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Biomedical subjects

M F Holick

Publications and source records attributed to M F Holick.

At least 55 records · Page 3Linked to original sources
PubMed1999

Analysis of 1,25-dihydroxyvitamin D(3) receptors (VDR) in basal cell carcinomas.

We have analyzed expression of 1,25-dihydroxyvitamin D(3) receptor (VDR) protein and mRNA in basal cell carcinomas (BCC) of human skin. VDR immunoreactivity in BCCs was compared with the staining pattern of the proliferation marker Ki-67 in the same tumors. Additionally, VDR staining was compared to staining pattern of apoptotic cells by terminal UTP nucleotide end labeling assay. Frozen sections of superficial type, nodular type, and fibrosing type BCCs were consistently immunoreactive for VDR (mAb 9A7gamma) with almost every tumor cell labeled (n = 15). In general, VDR staining was pronounced in peripheral tumor cells. VDR immunoreactivity was consistently stronger in tumor cells than in adjacent or unaffected epidermis. No visual correlation was found in BCCs comparing labeling patterns of Ki-67-positive or apoptotic cells and mAb 9A7gamma. VDR mRNA was increased in BCCs (n = 6) compared to normal human skin (n = 5), as revealed by reverse transcription-polymerase chain reaction analysis. Our findings indicate that VDR is strongly expressed in BCCs and may be involved in the growth regulation of this tumour, and VDR mRNA and protein are increased in BCCs as compared to normal human epidermis.

Antibodies, Monoclonal↗
PubMed1999

Immunological responses to ultraviolet light B radiation in Black individuals.

Immunological factors are important participants in the pathogenesis of experimental skin tumors. We therefore studied cutaneous immune responses in subjects with either low natural incidence (Black individuals), or a high frequency rate (White individuals) of skin cancer. We performed whole body irradiation with a low dose of ultraviolet light B (UV-B) and evaluated peripheral lymphocytes. UV-B irradiation was associated with small but significant changes in lymphocyte phenotype frequency. In White subjects this consisted of an increased number of CD19 (B cells) and CD 4/29 (inducer of helper T cells); Black subjects had a slight decrease in CD3 (T cells). Natural killer activity, not affected by UV-B in White subjects, increased significantly in Black subjects. UV-B was devoid of immunological effects in vitro for any of the parameters tested. As expected, the low UV-B dose used in this study induced increases of serum vitamin D3 concentrations in White subjects, with lack of response in the Black subjects. We conclude that Black individuals selectively exhibit an increase in Natural Killer activity in response to irradiation with low dose UV-B. This race group-specific immune response to ultraviolet radiation appears to require mediation by the skin. Enhanced Natural Killer activity could underlie at least partly the resistance in Black individuals to the development of photodependent skin cancer.

Adult↗
PubMed1999

Perspective on the consequences of short- and long-duration space flight on human physiology.

During the past three decades, humans have made significant progress in accomplishing their aspirations for exploring the Moon and the planets. It is now appreciated that humans undergo a remarkable number of physiologic adaptations in microgravity that affect most physiologic systems. Space motion sickness was one of the first adaptations that humans experienced in microgravity. However, it is self-limiting and, most of the time, is effectively treated pharmacologically. Of particular concern is that, in microgravity, there is marked wasting of the skeletal musculature and skeleton that appears to be unrelenting and could impact on the health and welfare of space travelers during prolonged space flights and on return to earth. Microgravity also has a significant impact on the cardiovascular system that could have potentially serious consequences in terms of cardiovascular health during long-duration space flights. Other adaptations such as decreased T-cell responsiveness and changes in circadian rhythms is only now being explored. We need to understand the role that microgravity has on human physiologic systems in order to develop strategies for permitting humans to experience prolonged microgravity without having significant impact on their health and welfare. Engineering some gravitational force as a component of long-duration space vehicles should be given a high priority.

Adaptation, Physiological↗
PubMed1998

Vitamin D and its major metabolites: serum levels after graded oral dosing in healthy men.

We determined the quantitative relationships between graded oral dosing with vitamin D3, 25(OH)D3, and 1,25(OH)2D3 for short treatment periods and changes in circulating levels of these substances. The subjects were 116 healthy men (mean age, 28 +/- 4 years, with usual milk consumption of < or = 0.47 l/day and mean serum 25(OH)D of 67 +/- 25 nmol/l). They were distributed among nine open-label treatment groups: vitamin D3 (25, 250 or 1250 micrograms/day for 8 weeks), 25(OH)D3 (10, 20 or 50 micrograms/day for 4 weeks) and 1,25(OH)2D3 (0.5, 1.0 or 1.0 microgram/day for 2 weeks). All treatment occurred between January 3 and April 3. We measured fasting serum, calcium, parathyroid hormone, vitamin D3, 25(OH)D and 1,25(OH)2D immediately before and after treatment. In the three groups treated with vitamin D3, mean values for circulating vitamin D3 increased by 13, 137 and 883 nmol/l and serum 25(OH)D increased by 29, 146 and 643 nmol/l for the three dosage groups, respectively. Treatment with 25(OH)D3 increased circulating 25(OH)D by 40, 76 and 206 nmol/l, respectively. Neither compound changed serum 1,25(OH)2D levels. However, treatment with 1,25(OH)2D3 increased circulating 1,25(OH)2D by 10, 46 and 60 pmol/l, respectively. Slopes calculated from these data allow the following estimates of mean treatment effects for typical dosage units in healthy 70-kg adults: an 8-week course of vitamin D3 at 10 micrograms/day (400 IU/day) would raise serum vitamin D by 9 nmol/l and serum 25(OH)D by 11 nmol/l; a 4-week course of 25(OH)D3 at 20 micrograms/day would raise serum 25(OH)D by 94 nmol/l; and a 2-week course of 1,25(OH)2D3 at 0.5 microgram/day would raise serum 1,25(OH)2D by 17 pmol/l.

Adult↗
PubMed1998

Perspective on the impact of weightlessness on calcium and bone metabolism.

As humans venture into space to colonize the moon and travel to distant planets in the 21st century, they will be confronted with a bone disease that could potentially limit their space exploration activities or put them at risk for fracture when they return to earth. It is now recognized that an unloading of the skeleton, either due to strict bed rest or in zero gravity, leads on average to a 1%-2% reduction in bone mineral density at selected skeletal sites each month. The mechanism by which unloading of the skeleton results in rapid mobilization of calcium stores from the skeleton is not fully understood, but it is thought to be related to down regulation in PTH and 1,25-dihydroxyvitamin D3 production. Bone modeling and mineralization in chick embryos is not affected by microgravity, suggesting that bone cells adapt and ultimately become addicted to gravity in order to maintain a structurally sound skeleton. Strategies need to be developed to decrease microgravity-induced bone resorption by either mimicking gravity's effect on bone metabolism, or enhancing physically or pharmacologically bone formation in order to preserve astronauts' bone health.

Animals↗
PubMed1998

Serum vitamin D metabolite levels and the subsequent development of prostate cancer (Hawaii, United States)

OBJECTIVES: Because several serum studies of vitamin D metabolites have produced equivocal results on their relation to prostate cancer risk, the purpose of this study is to evaluate this association further. METHODS: A nested case-control study in a cohort of 3,737 Japanese-American men examined from 1967 to 1970 was conducted in Hawaii (United States). At the time of examination, a single blood specimen was obtained, and the serum was frozen. After a surveillance period of over 23 years, 136 tissue-confirmed incident cases of prostate cancer were identified. Their stored sera and those of 136 matched controls were measured for the following: 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, calcium, phosphorus, and parathyroid hormone. RESULTS: There were no notable differences between cases and controls in their median serum levels of the five laboratory measurements. Odds ratios (OR) for prostate cancer, based on the quartiles of serum levels in controls, were also determined. The ORs for the highest quartiles relative to the lowest were 0.8 (95 percent confidence interval [CI] = 0.4-1.8) for 25-hydroxyvitamin D and 1.0 (CI = 0.5-2.1) for 1,25-dihydroxyvitamin D. CONCLUSION: It is possible that the lack of sufficient numbers of study subjects with low vitamin D levels affected the results. Nonetheless, the findings suggest that there is a lack of a strong association between vitamin D and prostate cancer.

Age Distribution↗
PubMed1998

Calcium supplementation prevents seasonal bone loss and changes in biochemical markers of bone turnover in elderly New England women: a randomized placebo-controlled trial.

Elderly women are at increased risk for bone loss and fractures. In previous cross-sectional and longitudinal studies of women residing in northern latitudes, bone loss was most pronounced during winter months and in those consuming less than 1 g calcium per day. In this study we sought to test the hypothesis that calcium supplementation by either calcium carbonate or dietary means would prevent seasonal bone loss and preserve bone mass. Sixty older postmenopausal women without osteoporosis were randomized to one of three treatment arms: Dietary milk supplementation (D-4 glasses of milk/day), Calcium carbonate (CaCO3-1000 mg/day in two divided doses), or placebo (P). After 2 yr, placebo-treated women consumed a mean of 683 mg/day of calcium and lost 3.0% of their greater trochanteric (GT) bone mineral density (BMD) (P < 0.03 vs. baseline); Dietary supplemented women averaged a calcium intake of 1028 mg/day and sustained minimal loss from the GT (-1.5%; P = 0.30), whereas CaCO3-treated women (total Ca intake, 1633 mg/day) suffered no bone loss from the GT and showed a significant increase in spinal and femoral neck BMD (P < 0.05). Femoral bone loss occurred exclusively during the two winters of the study (i.e. total loss, -3.2%; P < 0.02 in placebo-treated women) with virtually no change in GT BMD during summer. Serum 25-OH vitamin D declined by more than 20% (P < 0.001) in all groups during the winter months but returned to baseline in summer; PTH levels rose approximately 20% (P < 0.001) during winter but did not return to baseline during the summers. Urine N-telopeptide and osteocalcin levels increased significantly but only in the P-treated women and only during winter. Serum insulin growth factor binding protein 4, an inhibitory insulin growth factor binding protein, rose 15% (P < 0.03) from summer to winter, but this increase was significant only in those women consuming <1000 mg/day of calcium. By multivariate analysis, total calcium intake was the strongest predictor of bone loss from the hip. Urinary N-telopeptide also closely correlated with GT BMD but only during winter (P = 0.003). We conclude that calcium supplementation prevents bone loss in elderly women by suppressing bone turnover during the winter when serum 25-OH vitamin D declines and serum PTH increases. The precise amount of calcium necessary to preserve BMD in elderly women requires further studies, although in this study, at least 1000 mg/day of supplemental calcium was adequate prophylaxis against femoral bone loss.

Aged↗
PubMed1998

Oncogenic osteomalacia: clinical presentation, densitometric findings, and response to therapy.

A 72-yr-old white female who had previously enjoyed excellent health presented with global bone and muscle pain, and chronic fatigue. Her evaluation revealed an increased sedimentation rate and mild anemia, and a diagnosis of polymyalgia rheumatica was made. Prednisone therapy was of little benefit. A laboratory evaluation revealed mild hypocalcemia, marked hypophosphatemia, elevated alkaline phosphatase, normal 25- hydroxyvitamin D, and undectable 1,25-dihydroxyvitamin D. A diagnosis of oncogenic osteomalacia was made and the patient received calcitriol and neutraphos therapy. The patient's initial bone density by dual energy X-ray absorptiometry of the lumbar spine was 0.847 g/cm2 (T score -1.96) and of the femoral neck was 0.669 gm/cm2 (T score -2.89). After 40 mo of treatment with calcitriol and neutraphos, the bone mineral density of the lumbar spine and hip rose dramatically by 47.8 and 59.1%, respectively. Although oncogenic osteomalacia is a very rare metabolic bone disease, its recognition and appropriate treatment can have a dramatic effect not only on the bone mineral density of the patient, but also on the patient's general health and feeling of well-being.

Journal Article↗
PubMed1998

The utility of portable dual-energy X-ray absorptiometry of the wrist in patients referred to a bone health clinic: a pilot study.

Fifty white female patients referred to a bone health care clinic were studied. Patients with a history of fracture were excluded. At the time of hip and spine dual-energy X-ray absorptiometry (DXA), those willing underwent portable dual-energy X-ray absorptiometry (pDXA) of the wrist. The mean age of the patients was 57 yr. Bone mineral density (BMD) assessment was performed on each patient at four different sites: posterior-anterior lumbar spine, nondominant hip, the distal radius and ulna, and the proximal radius and ulna of the nondominant arm. Comparison of the pDXA results with that of the conventional DXA results showed the highest correlation between pDXA of the distal radius and ulna (DR + U) and the DXA of the femoral neck and lumbar spine. By defining a pDXA (DR + U) T-score </= -1 as a positive test and DXA T-score </=-1 as the presence of disease, we obtained a specificity of 93% and a sensitivity of 82% for decreased lumbar spine bone density (positive predictive value 97% and the negative predictive value 70%) and a specificity of 100% and a sensitivity of 83% (positive predictive value is 100% and the negative predictive value is 70%) for decreased femoral neck bone density.

Journal Article↗
PubMed1998

Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3.

Epidemiological and laboratory data support a role for vitamin D in the growth and differentiation of human prostatic cells. These findings prompted us to ask whether prostatic cells could convert 25-hydroxyvitamin D3 (25-OH-D3), the major circulating metabolite of vitamin D3, to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the hormonally active metabolite, in a manner similar to cultured human keratinocytes. Therefore, we investigated three well-characterized human prostate cancer cell lines, LNCaP, DU 145, and PC-3; two primary cultures of cells derived from noncancerous human prostates (one normal and one benign prostatic hyperplasia); and primary cultures of normal human keratinocytes for their ability to synthesize 1,25(OH)2D3. Assays were performed in the presence of 25-OH-D3 as the enzyme substrate and 1,2-dianilinoethane, an antioxidant and free radical scavenger, and in the presence and absence of clotrimazole, a cytochrome P450 inhibitor. DU 145 and PC-3 cells produced 0.31 +/- 0.06 and 0.07 +/- 0.01 pmol of 1,25(OH)2D3/mg protein/h, respectively. No measurable 1,25(OH)2D3 was detected in LNCaP cells. The normal and benign prostatic hyperplasia primary cultures and keratinocyte cultures produced 3.08 +/- 1.56, 1.05 +/- 0.31, and 2.1 +/- 0.1 pmol of 1,25(OH)2D3/mg protein/h, respectively, using a calf thymus receptor binding assay to measure 1,25(OH)2D3 in the presence of 1,2-dianilinoethane. The identity of the analyte as 1,25(OH)2D3 was supported by high performance liquid chromatography using [3H]25-OH-D3 as the enzyme substrate and a solvent system that is specific for 1,25(OH)2D3. The production of 1,25(OH)2D3 in the prostate cancer cell lines and in the primary cultures was completely inhibited in the presence of clotrimazole. This report demonstrates that two of three human prostate cancer cell lines, as well as primary cultures of noncancerous prostatic cells, possess 1alpha-hydroxylase activity and can synthesize 1,25(OH)2D3 from 25-OH-D3. Together with recent data indicating that 1,25(OH)2D3 inhibits the invasiveness of human prostate cancer cells (G. G. Schwartz et al., Cancer Epidemiol. Biomark. Prev., 6: 727-732, 1997), these data suggest a potential role for 25-OH-D3 in the chemoprevention of invasive prostate cancer.

Adult↗
PubMed1997

Rapid identification of Smith-Lemli-Opitz syndrome homozygotes and heterozygotes (carriers) by measurement of deficient 7-dehydrocholesterol-delta 7-reductase activity in fibroblasts.

To extend the enzyme deficiency in Smith-Lemli-Opitz syndrome (SLOS) to extrahepatic tissues, 7-dehydrocholesterol-delta 7-reductase activity was measured in fibroblasts from 10 controls, five SLOS homozygotes, and five obligate heterozygotes. In cells grown almost to confluence in cholesterol-containing medium (4 mg/dL), the conversion of [1,2-3H]7-dehydrocholesterol to cholesterol (7-dehydrocholesterol-delta 7-reductase activity) was 3.8 times higher in control than in homozygote cells and 2.2 times higher than in heterozygote cells. After 24 hours' exposure of the fibroblasts to cholesterol-deficient medium supplemented with lovastatin, 7-dehydrocholesterol-delta 7-reductase activity increased twofold in controls, but did not change significantly in either heterozygous or homozygous cells. In contrast, the activities of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and lathosterol 5-dehydrogenase, two key enzymes that precede 7-dehydrocholesterol-delta 7-reductase in the cholesterol biosynthetic pathway, and low-density lipoprotein (LDL) receptor-mediated binding were equal in control, homozygote, and heterozygote fibroblasts. Further, HMG-CoA reductase activity and LDL receptor-mediated binding increased after exposure of the cells to cholesterol-deficient medium. Fibroblast cholesterol concentrations were approximately equal, although homozygote cells contained 30 times more 7-dehydrocholesterol. Thus, markedly reduced 7-dehydrocholesterol-delta 7-reductase activity that cannot be upregulated after exposure of the cells to cholesterol-deficient medium is diagnostic for the biochemical defect in SLOS. Significantly reduced enzyme activity between the levels in controls and homozygotes without accumulation of 7-dehydrocholesterol in fibroblasts identified heterozygotes.

Fibroblasts↗
PubMed1997

Control of hair growth with parathyroid hormone (7-34).

Parathyroid hormone (PTH) related peptide (PTHrP) is thought to influence the proliferation and differentiation of the epidermis and hair follicle. As a means of elucidating the biologic function of PTHrP on the hair follicle, a PTHrP analog PTH (7-34), which is a PTH/PTHrP receptor antagonist, was given intraperitoneally twice daily to C57 BL/6 mice at different stages of the hair cycle. PTH (7-34) induced 99 +/- 4.5% (mean +/- SEM) of resting telogen hair follicles into a proliferative (anagen) state, whereas 100% of the hair follicles in the control group remained in telogen. To determine whether this peptide influenced the progression of the hair follicles from anagen to catagen (hair follicle maturation and regression), groups of mice that were either spontaneously in or induced to anagen received either PTH (7-34) or placebo. Morphometric analysis of the hair follicles from the middle back region of the spontaneous anagen mice that received PTH (7-34) revealed that 19 +/- 4% (mean +/- SEM) of the follicles were in anagen VI, whereas none (0%) were in anagen in the control group. Similarly, in induced anagen mice treated with PTH (7-34), 22.3 +/- 1.4 (mean +/- SEM) of the follicles were in anagen VI compared to only 1.3 +/- 0.7% in the control mice. Together these observations suggest that PTHrP is a hair follicle morphogen that may be a major factor responsible for controlling the hair cycle. These studies provide a new insight for development of PTHrP analogs for a wide variety of disorders related to disturbances of hair cycling.

Animals↗
PubMed1997

Expression of integrin subunits and CD44 isoforms in psoriatic skin and effects of topical calcitriol application.

Increasing evidence suggests involvement of integrins and CD44 isoforms in the pathogenesis of psoriasis, contributing to uncontrolled keratinocyte proliferation, neovascularization, and invasion of inflammatory cells. We have analyzed immunohistochemically in situ expression of integrins (CD29, CDw49b, CDw49c, CDw49e, CDw49f) and CD44 isoforms (CD44 standard, CD44 var/v6, CD44 v10) on frozen sections of normal and psoriatic skin (nonlesional skin, lesional skin before and along with topical calcitriol treatment). We did not observe visual changes of immunoreactivity in normal as compared to nonlesional psoriatic skin, while the staining pattern of CDw49c, CDw49f, and CD29 was severely altered in untreated lesional psoriatic skin. Most markedly, CDw49c, CDw49f, and CD29 were focally upregulated in suprapapillar epidermal compartments of lesional psoriatic skin, a staining pattern that is in accordance with the phenomenon that was described by Pinkus as "squirting papilla". Additionally, an increased proportion of inflammatory and endothelial cells revealed immunoreactivity for CD44(std.) in untreated lesional psoriatic as compared to nonlesional psoriatic or normal skin. After 8 weeks of topical calcitriol treatment (15 micrograms/g ointment), the staining pattern for CDw49c, CDw49f and CD29 was markedly changed in epidermis of lesional psoriatic skin, reverting to the staining pattern characteristic for the nonlesional psoriatic or normal human skin, although epidermal expression of CDw49f was still upregulated and CDw49e-, CDw49f-, CD29-, and CD44(std.)-immunoreactive inflammatory and endothelial cells were still to be found in the dermal compartment.

Administration, Topical↗
PubMed1997

Calcium absorptive effects of vitamin D and its major metabolites.

The absorptive response to graded doses of vitamin D3, 25(OH)D, and 1,25(OH)2D was measured in healthy adult men after treatment periods of eight, four, and two weeks, respectively. While no relationship was found between baseline absorption and serum vitamin D metabolite levels, all three vitamin D compounds significantly elevated 45Ca absorption from a 300 mg calcium load given as part of a standard test meal. 1,25(OH)2D was active even at the lowest dose (0.5 microgram/day), and the slope was such that doubling of absorption would occur at an oral dose of approximately 3 micrograms/day. 25(OH)D was also active in elevating absorption and did so without raising total 1,25(OH)2D levels. On the basis of the dose response curves for 1,25(OH)2D and 25(OH)D, the two compounds exhibited a molar ratio for physiological potency of approximately 100:1. The absorptive effect of vitamin D3 was seen only at the highest dose level (1250 micrograms, or 50,000 IU/day) and was apparently mediated by conversion to 25(OH)D. Analysis of the pooled 25(OH)D data from both the 25(OH)D- and vitamin D3-treated groups suggests that approximately one eighth of circulating vitamin D-like absorptive activity under untreated conditions in winter may reside in 25(OH)D. This is a substantially larger share than has been predicted from studies of in vitro receptor binding.

Absorption↗