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H Melhus

Publications and source records attributed to H Melhus.

At least 37 records · Page 2Linked to original sources
PubMed2000

Transient production of bone morphogenetic protein 2 by allogeneic transplanted transduced cells induces bone formation.

The aim of this study was to evaluate the use of transplantation of genetically modified allogeneic cells as a method to induce bone formation. In this study, we infected a murine osteoprogenitor cell line with a retroviral vector containing the human bone morphogenic protein 2 (BMP2) gene. Transduced cells exhibited more alkaline phosphatase activity than cells treated with any of the tested doses of recombinant human BMP2 protein (rhBMP2). The transduced cells were suspended in a collagen solution and injected into the quadriceps muscle in immunocompetent outbred mice. Radiographic and histological examinations demonstrate abundant ectopic bone formation in 85% of the transplanted animals (n = 13). PCR and Southern blot analysis for the puromycin resistance gene revealed that the transplanted cells were detectable for up to 1 week, but not at later time points. None of the animals developed tumors. Our results suggest that allogeneic BMP2-expressing transduced cells may have therapeutic potential for enhancing new bone formation. This model also provides a simple, inexpensive, and sensitive assay for evaluating in vivo the osteoinductive potentials of secreted proteins without the requirement of protein purification or the use of immunodeficient animals.

Animals↗
PubMed2000

Estrogen receptor alpha gene polymorphisms and endometrial cancer risk.

Since the estrogen receptor alpha (ER) is an important mediator of hormonal responses such as proliferation in estrogen-sensitive tissues, we hypothesized that polymorphisms in the ER gene could be functional and associated with endometrial cancer risk. We performed a population-based case-control study in Sweden, focusing on restriction fragment length polymorphisms for XbaI and PvuII and an upstream TA repeat polymorphism. In the main analysis, 154 cases and 205 controls who never used hormone replacement therapy took part and we calculated age-adjusted and multivariate odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression. The XbaI X allele appeared to confer a reduced risk for endometrial cancer. The multivariate OR for the XX genotype was 0.52 (95% CI 0.21-1.29) compared to the xx genotype and there were suggestions of decreasing risk with increasing number of X alleles (P for trend = 0.07). The PvuII PP genotype was also associated with a non-significantly decreased risk for endometrial cancer (multivariate OR 0.70, 95% CI 0.34-1.44) compared with the pp genotype (P for trend = 0.43). The multivariate OR for two short TA (<19 repeats) alleles versus two long alleles was 1.54 (95% CI 0. 73-3.27) and there were suggestions of increasing risk with increasing number of short alleles (P for trend = 0.26). We observed the same pattern of results in an expanded group of subjects, which included women who had used hormone replacement (in total 288 cases and 392 controls). Our data suggest that variants of the ER gene may be associated with an altered risk of endometrial cancer.

Aged↗
PubMed1999

Use of novel bone biopsy system to study molecular effects of growth hormone in human bone--a pilot study.

In this study, we have examined whether a novel bone biopsy system combined with reverse transcription-polymerase chain reaction (RT-PCR) or differential display PCR (ddPCR) can be used to detect specific mRNAs induced by growth hormone (GH) in human bone. In a 58-year-old man with complete GH deficiency as a result of empty sella, bone biopsies were taken before, and 5 and 24 h after administration of 24 recombinant human GH. Insulin-like growth factor binding protein-3 (IGFBP-3) mRNA levels in this patient, measured in a semiquantitative RT-PCR assay, increased about 40% 24 h after GH administration. This increase was not seen in a healthy control who did not receive GH, suggesting that the increase was an effect of GH rather than of the biopsy itself. Several differentially expressed mRNAs were detected by ddPCR. Thus, this pilot study suggests that our novel bone biopsy system may be suitable for in vivo studies of the molecular effects of substances with essential functions in human bone.

Base Sequence↗
PubMed1999

Smoking, antioxidant vitamins, and the risk of hip fracture.

Smoking increases the concentrations of free radicals, which have been suggested to be involved in bone resorption. We examined whether the dietary intake of antioxidant vitamins may modify the increased hip fracture risk associated with smoking. We prospectively studied 66,651 women who were 40-76 years of age. Forty-four of the cohort members who sustained a first hip fracture within 2-64 months of follow-up (n = 247) and 93 out of 873 age-matched controls were current smokers. Information on diet was obtained by a validated food-frequency questionnaire. The relative risk of hip fracture for current versus never smokers was analyzed in relation to the dietary intake of antioxidant vitamins stratified into two categories (low/high), where median intakes among the controls were used as cut-off points. After adjustment for major osteoporosis risk factors, the odds ratio (OR) for hip fracture among current smokers with a low intake of vitamin E was 3.0 (95% confidence interval 1.6-5.4) and of vitamin C 3.0 (1.6-5.6). In contrast, the OR decreased to 1.1 (0.5-2.4) and 1.4 (0.7-3.0) with high intakes of vitamin E and C, respectively. This effect was not seen for beta-carotene, selenium, calcium, or vitamin B6. In current smokers with a low intake of both vitamins E and C, the OR increased to 4.9 (2.2-11.0). The influence of the intake of these two antioxidant vitamins on hip fracture risk was less pronounced in former smokers. Our results suggest a role for oxidant stress in the adverse effects on the skeleton of smoking, and that an insufficient dietary intake of vitamin E and C may substantially increase the risk of hip fracture in current smokers, whereas a more adequate intake seems to be protective.

Adult↗
PubMed1998

Excessive dietary intake of vitamin A is associated with reduced bone mineral density and increased risk for hip fracture.

BACKGROUND: The highest incidence of osteoporotic fractures is found in northern Europe, where dietary intake of vitamin A (retinol) is unusually high. In animals, the most common adverse effect of toxic doses of retinol is spontaneous fracture. OBJECTIVE: To investigate whether excessive dietary intake of vitamin A is associated with decreased bone mineral density and increased risk for hip fracture. DESIGN: A cross-sectional study and a nested case-control study. SETTING: Two counties in central Sweden. PARTICIPANTS: For the cross-sectional study, 175 women 28 to 74 years of age were randomly selected. For the nested case-control study, 247 women who had a first hip fracture within 2 to 64 months after enrollment and 873 age-matched controls were selected from a mammography study cohort of 66,651 women 40 to 76 years of age. MEASUREMENTS: Retinol intake was estimated from dietary records and a food-frequency questionnaire. Bone mineral density was measured with dual-energy x-ray absorptiometry. Hip fracture was identified by using hospital discharge records and was confirmed by record review. RESULTS: In multivariate analysis, retinol intake was negatively associated with bone mineral density. For every 1-mg increase in daily intake of retinol, risk for hip fracture increased by 68% (95% CI, 18% to 140%; P for trend, 0.006). For intake greater than 1.5 mg/d compared with intake less than 0.5 mg/d, bone mineral density was reduced by 10% at the femoral neck (P = 0.05), 14% at the lumbar spine (P = 0.001), and 6% for the total body (P = 0.009) and risk for hip fracture was doubled (odds ratio, 2.1 [CI, 1.1 to 4.0]). CONCLUSION: High dietary intake of retinol seems to be associated with osteoporosis.

Adult↗
PubMed1998

Dyslexia.

Explore the source record for details and available documents.

Dyslexia↗
PubMed1998

Polymorphism at the Sp 1 binding site in the collagen type I alpha 1 gene does not predict bone mineral density in postmenopausal women in sweden.

Polymorphisms at the binding site of the Sp 1 transcription factor of the collagen type I alpha1 gene have recently been suggested to be an important marker for low bone mineral density (BMD) and vertebral fracture in a population of predominantly postmenopausal British women. We examined whether the unfavorable "s" allele was associated with low BMD in 64 patients with primary osteoporosis and in 72 healthy controls. We found no statistically significant differences between COLIA1 genotypes with regard to BMD at the spine and femoral neck. In 36 patients with severe osteoporosis with vertebral fracture the genotype frequencies were similar to that observed in 67 age-matched controls. These data indicate that the Sp 1 polymorphisms in the COLIA1 gene are unlikely to be of clinical value in identifying Swedish subjects who are at risk of postmenopausal osteoporosis.

Absorptiometry, Photon↗
PubMed1998

Oral isotretinoin therapy in severe acne induces transient suppression of biochemical markers of bone turnover and calcium homeostasis.

Although dietary vitamin A is required for normal growth and development, long-term or high-dose administration of vitamin A derivatives (retinoids) may produce a variety of skeletal side-effects in man. In this study we investigated the early effects of oral isotretinoin therapy on bone turnover and calcium homeostasis in eleven consecutive patients with nodulocystic acne. The effects on bone metabolism were correlated to radiological and bone mineral density measurements following drug therapy for six months. Markers of bone turnover, i.e. serum osteocalcin, the carboxyterminal propeptide of type I collagen, bone specific alkaline phosphatase, the carboxyterminal telopeptide of type I collagen, and urine levels of calcium and hydroxyproline decreased significantly within five days of treatment (p < 0.05). There was also a statistically significant decrease in serum calcium, with a minimum on day five, and a marked increase in serum parathyroid hormone (p < 0.05). With continued treatment, however, the abnormal levels of these markers returned to baseline values within 14 days. No significant roentgenological changes or effects on bone mineral density were found in response to the drug. The observed inhibitory effects of isotretinoin on bone turnover, despite elevated parathyroid hormone levels, indicates that the drug exerts a direct effect on bone tissue.

Acne Vulgaris↗
PubMed1997

Cloning of a novel retinoic acid-inducible mRNA from human osteoblast-like cells.

Retinoids have long been known to influence skeletal development and bone remodeling. Cells of the osteoblastic lineage play a key role in these processes. In this study we have used the differential display PCR technique to identify retinoic acid (RA)-induced mRNAs in human osteoblast-like cells. We report the cloning and sequencing of one such mRNA, AT-RA 6, which was specifically induced by all-trans RA both in normal human osteoblast-like cells and in MG-63 osteosarcoma cells. Maximal expression was found after 60 min, suggesting that this may be an early response gene. Expression was found in all tissues examined. No homology to known mRNA sequences was detected.

Cell Line↗
PubMed1996

Biosynthesis and function of all-trans- and 9-cis-retinoic acid in parathyroid cells.

We demonstrate that cultured human and bovine parathyroid cells incubated with all-trans-[11,12-3H]-retinol convert this tracer into all-trans- and 9-cis-retinoic acid. By using RT-PCR, cellular retinol-binding protein type I (CRBP I), cellular retinoic acid binding protein I and II (CRABP I and II), retinoic acid receptors (RARs) alpha, beta and gamma, and 9-cis-retinoic acid receptor (RXR) alpha transcripts were detected in human parathyroid cDNA. CRBP I and CRABP I expression was confirmed by immunohistochemistry. Both 9-cis- and all-trans-RA were found to suppress parathyroid hormone (PTH) secretion from dispersed human adenomatous parathyroid cells, which was augmented by combined treatment with 1mM RA and 100 nM 1,25 (OH)2D3. The present data establish parathyroid gland as a target for retinoids and as a site of synthesis of the hormonal forms of vitamin A (retinol), all-trans- and 9-cis-retinoic acid.

Alitretinoin↗
PubMed1996

Growth hormone and insulin-like growth factor-I do not activate identical genes in normal human osteoblasts.

In this study, we have examined the expression of mRNAs induced by growth hormone (GH) and insulin-like growth factor-I (IGF-I) in normal human osteoblasts using the differential display PCR method. Cells were incubated in the presence of 10(-7)M GH or IGF-I, RNA isolated and reverse-transcribed using an oligonucleotide primer, T11AC, anchored to the polyadenylate tail of a subset of mRNAs. The cDNA was then amplified using T11AC and an arbitrary 10-mer in the presence of [alpha-35S] dCTP. The PCR products were subsequently separated on a 6% DNA sequencing gel. The obtained patterns demonstrate that most, but not all, mRNAs induced by GH or IGF-I are identical. We conclude that GH and IGF-I do not induce expression of identical mRNAs in human osteoblasts. Our results support the dual effector theory of growth hormone action.

Cells, Cultured↗
PubMed1995

Epitope mapping of a monoclonal antibody that blocks the binding of retinol-binding protein to its receptor.

To define the receptor binding site of retinol-binding protein (RBP) we have generated monoclonal antibodies (mAbs) to human RBP and examined their ability to interfere with the receptor binding. MAbs to two conserved regions efficiently blocked the binding. No major conformational changes in the protein occurred upon mAb binding, since the mAbs could co-immunoprecipitate the RBP-transthyretin (TTR) complex. One blocking mAb showed reactivity to a synthetic peptide corresponding to one entrance loop of the retinol-binding pocket (amino acid residues 60-70). Thus, our results show that at least one of the entrance loops of the barrel of RBP is located in or close to the receptor binding site. It can also be concluded that the receptor and TTR binding sites involve different regions of RBP.

Antibodies, Monoclonal↗
PubMed1995

Inhibitory effects of 9-cis and all-trans retinoic acid on 1,25(OH)2 vitamin D3-induced bone resorption.

The effects of retinoic acid (RA), and calcitriol are mediated by specific nuclear receptors (RARs and VDR, respectively). Induction of RAR and VDR responsive elements in target genes requires a cofactor, the retinoid-X-receptor (RXR), with its ligand 9-cis RA. We have previously demonstrated the expression of RARs and RXRs in osteoblasts, and herein investigated the effects of the retinoids all-trans RA and 9-cis RA alone and combined with calcitriol on bone resorption in vitro, measured by 45Ca-release from prelabeled neonatal mouse calvarial bones. All-trans RA and 9-cis RA were powerful stimulators of bone resorption and essentially equipotent. At threshold concentrations (1 nM) both 9-cis RA and at-RA markedly inhibited the resorption induced by calcitriol (1 pM). The findings are compatible with a physiological role for retinoids in bone metabolism.

Animals↗
PubMed1995

Vitamin D receptor genotypes in primary hyperparathyroidism.

Vitamin D and parathyroid hormone (PTH) constitute the main regulators of systemic calcium homeostasis. As well as its calcaemic effects, active vitamin D3(1,25(OH)2D3) has a direct regulatory role on parathyroid cells. Active vitamin D3 acts via its receptor (VDR), and binding of the ligand-receptor complex to specific promoter regions of the PTH gene inhibits transcription. Active vitamin D3 constitutes a principal regulator of parathyroid cell growth, and polymorphism in the VDR gene has recently been related to bone mineral density and suggested as predisposing to osteoporosis. Impaired effects of active vitamin D3 may contribute to the relatively enhanced secretion and cell proliferation seen in hyperparathyroidism (HPT). Indeed, VDR dysfunction, of essentially unknown character, has been demonstrated in the pathological parathyroid tissue of primary HPT as well as HPT secondary to uraemia. Consistent with the essential role of active vitamin D3 in parathyroid regulation, the VDR gene polymorphism was studied in 90 postmenopausal women with primary hyperparathyroidism. The VDR genotype bb was found in 60.0% of HPT patients and in 33.3% of the postmenopausal female controls (P < 0.001). As the b allele has been linked to decreased transcriptional activity or messenger RNA stability, reduced VDR expression may impede regulatory actions of vitamin D and may contribute to parathyroid tumorigenesis in these patients.

Aged↗
PubMed1995

[Vitamin D and osteoporosis].

Vitamin D constitutes a complex endocrine-regulated system, and is both a prohormone for the endogenous synthesis of the active hormone, calcitriol, and a vitamin which may be administered to supply the organism's requirements. No single test or investigation is available for the demonstration of vitamin D deficiency. Both vitamin D intake and ability to synthesise vitamin D decrease with increasing age, and particularly the elderly in institutionalised care are at risk of developing vitamin D deficiency. Iceland excepted, mean daily vitamin D consumption in the Nordic countries is less then 5 micrograms; and in approximately 10-25 per cent of the population, daily intake is less than 2.5 micrograms which is insufficient to maintain an adequate serum calcidiol concentration in individuals unexposed to sunlight. The recommended daily intake of 5 micrograms, currently adopted in the Nordic countries, may be too low-an intake of 10 micrograms is probably necessary to satisfy requirements in the elderly.

Adrenal Cortex Hormones↗