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Biomedical subjects

C P White

Publications and source records attributed to C P White.

At least 19 recordsLinked to original sources
PubMed2000

Increased formation and decreased resorption of bone in mice with elevated vitamin D receptor in mature cells of the osteoblastic lineage.

The microarchitecture of bone is regulated by complex interactions between the bone-forming and resorbing cells, and several compounds regulate both actions. For example, vitamin D, which is required for bone mineralization, also stimulates bone resorption. Transgenic mice overexpressing the vitamin D receptor solely in mature cells of the osteoblastic bone-forming lineage were generated to test the potential therapeutic value of shifting the balance of vitamin D activity in favor of bone formation. Cortical bone was 5% wider and 15% stronger in these mice due to a doubling of periosteal mineral apposition rate without altered body weight or calcium homeostatic hormone levels. A 20% increase in trabecular bone volume in transgenic vertebrae was also observed, unexpectedly associated with a 30% reduction in resorption surface rather than greater bone formation. These findings indicate anabolic vitamin D activity in bone and identify a previously unknown pathway from mature osteoblastic cells to inhibit osteoclastic bone resorption, counterbalancing the known stimulatory action through immature osteoblastic cells. A therapeutic approach that both stimulates cortical anabolic and inhibits trabecular resorptive pathways would be ideal for treatment of osteoporosis and other osteopenic disorders.

Animals↗
PubMed1998

The roles of exercise and fall risk reduction in the prevention of osteoporosis.

In summary, the optimal model for the prevention of osteoporotic fractures includes maximization and maintenance of bone strength and minimization of trauma. Numerous determinants of each have been identified, but further work to develop preventative strategies based on these determinants remains to be undertaken. Physical activity is a determinant of peak BMD. There also is evidence that activity during growth modulates the external geometry and trabecular architecture, potentially enhancing skeletal strength, while during the adult years activity may reduce age-related bone loss. The magnitude of the effect of a 7% to 8% increase in peak BMD, if maintained through the adult years, could translate to a 1.5-fold reduction in fracture risk. Moreover, in the older population, appropriate forms of exercise could reduce the risk of falling and, thus, further reduce fracture risk. These data must be considered as preliminary in view of the paucity of long-term fracture outcome data from randomized clinical trials. However, current information suggests that the optimal form of exercise to achieve these objectives may vary through life. Vigorous physical activity (including weight-bearing, resistance, and impact components) during childhood may maximize peak BMD. This type of activity seems optimal through the young adult years, but as inevitable age-related degeneration occurs, activity modification to limit the impact component of exercise may become necessary. In the elderly, progressive strength training has been demonstrated to be a safe and effective form of exercise that reduces risk factors for falling and may also enhance BMD. In the frail elderly, activity to improve balance and confidence also may be valuable. Group activities such as Tai Chi may be cost-effective. Precise prescriptions must await the outcome of well-designed, controlled longitudinal studies that include fracture as an outcome. However, increased physical activity seems to be a sensible component of strategies to reduce osteoporotic fracture.

Accidental Falls↗
PubMed1997

Human and murine osteocalcin gene expression: conserved tissue restricted expression and divergent responses to 1,25-dihydroxyvitamin D3 in vivo.

Human and murine osteocalcin genes demonstrate similar cell-specific expression patterns despite significant differences in gene locus organization and sequence variations in cis-acting regulatory elements. To investigate whether differences in these regulatory regions result in an altered response to 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] in vivo, we compared the response of the endogenous mouse osteocalcin gene to a bacterial reporter gene directed by flanking regions of the human osteocalcin gene in transgenic mice. Transgene expression colocalized with endogenous osteocalcin expression in serial sections, being detected in osteoblasts, osteocytes and hypertrophic chondrocytes. In calvarial cell culture lysates from transgenic and nontransgenic mice, the endogenous mouse osteocalcin gene did not respond to 1,25-(OH)2D3 treatment. Despite this, transgene activity was significantly increased in the same cells. Similarly, Northern blots of total cellular RNA and in situ hybridization studies of transgenic animals demonstrated a maximal increase in transgene expression at 6 h after 1,25-(OH)2D3 injection (23.6+/-3.6-fold) with a return to levels equivalent to uninjected animals by 24 h (1.2+/-0.1-fold). This increase in transgene expression was also observed at 6 h after 1,25-(OH)2D3 treatment in animals on a low calcium diet (25.2+/-7.7-fold) as well as in transgenic mice fed a vitamin D-deficient diet containing strontium chloride to block endogenous 1,25-(OH)2D3 production (7.5+/-0.9-fold). In contrast to the increased transgene expression levels, neither endogenous mouse osteocalcin mRNA levels nor serum osteocalcin levels were significantly altered after 1,25-(OH)2D3 injection in transgenic or nontransgenic mice, regardless of dietary manipulations, supporting evidence for different mechanisms regulating the response of human and mouse osteocalcin genes to 1,25-(OH)2D3. Although the cis- and trans-acting mechanisms directing cell-specific gene expression appear to be conserved in the mouse and human osteocalcin genes, responsiveness to 1,25-(OH)2D3 is not. The mouse osteocalcin genes do not respond to 1,25-(OH)2D3 treatment, but the human osteocalcin-directed transgene is markedly upregulated under the same conditions and in the same cells. The divergent responses of these homologous genes to 1,25-(OH)2D3 are therefore likely to be due to differences in mouse and human osteocalcin-regulatory sequences rather than to variation in the complement of trans-acting factors present in mouse osteoblastic cells. Increased understanding of these murine-human differences in osteocalcin regulation may shed light on the function of osteocalcin and its regulation by vitamin D in bone physiology.

Animals↗
PubMed1995

The life-expectancy of persons with cerebral palsy.

Survival rates for persons with cerebral palsy were calculated using information from a population-based registry which has been collecting data since 1952. The 30-year survival rate approximates 87 per cent. Adverse factors affecting survival are the type of cerebral palsy (spastic quadriplegia having the worst prognosis), epilepsy and severe or profound mental retardation. The length of time over which the data were collected precludes estimating survival time beyond 30 years.

Adolescent↗
PubMed1995

Effects of estrogen exposure and reproductive factors on bone mineral density and osteoporotic fractures.

The risk of osteoporotic fracture is related to peak bone mass achieved at skeletal maturity and subsequent bone loss. Although premature menopause is a risk factor for osteoporosis, the effect of exposure to endogenous estrogen during a woman's reproductive years is poorly characterized. We analyzed the relationship between reproductive factors and estrogen exposure on bone mineral density (BMD) and incidence of atraumatic fracture in data from 1091 women (age: 70 +/- 7.2 yr; mean +/- SD) participating in the Dubbo Osteoporosis Epidemiology Study. Age- and weight-adjusted BMD among women who had used estrogen replacement therapy (ERT) for more than 5 yr was higher at the lumbar spine and femoral neck by 13.7% and 10.2% (P < 0.001), respectively, compared with women who had used ERT for less than 5 yr or nonusers. Duration of exposure to estrogen (years of menstruation plus postmenopausal ERT use) was associated with higher BMD, such that BMD increased by 2-3% for every 10-yr increase in years of estrogen exposure; thus women who menstruated for more than 40 yr had a 6-8% higher BMD than did women who menstruated for less than 30 yr. Higher BMD was also significantly associated with high parity, such that nulliparous women had 5-6% lower BMD than did their peers of the same age and weight. The incidence of atraumatic fractures among non-ERT users was higher than that of ERT-users [odds ratio (OR): 1.06; 95% confidence interval (CI): 0.94-1.16] and was significantly lower among parous women than among nulliparous women (OR 0.94; 95% CI: 0.84-0.98) in univariate analysis. Longer duration of menstruation was associated with lower fracture incidence (OR for 1 SD = 6.6 yr: 0.93; 95% CI: 0.86-1.02). Moreover, when all of these factors were considered simultaneously, parity remained a significant determinant of fracture as well as femoral neck BMD. We conclude that high parity and longer duration of exposure to estrogen, either through natural menstruation or postmenopausal ERT, have protective effects on BMD and are associated with a reduced incidence of atraumatic fracture in a population-based study.

Aged↗
PubMed1994

Vitamin D receptor alleles and bone physiology.

The vitamin D endocrine system is central to the control of bone and calcium homeostasis. The active hormonal form of vitamin D, 1,25 dihydroxyvitamin D (calcitriol), the circulating level of which is tightly regulated, acts through a specific receptor to mediate its genomic actions on almost every aspect of calcium homeostasis. Because of its transactivation function, it is possible that a small difference in vitamin D receptor level could be amplified into a biologically significant alteration in physiological setpoint. The recent finding that polymorphisms in the vitamin D receptor gene are predictive of bone density (Morrison et al., Nature 367:284-287, 1994) is the first example of an allelic effect in such a homeostatically controlled system. This raises the possibility that such central operators may exist in other regulatory pathways, and could explain a large part of the observed "normal" population distribution that exists for all physiological parameters.

Alleles↗
PubMed1994

Somatosensory evoked potentials following posterior tibial nerve stimulation predict later motor outcome.

Posterior tibial nerve somatosensory evoked potentials (PTN-SEPs) were performed on 50 neonates at high risk of future neurodevelopmental impairment just before their discharge from the neonatal intensive-care unit. The close association of sensory pathways with motor tracts and the need for sensory input and integration for normal motor functioning would indicate that CNS lesions producing motor deficits may be detected by this method. Follow-up of these infants revealed a highly significant relationship between bilaterally abnormal PTN-SEPs and the presence of cerebral palsy at three years of age. Normal PTN-SEPs were associated with a normal outcome in 24 of 25 infants. In this group of neonates, PTN-SEPs were more predictive than cranial ultrasound.

Brain Diseases↗
PubMed1994

Osteopenia in cerebral palsy.

The bone mineral density of the lumbar spine was assessed in nine non-ambulant children with cerebral palsy combined with measurements of serum 25-hydroxyvitamin D, parathyroid hormone, and urinary calcium excretion. Three children with recurrent fractures received treatment with bisphosphonates for periods ranging from 12-18 months. All the children demonstrated a severe reduction in bone mineral density even when allowance was made for their body weight. There were no consistent abnormalities of vitamin D or parathyroid hormone status. Three children had gross hypercalciuria. Each of the children treated with bisphosphonates demonstrated an increment in bone density ranging from 20-40% with no apparent adverse effects.

25-Hydroxyvitamin D 2↗
PubMed1993

Oculocerebral hypopigmentation syndrome associated with Bartter syndrome.

We describe a 20-year-old man with tyrosinase-negative oculocutaneous albinism, mental retardation, epilepsy, sensorineural deafness, ataxia, and Bartter syndrome. When combined, these neurocutaneous and renal findings form a previously unreported combination. The neurological and cutaneous manifestations of this case are distinctly different from those of the syndrome first reported by Cross et al. [1967]. The literature is reviewed and an attempt is made at classifying the oculocerebral hypopigmentation syndromes.

Adult↗
PubMed1992

Visual hallucinations after acute visual loss in a young child.

A four-year-old boy developed complex visual hallucinations consisting of moving figures, animals and other familiar objects one week after becoming totally blind. This followed a six-month period of gradually deteriorating vision and was precipitated by the debulking of a large optic nerve glioma. Although visual hallucinations are well recognised in adults with visual loss, secondary to both ophthalmological and neurological causes, they have not been reported in young children.

Blindness↗
PubMed1990

Tumor necrosis factor-alpha induces vitamin D-1-hydroxylase activity in normal human alveolar macrophages.

The induction of 1-hydroxylase in alveolar macrophages by tumor necrosis factor-alpha (TNF) was examined in view of recent evidence suggesting that local production of 1,25-(OH)2D3 may play a role in the regulation of immune functions. Incubation of pulmonary alveolar macrophages from normal human subjects with recombinant TNF caused a 2- to 10-fold increase in 25-hydroxyvitamin D3-1-hydroxylase activity. The dose-response curve was linear over the range 0.05-5.0 IU/ml, and no further increase was seen at higher concentrations. The increase in 1-hydroxylase activity was present after 12 h and reached a maximum after 3 days. The effect of TNF was inhibited in a dose-dependent manner by the presence of 1,25(OH)2D3 (10(-10)-10(-8) M) in the incubation media for 5 days but was unaffected by 10(-9) M 1,25(OH)2D3 after 12 h. The enhancement of macrophage 1-hydroxylase activity by TNF was comparable to that induced by gamma interferon (IFN) but the effects of maximal doses of both agents were not additive. The presence of antibody to TNF resulted in a 76% inhibition of TNF-induced 1-hydroxylase but had no significant effect on IFN-induced 1-hydroxylase activity.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1990

Testing a 3-D radiation therapy planning program.

This report describes a systematic effort to test all functions of a large 3-D radiation therapy planning program, including graphics and user interaction. Previous studies in quality assurance for radiation therapy programs do not adequately address the problem of programming errors. They compare dose estimates calculated by planning programs to actual doses measured in phantoms, so they cannot distinguish programming errors from measurement errors or physical unsoundness of the beam model. Moreover, they fail to exercise graphics and user interaction functions. This report describes a different methodology: test cases are derived from the program specification, results are calculated by an independent technique, and compared to program output. Derivation of test cases is described in detail. Effectiveness of testing is assessed by reporting the number of errors revealed by testing and comparing to the number of errors discovered during routine use in five successive program versions. The size of the test set is related to the total program size, and the effort devoted to deriving and performing tests is compared to the total program development effort. We conclude that systematic testing can reveal errors that are not found by informal testing, routine program use, or comparison with measurements. However, additional errors remain that are only discovered during use. This study suggests that a typical large planning system may include more than 100 errors when it is released for clinical use. Methods for increasing testing effectiveness are recommended.

Radiotherapy, Computer-Assisted↗
PubMed1990

Advances in the management of diabetes mellitus.

This article shall highlight several areas where recent developments have made, and may make in the future, practical advances to diabetes care. These advances have been in the areas of insulin therapy, glucose monitoring, identifying pre-diabetics and using immunosuppressive agents in pre-diabetes and early diabetes, pancreatic transplantation, and managing acute and chronic complications of diabetes.

Blood Glucose↗
PubMed1989

Maturation of the cortical evoked response to posterior-nerve stimulation in the preterm neonate.

Short-latency somatosensory evoked potentials elicited by stimulation of the posterior tibial nerve at the ankle were studied in 75 preterm infants. Normative data for the latency of the first cortical component (P1) were obtained for infants from 27 weeks gestation to term, and showed a linear decrease with increasing gestational age. As the pathway of this response traverses areas of the brain likely to be affected by ischaemic and haemorrhagic lesions, abnormalities in the response might indicate later motor disorder.

Afferent Pathways↗
PubMed1987

The use of Teflon-embedded calcium sulphate: dysprosium thermoluminescent dosimeters for chest radiography.

As part of a U.S. multi-regional pilot study conducted by the six Centers for Radiological Physics, 12-mm-diameter by 0.4-mm-thick CaSO4:Dy Teflon-embedded discs were evaluated and used to measure patient entrance exposure on 60 "average" patients at 12 clinical centers. The discs were found to have adequate sensitivity, reproducibility and linearity up to 69.7 microC kg-1 (270 mR). The minimum measurable exposure was estimated as 0.4 microC kg-1 (1.5 mR). All responses were corrected for energy dependence, which varied +/- 20% from 1.7 to 6.5 mm Al half-value layer. Patient entrance exposure values ranged from 1.3 to 28 microC kg-1 (5 to 110 mR), with a median value of 5.2 microC kg-1 (20 mR). This value agreed with exposure measurements made on the chest radiography equipment using an ionization chamber and a phantom which simulated an "average" patient, and with published Nationwide Evaluation of X-Ray Trends (NEXT) data for the same period.

Calcium Sulfate↗
PubMed1986

Monocyte-derived growth factors for human tumor clonogenic cells.

Human peripheral blood monocytes secrete a soluble factor that enhances the ability of human epithelial tumor cell lines to clone in soft agar. Monocytes increased colony growth in a concentration-dependent manner, although inhibition of cell growth was observed in the presence of high concentrations of monocytes. Addition of indomethacin to monocytes did not abrogate this inhibition. Exposure of monocytes to endotoxin increased their ability to secrete stimulatory factors. Nonadherent lymphocytes were unable to support colony growth. Conditioned media from unstimulated monocytes also increased colony growth. Growth-promoting activity was detected in the media within the first 24 hr of culture, reaching a peak at 72 hr. Activity was not observed in monocyte lysates. Monocytes released this activity when cultured in the presence of both serum-free and serum-containing media. The activity was nondialyzable, relatively heat stable, and failed to adhere to CM-Sephadex. The demonstration of a monocyte-derived factor that enhances growth of epithelial tumor colonies supports findings indicating that inflammatory products may enhance tumor cell growth in vitro.

Adenocarcinoma↗