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Biomedical subjects

D Feldman

Publications and source records attributed to D Feldman.

At least 91 records · Page 5Linked to original sources
PubMed1998

The vitamin D receptor gene start codon polymorphism: a functional analysis of FokI variants.

The vitamin D receptor (VDR) gene contains a start codon polymorphism (SCP) which is three codons upstream of a second start site (ATG). The SCP genotype can be determined with the restriction enzyme FokI, where "f" indicates the presence of the restriction site and the first ATG, while "F" indicates its absence. Recent evidence suggests that the ff genotype is correlated with lower bone mineral density (BMD) in some populations. The SCP results in alternate VDRs that differ structurally, with the F variant (F-VDR) being three amino acids shorter than the f variant (f-VDR). To determine whether there are functional differences between the f-VDR and the F-VDR, we studied the two VDR forms expressed in COS-7 cells. The proteins were distinguishable from one another on Western blots by their different mobilities, confirming the larger size of f-VDR. Ligand binding studies showed no significant differences between the affinities of the two VDR forms for [3H]-1,25-dihydroxyvitamin D3 ([3H]-1,25(OH)2D3) (Kd = 131+/-78 pM, f-VDR; Kd = 237+/-190 pM, F-VDR; p = 0.24); however, a 2-fold difference in affinity can not be discriminated by this method. There were no differences in the abilities of the two receptor forms to bind DNA as determined by electrophoretic mobility shift assays. The ability of the two VDR forms to transactivate target genes was investigated using three different vitamin D responsive luciferase reporter constructs: 24-hydroxylase, osteocalcin, and osteopontin. In these transactivation experiments, 1,25(OH)2D3 dose-response (0.1-10 nM) curves revealed that the ED50 values for transactivation were indistinguishable between the two VDR forms. Additionally, cultured human fibroblasts with FF, Ff, and ff genotypes had similar sensitivity to 1,25(OH)2D3 with respect to the induction of 24-hydroxylase mRNA. In summary, we were unable to detect significant differences in ligand affinity, DNA binding, or transactivation activity between f-VDR and F-VDR forms. We must emphasize, however, that the sensitivity of the methods used limits our ability to detect minor differences in VDR affinity and function. In conclusion, we cannot define a mechanism whereby the SCP in the VDR might contribute to population differences in BMD.

Analysis of Variance↗
PubMed1998

Hereditary 1,25-dihydroxyvitamin D-resistant rickets due to an opal mutation causing premature termination of the vitamin D receptor.

Mutations in the vitamin D receptor (VDR) gene have been shown to cause hereditary vitamin D-resistant rickets (HVDRR). The patient in this study is a young French-Canadian boy with no known consanguinity in his family. The child exhibited the clinical characteristics of HVDRR with early onset rickets, hypocalcemia, secondary hyperparathyroidism, and elevated 1,25-dihydroxyvitamin D (1,25(OH)2D) levels as well as total alopecia. Fibroblasts were cultured from a skin biopsy of the patient and used to assess the VDR. Northern blot analysis showed that a normal size VDR transcript was expressed; however, [3H]1,25(OH)2D3-binding levels were very low and Western blot analysis failed to detect any VDR protein. Total resistance to 1,25(OH)2D3 was demonstrated by the failure of the cultured fibroblasts to induce the transcription of the 25-hydroxyvitamin D-24-hydroxylase gene when treated with high concentrations of 1,25(OH)2D3. Analysis of the DNA sequence revealed a unique C to T base change corresponding to nucleotide 218 of the VDR cDNA. This single base substitution changes the codon for arginine (CGA) to an opal stop codon (TGA), resulting in the truncation of the VDR at amino acid 30. The Arg30stop mutation prematurely terminates translation and deletes 398 amino acids including most of the zinc fingers as well as the entire ligand-binding domain. Restriction fragment length polymorphism analysis of a DdeI restriction site created by the mutation showed that the parents were heterozygous for the mutant allele. In conclusion, the Arg30stop mutation truncates the VDR and leads to a hormone-resistant condition which is the molecular basis of HVDRR in this patient.

Alopecia↗
PubMed1998

Resolution of human parvovirus B19-induced nonimmune hydrops after intrauterine transfusion.

Our objective is to report our experience with cases of prolonged recovery from nonimmune hydrops secondary to human parvovirus B19 infection occurring after intrauterine transfusion. We reviewed cases referred to our unit over a 10 year period for exposure to parvovirus B19 infection. Those cases with serologic evidence of recent infection were identified. The cases requiring intrauterine transfusion were reviewed for demographic details, time of exposure, parvovirus B19 serology, gestational age at detection of nonimmune hydrops, number and results of fetal blood samples, duration from intrauterine transfusion to resolution of hydrops, and neonatal outcome. Of 38 cases identified through serologic evidence of recent parvovirus B19 infection, 35 (92.1%) did not develop hydrops, and these were followed by serial ultrasonography for 8 weeks from the time of exposure. Three cases (7.9%) developed hydrops and required intrauterine transfusion; in two the transfusion was intravascular and in one it was intraperitoneal. The mean duration from intrauterine transfusion to resolution of hydrops was 8 weeks 2 days. Pregnancy outcome in all cases was normal. In cases of nonimmune hydrops secondary to parvovirus B19 infection, resolution of the hydrops after intrauterine transfusion may take up to 12 weeks with a normal pregnancy outcome.

Adult↗
PubMed1998

[Characteristics of Israeli primary health care physicians who treat depression].

Primary health care physicians have a pivotal role in treating mental health problems. We determined the proportion of primary care physicians in Israel who treat depression and their characteristics. The study was based on a stratified national random sample of primary care physicians (n677, response rate 78%). From these physicians' reports 22% always treat depression, 36.6% usually, 28.6% sometimes, and 12.6% never. Based on a logistic regression model the physicians who always or usually treated depression were distinguished from the other physicians by their treating more medical conditions on their own, seeing themselves as having more first contact for psychosocial problems, having frequent contact with social workers and specializing in family medicine. Primary health care physicians play a major role in treating depression on their own. This raises new questions about how they treat depression themselves, and under what circumstances they treat or refer to a specialist.

Depression↗
PubMed1997

Hereditary vitamin D resistant rickets caused by a novel mutation in the vitamin D receptor that results in decreased affinity for hormone and cellular hyporesponsiveness.

Mutations in the vitamin D receptor (VDR) result in target organ resistance to 1alpha,25-dihydroxyvitamin D [1,25(OH)2D3], the active form of vitamin D, and cause hereditary 1,25-dihydroxyvitamin D resistant rickets (HVDRR). We analyzed the VDR of a patient who exhibited three genetic diseases: HVDRR, congenital total lipodystrophy, and persistent mullerian duct syndrome. The patient was treated with extremely high dose calcitriol (12.5 microg/d) which normalized serum calcium and improved his rickets. Analysis of [3H]1,25(OH)2D3 binding in the patient's cultured fibroblasts showed normal abundance of VDR with only a slight decrease in binding affinity compared to normal fibroblasts when measured at 0 degrees C. The patient's fibroblasts demonstrated 1,25(OH)2D3-induction of 24-hydroxylase mRNA, but the effective dose was approximately fivefold higher than in control cells. Sequence analysis of the patient's VDR gene uncovered a single point mutation, H305Q. The recreated mutant VDR was transfected into COS-7 cells where it was 5 to 10-fold less responsive to 1,25(OH)2D3 in gene transactivation. The mutant VDR had an eightfold lower affinity for [3H]1,25(OH)2D3 than the normal VDR when measured at 24 degrees C. RFLP demonstrated that the patient was homozygous for the mutation while the parents were heterozygous. In conclusion, we describe a new ligand binding domain mutation in the VDR that causes HVDRR due to decreased affinity for 1,25(OH)2D3 which can be effectively treated with extremely high doses of hormone.

Calcitriol↗
PubMed1997

Physical illness among all discharged psychiatric inpatients in a national case register.

Previous studies have found that although psychiatric patients tend to have more physical illness than the rest of the population, it frequently goes unrecognized and untreated in psychiatric settings. This study investigated rates of reported physical illness among hospitalized psychiatric patients in preparation for national reform in mental health services. Data from the Israeli National Psychiatric Case Registry were analyzed on reported physical illness among all 38,714 psychiatric discharges during 1989-1991. Physical illness was reported for 10.62% of patients under age 25, 14.04% of patients 25 to 44, 34.27% of patients 45 to 65, and 61.26% of patients 65 and older. Rates differed among hospitals. Reported physical illness was considerably lower than expected as compared with other studies. Underdiagnosis is suggested as a possible explanation. Study results were used to add differential payment for physical comorbidity under the new National Health Insurance Law. Other corrective measures are discussed.

Adult↗
PubMed1997

Method of measurement of pancreatic elastase II activity and postnatal development of proteases in human duodenal juice and bovine and porcine pancreatic tissue.

A specific method for pancreatic elastase II activity analysis was developed. True elastase II activity could be discriminated from that of elastase I and chymotrypsin. The postnatal development of four pancreatic proteases in the duodenal juice of children and in the pancreatic homogenates of calves and piglets was measured. The study was carried out on patients without (14 children) and with (5 children) pancreatic insufficiency. Calves and piglets were either milk-fed or weaned until slaughter at different ages. Profiles of enzyme development were globally similar in milk-fed piglets and calves, while in children without pancreatic insufficiency, no significant change was observed between 4 and 168 months. In children with pancreatic insufficiency, enzyme activity was low. In animals, elastase II and chymotrypsin activities were maximal at birth, decreased with age, and probably were associated with the digestion of milk protein. In contrast, elastase I and trypsin activities increased markedly after weaning in connection with the intake of solid food.

Adolescent↗
PubMed1997

1,25-dihydroxyvitamin D3 induction of nerve growth factor in L929 mouse fibroblasts: effect of vitamin D receptor regulation and potency of vitamin D3 analogs.

Decreased nerve growth factor (NGF) synthesis in the hippocampus and reduced nerve growth factor receptor immunoreactivity in CH1-4 basal forebrain areas have been implicated in neurodegeneration. Vitamin D receptors (VDR) have been located in brain areas affected by neurodegenerative diseases. 1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3], the active form of vitamin D, has been shown to induce NGF in L929 mouse fibroblasts and rat hippocampus. In the present study we analyzed the VDR in L929 cells, which we used as a model system. We studied the regulation of VDR abundance and the ability of 1,25-(OH)2D3 to induce NGF synthesis. Scatchard analysis of [3H]1,25-(OH)2D3 binding showed the VDR concentration to be 173 fmol/mg protein and the affinity to be 0.12 nM. VDR was localized to nuclei of L929 cells by immunocytochemistry. Treatment of cells with forskolin (FSK; 50 microM), which activates the cAMP-protein kinase A pathway, resulted in an 8- to 10-fold up-regulation of VDR by 6 h, and VDR remained elevated at 24 h, as we have reported for other cells. NGF secretion was measured in serum-free conditioned medium using a double sided enzyme-linked immunosorbent assay. 1,25-(OH)2D3 treatment (0.1 pM to 10 nM) for 24 h increased the NGF concentration 2- to 3-fold, an effect that plateaued at 1 nM 1,25-(OH)2D3. VDR up-regulation by FSK pretreatment augmented the NGF response to 1,25-(OH)2D3 2-fold compared to that in vehicle-pretreated cells for a total 6-fold increase compared to basal NGF levels. The vitamin D analogs EB-1089 and 22-oxacalcitriol, which have been found to be less calcemic than 1,25-(OH)2D3, also induced NGF synthesis. The effects of these analogs were further enhanced by prior up-regulation of VDR with FSK. In conclusion, we have characterized the VDR in L929 cells and shown that 1,25-(OH)2D3 and its less calcemic analogs induce NGF. Furthermore, up-regulation of VDR abundance enhanced NGF induction. These effects of 1,25-(OH)2D3 and its analogs via VDR to regulate NGF synthesis may have significance for the eventual treatment of neurodegenerative diseases that are caused by decreased NGF production.

Animals↗
PubMed1997

1alpha,25-dihydroxyvitamin D3 actions in LNCaP human prostate cancer cells are androgen-dependent.

We and others have recently shown that 1alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] significantly inhibits cell proliferation and increases secretion of prostate-specific antigen (PSA) in LNCaP cells, an androgen-responsive human prostate cancer cell line. The present study was designed to investigate the possible interactions between 1,25-(OH)2D3 and androgens in the regulation of LNCaP cellular function. LNCaP cell growth was dose-dependently inhibited by 1,25-(OH)2D3 (60% inhibition at 10 nM) when cells were cultured in medium supplemented with FBS (FBS medium). 1,25-(OH)2D3-treated cells showed a 5-fold increase in PSA secretion, similar to the increase seen in dihydrotestosterone (DHT)-treated cells. In combination, 1,25-(OH)2D3 and DHT synergistically enhanced PSA secretion 22-fold. This synergistic effect was even greater when cells were cultured in medium supplemented with charcoal-stripped serum (CSS medium), where endogenous steroids are substantially depleted. Under these conditions, 1,25-(OH)2D3 and DHT together stimulated PSA secretion up to 50-fold over the untreated control. Radioligand binding assays and Western blot analyses showed that the androgen receptor (AR) content was increased significantly by 1,25-(OH)2D3 at 48 h. Furthermore, the steady-state mRNA level of AR was up-regulated approximately 2-fold by 1,25-(OH)2D3 at 24 h. When cells were grown in CSS medium, 1,25-(OH)2D3 alone no longer inhibited cell growth or induced PSA secretion. Titration experiments revealed that the addition of DHT at 1 nM to the medium restored the antiproliferative activity of 1,25-(OH)2D3. Conversely, an antiandrogen, Casodex, completely blocked 1,25-(OH)2D3 antiproliferative and PSA stimulation activities when cells were cultured in FBS medium. In conclusion, these results demonstrate that the antiproliferative and PSA induction activities of 1,25-(OH)2D3 in LNCaP cells are dependent upon androgen action and that AR up-regulation by 1,25-(OH)2D3 likely contributes to the synergistic actions of 1,25-(OH)2D3 and DHT in these cells.

Analysis of Variance↗
PubMed1997

Analysis of vitamin D analog-induced heterodimerization of vitamin D receptor with retinoid X receptor using the yeast two-hybrid system.

Several synthetic analogs of 1 alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] are potent inducers of cellular differentiation and inhibitors of cell growth, yet they are less calcemic than 1,25-(OH)2D3 itself. The mechanisms by which these vitamin D analogs elicit a different profile of cellular activities than 1,25-(OH)2D3 are not fully understood. We propose that the analogs bind to the vitamin D receptor (VDR) to produce a conformational change that is more or less constrained than that induced by 1,25-(OH)2D3. This conformational change determines the extent of the VDR-retinoid X receptor (RXR) heterodimerization which, in turn, determines the interaction with other factors that specify the selectivity and magnitude of gene transactivation. We used the yeast two-hybrid system to evaluate a series of six vitamin D analogs for their ability to induce VDR-RXR heterodimerization. The VDR-RXR interaction was elicited by the analogs in a concentration-dependent manner. To evaluate how this activity compared with other known steps in 1,25-(OH)2D3 action, we also measured the ability of the same six analogs to bind to VDR, to enhance the binding of VDR-RXR to DNA, to transactivate a vitamin D-response element-reporter construct, and to inhibit proliferation in mammalian cells. Our results indicate that, for most analogs, the level of transcriptional activation correlates well with the strength of VDR-RXR heterodimerization in intact cells. We conclude that the yeast two-hybrid system provides a useful means to investigate heterodimerization potency and that this property contributes significantly to the overall pattern of analog activity. The yeast two-hybrid system, being an intact cell assay and easy to perform, may be a useful supplement to the conventional assays employed to screen vitamin D analogs.

Animals↗
PubMed1997

Revamping mental health care in Israel: from the Netanyahu Commission to National Health Insurance Law.

This paper describes the basis for the reform in mental health care system in Israel as presented in the report of the Netanyahu Commission (State Commission for Investigation of Functioning and Efficiency of the Health Care System in Israel, 1990) and the report of the State Comptroller's office (State Comptroller, 1991). These reports pointed to seven major problem areas in the mental health care system: (1) segregation of mental health and general health care systems, (2) variations in availability of services across the country, (3) conflict of interests within Ministry of Health which provides services and oversight, (4) overuse of hospital based care and under use of community based care, (5) reliance on hospitals for custodial care, (6) lack of appreciation of mental health service needs of non-severely mentally ill, and (7) lack of regional service planning. The article describes these problems and the proposed solutions.

Health Care Reform↗
PubMed1997

Vitamin D receptor polymorphisms, bone mineral density, and bone metabolism in postmenopausal Mexican-American women.

Common polymorphisms in the vitamin D receptor (VDR) gene have been shown to correlate with bone mineral density (BMD). However, attempts to replicate the original findings in other populations have yielded variable results. These disparities may reflect ethnic or environmental differences in the expression of the VDR effect upon BMD. We examined a relatively ethnically homogeneous group of 103 healthy postmenopausal Caucasian women of Mexican descent living in Northern California. We determined the VDR genotype and measured the BMD at the lumbar spine and femoral neck by dual-energy X-ray absorptiometry, as well as several biochemical indices of mineral metabolism. The prevalence of the BB genotype, associated in previous studies with the lowest BMD, was 8% and highly linked to the tt genotype. Absolute and age-adjusted BMD at both hip and spine showed a trend toward lower BMD in the BB, AA, and tt genotypes, but this trend did not achieve statistical significance. There were no consistent intergroup differences in change in BMD over 2 years of follow-up, nor in mean serum concentrations of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, osteocalcin, or total urinary pyridinolines. Intact parathyroid hormone concentrations were significantly higher in subjects with the AA genotype, with a trend toward higher values in those with the BB and tt genotypes as well. Our data suggest that there may be a decrease in BMD associated with the B, A, and t alleles, but the intergroup difference in BMD is 0.2-0.5 standard deviations (SD) at the lumbar spine and 0.3 SD at the femoral neck, decreases that are smaller than previously reported. Given the relatively low prevalence of the BB/tt genotype in Mexican-American Caucasians, a larger sample would be required to detect a significant association between VDR alleles and differences in BMD of the magnitude suggested by our data. We conclude that a genotype effect of this magnitude, if present, would be clinically relevant, but the impact on BMD is too small to detect with statistical significance in a study of this size.

Aged↗
PubMed1997

The vitamin D receptor start codon polymorphism (FokI) and bone mineral density in premenopausal American black and white women.

This study examines the association between bone mineral density (BMD) and a start codon polymorphism (SCP) at the translation initiation site of the vitamin D receptor (VDR) gene. The thymine/cytosine (T/C) polymorphism in the first of two start (ATG) codons can be detected by a restriction fragment length polymorphism (RFLP) using the endonuclease FokI, which recognizes ATG as part of its restriction site. F indicates absence of the first ATG and a VDR that is shorter by three amino acids. The FokI genotype was determined in 154 premenopausal American women (72 black and 82 white) who were 20-40 years old. BMD of the total body, femoral neck, and lumbar spine were measured by dual-energy X-ray absorptiometry. The distribution of the SCP genotypes differed significantly by race (p < 0.001): 4% of blacks versus 18% of whites were ff homozygous and 65% of blacks versus 37% of whites were FF homozygous. There was no statistically significant interaction between race and SCP genotype in analyses of BMD at any skeletal site. In the group as a whole, the ff women had femoral neck BMD that was 7.4% lower than that of the FF women. The ff white women had total body BMD values that were 4.3% lower and femoral neck values that were 12.1% lower than FF white women. Total body and femoral neck BMD did not differ significantly by genotype in black women, and spine BMD did not differ by genotype in either race. Addition of the SCP genotype to analysis of covariance models comparing BMD of the black and white women reduced estimated differences in femoral neck BMD between the two groups by about 35%. In conclusion, the SCP polymorphism, detected with the endonuclease FokI, appears to influence peak bone density, particularly at the femoral neck. Racial differences in its distribution may explain some of the racial difference in femoral neck BMD.

Adult↗
PubMed1997

Juvenile fibromyalgia: clinical and polysomnographic aspects.

OBJECTIVE: To identify the child-mother diagnostic correlation in fibromyalgia (FM), to study sleep disturbance in juvenile FM, and to compare clinical aspects and sleep disorders between these groups. METHODS: We studied 34 children with confirmed FM aged 11 +/- 1 years, 10 children with diffuse pain, and 17 age and sex matched asymptomatic controls. The respective 61 mothers were included: 34 asymptomatic and 27 with FM. All participants were subjected to clinical evaluation, a sleep questionnaire, and nocturnal polysomnography, preceded by a night of adaptation. Sleep scoring was done visually and a computerized analysis was performed for alpha, theta, and delta waves in slow wave sleep (SWS). RESULTS: A significant predominance of mothers with FM was observed in the group of children with FM (71%) compared to children with diffuse pain (30%) and asymptomatic children (0%). According to the sleep questionnaire, the complaints of superficial sleep and nonrestorative sleep were more prominent in mothers with FM than in children with FM, whereas motor agitation during sleep was more frequent in the children with FM. Polysomnographic anomalies were also more prominent in mothers with FM than in children with FM in terms of decrease in sleep efficiency, increase of number of arousals during sleep, and alpha intrusion in SWS. Both FM groups presented an increased alpha + theta time/delta time index during SWS compared to respective controls, and mothers with FM also showed an increase in alpha time/delta time index during SWS, compared to asymptomatic mothers. A correlation was found between alpha + theta time/delta time index during SWS and intensity of clinical manifestations of pain and sleep anomalies in children and their mothers. CONCLUSION: Significant concordance was observed regarding FM diagnosis in children and their mothers. Sleep complaints and polysomnography findings were less prominent in affected children compared to mothers with FM. In addition, we observed a significant correlation between polysomnographic indexes, sleep anomalies, and pain manifestations in children and their mothers.

Adult↗
PubMed1996

Syndrome of lipoatrophic diabetes, vitamin D resistant rickets, and persistent Müllerian ducts in a Turkish boy born to consanguineous parents.

Congenital lipodystrophy (MIM 269700), persistent Müllerian ducts (MIM 261550), and vitamin D resistant rickets (MIM 277440) were observed in an 8 1/2-year-old boy born to consanguineous parents. Measurements of hormone sensitive lipase activity from a sample of the suprapubic fat depot were normal. Although the insulin receptor appeared normal (including autophosphorylation), insulin action, assessed by induction of total mRNA, was decreased. The vitamin D receptor was normal in size and amount, with a slight decrease in affinity for 1,25(OH)2D3. Induction of 24-hydroxylase, used as a measure of responsiveness to 1,25(OH)2D3, was only mildly defective. Assessment of anti-Müllerian hormone (AMH) failed to show any abnormalities explaining the persistent Müllerian ducts. We speculate that a defect in general hormone action common to 1,25(OH)2D3, insulin, and AMH may exist in this patient although we can not exclude the unlikely possibility that he is homozygous for two or three individually rare mutations.

Adult↗