoporotic fractures consists of non-drug and drug therapy. Components of non-drug therapy include improvement of muscle strength and coordination, treatment of modifiable causes of falls, a diet rich in calcium and sufficient in calories, adequate supply of vitamin D and a careful approach towards drugs known to increase falls or osteoporosis. Assessment of clinical risk factors in combination with bone mineral density measurements can identify persons at high risk of fracture who benefit most from pharmacological treatment. Particular attention should be paid to patients with previous fragility fractures and long-term oral glucocorticoid therapy.
Calcium↗
Patterns of hormone replacement therapy in a population-based cohort of postmenopausal German women. Changes after HERS II and WHI.
In July 2002, data from the Women's Health Initiative (WHI) trial provided strong evidence for an increased risk of cardiovascular disease with use of combined estrogen plus progestogen in postmenopausal women. These unexpected results triggered a large and ongoing discussion about the role of hormone replacement therapy (HRT). We investigated the frequency of HRT before and after the publications of the WHI trial and the Heart and Estrogen/Progestin Replacement Study II (HERS II) in a population-based random sample of German women aged 45 - 65 years. A total of 8380 women completed a questionnaire on menopausal status, hysterectomy and HRT. 75 % were postmenopausal. Mean age was 56.1 years; mean age of natural menopause 49.9 years; mean duration of postmenopause was 11 years; 27 % of the women had undergone hysterectomy. The percentage of current HRT users dropped by 16 % (35.4 % to 29.8 %, p = 0.004), past users increased from 19.8 % to 23.5 % (p = 0.03). Among current HRT users, the share of combined conjugated estrogen/progestogen decreased by 41 % (p = 0.008). We observed a decreased prevalence of HRT among German women 7 months after publication of the HERS II and WHI results. The decline was, however less pronounced than reported from other countries. The use of conjugated estrogen/gestagen combinations declined disproportionately compared to other formulations.
Aged↗
Enhanced expression of group IIA secreted phospholipase A2 by elevated glucose levels in cytokine-stimulated rat mesangial cells and in kidneys of diabetic rats.
BACKGROUND: Group IIA secreted phospholipase A2 (sPLA2-IIA) has been implicated in various inflammatory processes including the kidney. Previously it has been shown that potent proinflammatory cytokines such as interleukin 1beta (IL-1beta) increase sPLA2-IIA expression and secretion in rat mesangial cells. AIM: The present study examines the effects of glucose on sPLA2-IIA regulation in interleukin-1beta (IL-1beta) treated mesangial cell cultures and in diabetic kidneys of Sprague-Dawley rats. MATERIALS AND METHODS: Rat mesangial cells were grown either in low glucose (5.55 mM D-Glucose) or high glucose (25 mM) conditions followed by assessment of sPLA2-IIA transcription, expression and secretion after 24 h. The model of streptozotocin induced diabetes mellitus in Sprague-Dawley rats was used for the in vivo experiments. Diabetic kidneys where examined for sPLA2-IIA-mRNA and -protein expression as well as IL-1beta-levels at 2, 4 and 6 weeks after induction of diabetes mellitus. RESULTS: Increased concentration of glucose had a weak, but significant stimulatory effect on sPLA2-IIA expression, which was markedly up-regulated (2-3-fold) in IL-1beta treated mesangial cells compared to the levels obtained in low glucose medium. Concerning the underlying mechanism, we found that high concentration of glucose increased the activity of the rat sPLA2-IIA-promoter, whereas mRNA stability was not affected. Furthermore, the in vivo experiments revealed a marked up-regulation of sPLA2-IIA mRNA and protein in the diabetic rat kidneys 2 - 4 weeks after induction. Since the strong up-regulation of sPLA2-IIA in vitro under high glucose conditions occurred mainly in presence of cytokine, we measured the levels of IL-1beta in diabetic kidneys by ELISA. We detected rat IL-1beta only in diabetic, but not in control rat kidneys. CONCLUSIONS: The changes of sPLA2-IIA expression under increased glucose concentrations as well as in diabetic rat kidneys suggest a function of this enzyme as an acute phase protein providing lipid autacoids that may contribute to early changes in the course of diabetic nephropathy.
Analysis of Variance↗
Hypoxia induces macrophage inflammatory protein-2 (MIP-2) gene expression in murine macrophages via NF-kappaB: the prominent role of p42/ p44 and PI3 kinase pathways.
We have previously reported that hypoxia induces a pronounced inflammatory response in the mouse lung associated with elevated levels of specific chemokines. To further explore the mechanisms involved in lung inflammation, we exposed RAW 264.7 cells as well as mouse primary macrophages to hypoxia and analyzed chemokine gene expression. Among the genes examined, macrophage inflammatory protein-2 (MIP-2) expression was prominently induced by hypoxia both at the mRNA and the protein level. When RAW 264.7 cells were transfected with a panel of plasmids harboring a luciferase marker gene under the control of wild-type or mutant variants of the MIP-2 gene promoter, a strong hypoxic induction of expression (9- to 17-fold) was observed. This induction was abolished by a mutation targeted to an NF-kappaB binding site in the MIP-2 promoter. Concordantly, specific NF-kappaB binding to the cognate sequence was enriched in nuclear extracts from hypoxic but not normoxic RAW 264.7 cells. The mechanism of MIP-2 gene induction by hypoxia was further characterized using inhibitors of signaling kinases. Inhibition of the p42/p44 and PI3 kinases but not p38 MAPK abolished the NF-kappaB-driven upregulation of MIP-2 gene expression by hypoxia. This attenuation of the NF-kappaB response to hypoxia did not involve decreased nuclear NF-kappaB abundance but correlated with diminished transactivation potential of the p65 subunit. Our results indicate that the hypoxic signal for induction of MIP-2 gene expression is implemented through enhanced NF-kappaB activity and transmitted along the p42/44 and PI3 kinase pathways.
Animals↗
[Osteoporosis].
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Absorptiometry, Photon↗
Downregulation of iNOS expression in rat mesangial cells by special extracts of Harpagophytum procumbens derives from harpagoside-dependent and independent effects.
Special extracts from the roots of Harpagophytum procumbens (Devil's Claw) are used in the supportive treatment of inflammatory diseases, and the iridoid derivative harpagoside is thought to be the active principle. To investigate, whether Harpagophytum extracts may also be useful therapeutics in the treatment of inflammatory kidney diseases, we studied the effects of two different extracts containing 8.9% (extract 1) and 27% harpagoside (extract 2), respectively, on IL-1beta-induced nitric oxide (NO) formation as well as transcriptional regulation of inducible NO synthase (iNOS) in rat renal mesangial cells. We observed a concentration-dependent suppression of nitrite formation by about 80%, which was due to an inhibition of iNOS expression. Moreover, a reduction of iNOS promoter activity and nuclear NF-kappaB translocation was observed, indicating that the extracts interfere with the transcriptional activation of iNOS. Three further Harpagophytum extracts containing about 2% harpagoside did not inhibit NO formation suggesting, that only extracts with a high harpagoside content elicit iNOS inhibition. However, pure harpagoside was only inhibitory at concentrations between 0.3 and 1 mg/ml, which is much higher than the harpagoside content present in an effective concentration of the total extracts. Moreover, a harpagoside-free extract 1 also markedly inhibited iNOS expression, indicating that other extract constituents are involved in this effect. Extract 1 exerted a strong antioxidative effect, whereas no such effect could be demonstrated for harpagoside. Together, these data show that special Harpagophytum extracts may represent potential antiinflammatory drugs in the treatment of glomerular inflammatory diseases.
Animals↗
Concentration of insulin-like growth factor (IGF)-I in iliac crest bone matrix in premenopausal women with idiopathic osteoporosis.
Previous studies have shown a link between low serum insulin-like growth factor-I (IGF-I) and decreased bone mass of patients with osteoporosis. However, whether serum levels are representative for the growth factor concentration or activity available in human bone tissue is controversial. In the present study, IGF-I was assessed in serum and bone matrix extracts from the iliac crest in 19 eugonadal women with idiopathic osteoporosis and in 38 age-matched controls. In addition, the relationship between the skeletal levels of IGF-I and bone mineral density (BMD) or the susceptibility to osteoporotic fractures in women with osteoporosis was examined. Bone matrix extraction was performed based on a guanidine-HCL/ethylendiamine-tetraacetic acid (EDTA) method. No significant difference in both serum and bone matrix IGF-I levels between groups was observed. Serum IGF-I concentrations failed to be associated with bone matrix IGF-I levels in osteoporotic patients. However, in premenopausal women with idiopathic osteoporosis, skeletal IGF-I positively correlated with BMD at the lumbar spine (r = + 0.58, p = 0.01). In contrast, neither femoral neck BMD nor Ward's triangle BMD was associated with bone matrix IGF-I concentrations. A tendency towards lower levels of bone matrix IGF-I in subjects with vertebral fractures as compared to those without fractures was observed in age-adjusted analyses, however the difference failed to remain statistically significant after adjustment for bone mineral density. These data provide no clear evidence for low bone matrix IGF-I as a determinant factor of age-unrelated osteoporosis. However, low skeletal IGF-I concentrations may aggravate osteoporosis in these women.
Absorptiometry, Photon↗
Influence of fluor salts, hormone replacement therapy and calcitonin on the concentration of insulin-like growth factor (IGF)-I, IGF-II and transforming growth factor-beta 1 in human iliac crest bone matrix from patients with primary osteoporosis.
OBJECTIVE: Data from cell culture experiments suggest that local growth factors (GFs) may mediate the effects of estrogens, calcitonin or fluor ions on the skeleton. To assess the in vivo relevance of the in vitro reports, the effect of fluor salts, hormone replacement therapy (HRT) and calcitonin on the concentrations of IGF-I, IGF-II and transforming growth factor (TGF)-beta 1 in bone matrix extracts from osteoporotic patients was evaluated. DESIGN: Iliac crest bone biopsies were obtained from 170 patients (76 men and 94 women) with primary osteoporosis aged 55.5+/-0.8 Years. METHODS: Bone matrix extraction was performed based on a guanidine-HCl/ethylendiamine-tetra-acetic acid method. RESULTS: In comparison with age- and body mass index (BMI)-matched controls, no influence of long-term therapy with fluor ions (n=41) or calcitonin (n=16) on the bone matrix concentration of GFs was noticed. Postmenopausal women with osteoporosis on HRT (n=39) had lower skeletal IGF-I but not IGF-II levels as compared with age- and BMI-matched non-users. However, the lower rate of bone turnover in women with HRT may account for this difference, since the significance was lost after adjustment for alkaline phosphatase. Likewise, a tendency for lower TGF-beta 1 levels was observed in HRT users as compared with non-users but was lost after adjustment for bone turnover. None of the therapies influenced the serum levels of GFs when patients receiving continuous therapy for at least 1 Year before bone biopsy were considered. CONCLUSIONS: Our data suggest no direct effect of fluor therapy on skeletal GFs levels. At the concentrations used, neither HRT nor calcitonin appeared to exert any significant influence on serum or bone matrix GF levels.
Biopsy↗
[Evidence-based clinical practice guidelines for diagnosis and treatment of osteoporosis].
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Adult↗
[Osteoporosis in Germany, 2003 -- a stock taking].
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Accidental Falls↗
[Hypercalcemic crisis].
Severe hypercalcemia is a life-threatening medical emergency. It is most commonly caused by malignant tumors, but can also be caused by primary hyperparathyroidism or less often by a dysregulated production of active vitamin D in granulomatous disorders. Symptoms include nausea, vomiting, renal insufficiency, severe dehydration, lethargy, confusion, and even coma. Severity of symptoms, calcium concentrations, and the overall status of the patient are important considerations in selecting appropriate therapy. Hydration to correct volume depletion is the cornerstone of acute therapy. Loop diuretics may be added to saline hydration after extracellular fluid volume has been replenished to enhance urinary calcium excretion and mitigate fluid overload from rehydration. Calcitonin and intravenous infusion of bisphosphonates reduce serum calcium levels by interfering with calcium release from the skeleton. Dialysis with a low or zero calcium dialysate is reserved for patients who are refractory to these measures. Corticosteroids are effective with hypercalcemia due to increased vitamin D levels and in multiple myeloma.
Aged↗
The effects of triiodothyronine on human osteoblast-like cells metabolism and interactions with growth hormone.
The expression of thyroid hormones receptors in osteoblasts and osteoclasts has involved these cells as direct targets for triiodothyronine (T3), but thyroid hormones may also interact with other hormones or local growth factors to exert their actions on bone cells. Among these, growth hormone (GH) is recognised as participating in the acquisition and maintenance of bone mass and exerting stimulatory effects on human osteoblastic cells. The aim of this study was to investigate T3 effects on primary human adult osteoblast-like cells (HOB) as well as to test for possible interactions between T3 and GH on bone cell metabolism. Primary human bone cell cultures were obtained by outgrowth from trabecular bone fragments from the hip and knee. Dose-response studies demonstrated enhanced [3H]-thymidine incorporation for T3 at 10(-9), 10(-8), 10(-7) and 20(-7) M, with a maximal response of 162.81 +/- 12.97 % with T3 10(-8) M, compared to vehicle (p < 0.001). Time-course studies showed an increased osteoblast-like cell proliferation after 24 h, followed by a decrease of cell proliferation by 48 h and 72 h of culture, respectively, when compared to control cells, with a maximal response after 72 h (T3 10(-10) M: 45.21 +/- 6.97 %, p < 0.01). In addition, T3 markedly increased specific alkaline phosphatase (AP) activity in HOB (10(-10) M: 169.86 +/- 12.14 % vs. control, p < 0.001), but no significant influence on type I procollagen propeptide (PICP) production was observed. At 10(-9) - 10(-7) g/ml, GH significantly enhanced HOB proliferation (p < 0.001) however, GH effects were not dose-dependent. Triiodothyronine, at a high concentration (10(-7) M), stimulated GH-receptor (GHR) mRNA levels by 165.20 +/- 16.54 % after 24 h (p < 0.05). Correspondingly, a synergistic effect of T 3 with the same concentration and GH on cell proliferation in human adult osteoblast-like cells was found.
Adult↗
Interferon-gamma induces expression of interleukin-18 binding protein in fibroblast-like synoviocytes.
OBJECTIVE: To investigate expression of the endogenous antagonist of interleukin 18 (IL-18) bioactivity, IL-18 binding protein isoform a (IL-18BPa), in fibroblast-like synoviocytes (FLS). METHODS: Long-term cultured FLS from rheumatoid arthritis (RA), osteoarthritis (OA) and spondylarthropathy patients were analysed for spontaneous and cytokine-induced IL-18BPa expression. Messenger RNA and release of IL-18BPa were assessed by semi-quantitative and quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) as well as immunoblot analysis, respectively. RESULTS: All investigated FLS cultures expressed low amounts of IL-18BPa transcripts. However, there was no detectable release of IL-18BPa from unstimulated synoviocytes. Of the investigated cytokines, only interferon (IFN)-gamma markedly up-regulated IL-18BPa mRNA levels. Induction was accompanied by release of IL-18BPa immunoreactivity from FLS. Conditioned media from IFN-gamma-stimulated FLS cultures reduced IL-12/IL-18-dependent IFN- production by peripheral blood mononuclear cells. CONCLUSION: The present data imply that IFN--activated synoviocytes mediate a negative feedback loop via IL-18BPa, which may limit IL-18 biological activity in arthritis.
Arthritis↗
[Rational and cost effective osteoporosis prevention and therapy].
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Aged↗
Expression of Interleukin-6 (IL-6) and IL-6 receptor mRNA in human bone samples from pre- and postmenopausal women.
Interleukin-6 (IL-6) has been attributed to induction of osteoclastogenic-precursor cell proliferation and maturation. Estrogens suppress IL-6 production in stromal/osteoblastic cells in vitro. Conversely, estrogen withdrawal is associated with increased IL-6 production. IL-6 is therefore thought to be an important mediator of the increased bone resorption after menopause. However, evidence supporting a rise in the expression of IL-6 or the IL-6 receptor in human bone tissue with menopause is still lacking. To address this question, we established a 5'-nuclease assay to quantitate the expression of human IL-6 and the gp80 subunit of the IL-6 receptor in human bone samples. The number of mRNA copies was normalized to the number of copies of beta actin mRNA. Osteocalcin expression served as an independent control. The study population consisted of 169 women (mean age 52.4 +/- 11.6 years) who underwent surgery for early breast cancer. Serum IL-6 was measured by enzyme-linked immunosorbent assay, serum crosslaps as a marker of bone resorption were measured by electrochemiluminescent assay, and serum osteocalcin was measured by chemoluminescence assays. RNA expression of osteocalcin in bone tissue from early postmenopausal women was higher compared with premenopausal women. Local expression was positively associated with circulating osteocalcin and crosslaps concentrations. Postmenopausal women also had higher circulating IL-6 concentrations. In contrast, bone samples from postmenopausal women lacked an increased expression of either IL-6 or gp80 compared with bone samples from premenopausal women. In conclusion, we failed to detect local increases in IL-6 or IL-6 receptor expression in human bone tissue with menopause. If direct changes in the IL-6 system in bone tissue are involved in postmenopausal bone loss, these changes appear to be below the detection limit of our assay system.
Adult↗
[Evaluation of osteoporosis].
Physical examination, bone densitometry and x-ray are the mainstay in the evaluation of osteoporosis. A limited number of simple blood tests are sufficient to discriminate most secondary forms of osteoporosis and to exclude osteomalacia. Bone-specific biochemical markers play an increasing role in monitoring osteoporosis therapy. They may also play a role in treatment decision in the coming years. Bone biopsies are helpful if findings are unclear or inconsistent. The present review gives a summary of the opportunities and limitations of the above diagnostic procedures.
Absorptiometry, Photon↗
[Disordered hormone regulation in gynecomastia].
Gynecomastia develops when there is an increase in the ratio of estrogen to androgens. Whereas mild forms of gynecomastia are frequently encountered in the male population, any breast enlargement that is prominent, painful, progressive or of recent onset always requires a careful evaluation, as it may be an important clue to disease elsewhere. Underlying causes are plenty and include drugs, congenital and acquired disorders of androgen and estrogen production, various tumors, renal failure, cirrhosis of the liver, and thyrotoxicosis. Evaluation includes a careful patient's history, physical examination of sexual characteristics and the breast tissue, and measurements of serum LH, FSH, testosterone, estradiol, hCG-beta, TSH and tests of liver and kidney function.
Androgens↗