Search PubMed⌕ Search

Biomedical subjects

D B Campbell

Publications and source records attributed to D B Campbell.

At least 19 recordsLinked to original sources
PubMed1999

Topography of the lunar poles from radar interferometry: a survey of cold trap locations.

Detailed topographic maps of the lunar poles have been obtained by Earth-based radar interferometry with the 3.5-centimeter wavelength Goldstone Solar System Radar. The interferometer provided maps 300 kilometers by 1000 kilometers of both polar regions at 150-meter spatial resolution and 50-meter height resolution. Using ray tracing, these digital elevation models were used to locate regions that are in permanent shadow from solar illumination and may harbor ice deposits. Estimates of the total extent of shadowed areas poleward of 87.5 degrees latitude are 1030 and 2550 square kilometers for the north and south poles, respectively.

Ice↗
PubMed1999

Tottering mouse motor dysfunction is abolished on the Purkinje cell degeneration (pcd) mutant background.

Tottering (tg) mice inherit a recessive mutation of the calcium channel alpha 1A subunit gene, which encodes the pore-forming protein of P/Q-type voltage-sensitive calcium channels and is predominantly expressed in cerebellar granule and Purkinje neurons. The phenotypic consequences of the tottering mutation include ataxia, polyspike discharges, and an intermittent motor dysfunction best described as paroxysmal dystonia. These dystonic episodes induce c-fos mRNA expression in the cerebellar circuitry, including cerebellar granule and Purkinje neurons, deep cerebellar nuclei, and the postsynaptic targets of the deep nuclei. Cellular abnormalities associated with the mutation include hyperarborization of brainstem nucleus locus ceruleus axons and abnormal expression of L-type calcium channels in cerebellar Purkinje cells. Here, the role of these two distinct neural pathways in the expression of tottering mouse intermittent dystonia was assessed. Lesion of locus ceruleus axons with the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzyl-amine (DSP-4) did not affect the frequency of tottering mouse dystonic episodes. In contrast, removal of cerebellar Purkinje cells with the Purkinje cell degeneration (pcd) mutation by generation of tg/tg; pcd/pcd double mutant mice completely eliminated tottering mouse dystonia. Further, the c-fos expression pattern of tg/tg; pcd/pcd double mutants following restraint was indistinguishable from that of wild-type mice, suggesting that the pcd lesion eliminated an essential link in this abnormal neural network. These data suggest that the cerebellar cortex, where the mutant gene is abundantly expressed, contributes to the expression of tottering mouse dystonic episodes.

Animals↗
PubMed1999

L-type calcium channels contribute to the tottering mouse dystonic episodes.

Tottering mice inherit a recessive mutation of the calcium channel alpha1A subunit that causes ataxia, polyspike discharges, and intermittent dystonic episodes. The calcium channel alpha1A subunit gene encodes the pore-forming protein of P/Q-type voltage-dependent calcium channels and is predominantly expressed in cerebellar granule and Purkinje neurons with moderate expression in hippocampus and inferior colliculus. Because calcium misregulation likely underlies the tottering mouse phenotype, calcium channel blockers were tested for their ability to block the motor episodes. Pharmacologic agents that specifically block L-type voltage-dependent calcium channels, but not P/Q-type calcium channels, prevented the inducible dystonia of tottering mutant mice. Specifically, the dihydropyridines nimodipine, nifedipine, and nitrendipine, the benzothiazepine diltiazem, and the phenylalkylamine verapamil all prevented restraint-induced tottering mouse motor episodes. Conversely, the L-type calcium channel agonist Bay K8644 induced stereotypic tottering mouse dystonic at concentrations significantly below those required to induce seizures in control mice. In situ hybridization demonstrated that L-type calcium channel alpha1C subunit mRNA expression was up-regulated in the Purkinje cells of tottering mice. Radioligand binding with [3H]nitrendipine also revealed a significant increase in the density of L-type calcium channels in tottering mouse cerebellum. These data suggest that although a P/Q-type calcium channel mutation is the primary defect in tottering mice, L-type calcium channels may contribute to the generation of the intermittent dystonia observed in these mice. The susceptibility of L-type calcium channels to voltage-dependent facilitation may promote this abnormal motor phenotype.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1998

Cerebellar circuitry is activated during convulsive episodes in the tottering (tg/tg) mutant mouse.

Tottering (tg) is an autosomal recessive mutation of the calcium channel alpha1A subunit in the mouse that results in epileptic spike and wave discharges, mild ataxia and paroxysmal episodes of involuntary spasms of the limbs, trunk and face. These convulsions have been especially difficult to characterize because of their unpredictable occurrence and lack of electroencephalographic correlates. However, it is, in fact, possible to induce these convulsions, making this facet of the tottering phenotype amenable to controlled experimentation for the first time. Here, the neuroanatomical basis of the convulsions in tottering mice has been identified using in situ hybridization for c-fos messenger RNA to chart abnormal neuronal activity. Convulsion-induced c-fos messenger RNA expression was most prominent in the cerebellum of convulsing tottering mice. Additionally, cerebral cortex and principal cerebellar relay nuclei were also activated during a convulsion. The c-fos activation in the cerebellum temporally preceded expression in cerebral cortex, suggesting that cerebral cortex is not driving the expression of convulsions. These results suggest that the cerebellum, a region not classically associated with paroxysmal events, is important in the generation and/or maintenance of the intermittent convulsions in tottering mutant mice.

Animals↗
PubMed1998

Tumor cell growth inhibition by caveolin re-expression in human breast cancer cells.

Cancer development is a multistage process that results from the step-wise acquisition of somatic alterations in diverse genes. Recent studies indicate that caveolin-1 expression correlates with the level of oncogenic transformation in NIH3T3 cells, suggesting that caveolin in caveolae may regulate normal cell proliferation. In order to better understand potential functions of caveolin-1 in cancer development, we have studied expression levels of caveolin-1 in human breast cancer cells, and have found that caveolin expression is significantly reduced in human breast cancer cells compared with their normal mammary epithelial counterparts. When the caveolin cDNA linked to the CMV promoter is transfected into human mammary cancer cells having no detectable endogenous caveolin, overexpression of caveolin-1 resulted in substantial growth inhibition, as seen by the 50% decrease in growth rate and by approximately 15-fold reduction in colony formation in soft agar. In addition, characterization of caveolin-1 expression during cell cycle progression indicates that expression of alpha-caveolin-1 is regulated during cell cycle. Furthermore p53-deficient cells showed a loss in caveolin expression. In summary, the overall expression patterns, its ability to inhibit tumor growth in culture, its regulation during the cell cycle, and the loss of expression in p53-deficient cells all are consistent with an important growth regulating function for caveolin-1 in normal human mammary cells, that needs to be repressed in oncogenic transformation and tumor cell growth.

Animals↗
PubMed1998

H-cadherin expression inhibits in vitro invasiveness and tumor formation in vivo.

H-cadherin is a newly characterized cadherin molecule whose expression is decreased in a variety of human carcinoma cells, suggesting that it may play a role in maintaining normal cellular phenotype. To investigate how re-expression of H-cadherin could influence the malignant phenotype of human breast carcinoma cells in vivo, we transfected both control and H-cadherin expression vectors into human breast cancer cells (MDAMB435), which do not express H-cadherin constitutively. We found that invasiveness of these cells could be prevented by transfection with H-cadherin. We also compared the ability of control- and H-cadherin-transfected cells to induce subcutaneous tumors after injection into mammary fat pads of nude mice. Our results show that H-cadherin transfection produced a marked inhibition of tumor growth and modified the morphology of tumor cells: tumors from mice injected with control cells were significantly larger and contained larger cells having a higher degree of pleomorphism than those of tumors generated from carcinoma cells expressing H-cadherin. Altogether, these results indicate that H-cadherin expression antagonizes tumor growth in nude mice, presumably by enhancing cell-cell association in a tissue environment. These findings strongly suggest that H-cadherin could provide a possible target for corrective gene therapy against breast cancer.

Animals↗
PubMed1997

Rapid genotyping of mutant mice using dried blood spots for polymerase chain reaction (PCR) analysis.

Spontaneous neurologic mutations in the mouse provide powerful tools for the study of mammalian central nervous system development. The study of mouse neurologic mutants has led to a better understanding of the complex mechanisms involved in the development of the nervous system. Because few of these mutations have been identified, molecular probes distinguishing heterozygotes from homozygotes are generally unavailable. Further, most neurologic mouse mutants breed poorly as homozygotes, making it necessary to breed heterozygotes and select homozygous mutant progeny based on phenotype. The requirement for heterozygous breeding and the lack of molecular markers specific for the mutation have hampered developmental studies because the underlying neurologic perturbations occur before the mutant mice can be identified by phenotype. The recent identification and chromosomal assignment of simple sequence repeats (SSRs), repetitive sequences of DNA found at a high density throughout the mouse genome, provide the tools for mapping mutations in the mouse and for subsequent genotyping of potential mutants prior to phenotype onset. The SSRs are useful because these markers are polymorphic (for review see Weber, J.L., Human DNA polymorphisms based on length variations in simple-sequence tandem repeats. In: K.E. Davies and S.M. Tilghman (Eds.), Genetic and Physical Mapping. Genome Analysis, Vol. I, Cold Spring Harbor Laboratory Press, Plainview, NY, 1990, pp. 159-181 [16]), that is, the size of the individual SSRs differs among strains of mice. Following polymerase chain reaction (PCR) amplification of an SSR and separation of PCR products by polyacrylamide gel electrophoresis, one can easily visualize differences in the size of the PCR product between mouse strains. Many mutations in the mouse arose spontaneously on inbred strains and were subsequently backcrossed onto a different strain. After many generations of congenic backcrosses, the only DNA retained from the original mutant strain is composed of the mutant gene and closely linked regions. Thus, it is possible to cross the mutant strain to a different mouse strain and map the mutation by correlating mutant phenotype to SSRs the same size as the original mutant strain. We have mapped the tottering (tg), Purkinje cell degeneration (pcd), and nervous (nr) mutations using SSRs in backcrossed mouse strains. The SSRs distinguishing mutant from normal strains can then be used to genotype potential mutant pups before the onset of the mutant phenotype. The protocol described below can be adapted to almost any mutation congenically inbred for genotyping. Here we describe a method for selecting primers appropriate for genotyping potential mouse mutants and a rapid protocol for genotype screening. Even with SSRs distinguishing mutant from normal mice, genotyping several mice simultaneously can be a daunting task. This is primarily because the protocols available for preparing DNA for PCR amplification are time-consuming, requiring several purification steps including phenol extractions. Although kits are commercially available for DNA preparation without organic extractions, these kits tend to be expensive. The protocol described is a rapid, inexpensive method of determining the genotype of mice using PCR analysis of dried blood spots. The protocol only requires PCR primers distinguishing among alleles and is therefore ideal for the rapid identification of potential mutants for those mouse mutations which have been mapped using microsatellite markers. The DNA preparation protocol may also be used in rapid screening of potential transgenic mice.

Animals↗
PubMed1997

Traumatic adult respiratory distress syndrome.

ARDS is the pulmonary manifestation of both direct and indirect insults to the lung. Trauma patients are at particular risk for ARDS from the direct effects of their injuries, as well as from complications that may occur during their hospital courses. ARDS prevention can be enhanced through diverse areas of medical focus. Public health issues addressing trauma prevention, improved understanding and treatment of trauma-related pathophysiology, as well as a better understanding of basic pathophysiology of this disease process will allow refinement and improvement of our management practices. Newer modes of mechanical ventilation may help us to avoid ventilator-induced exacerbation of lung injury. As we define the role of nonconventional therapies, such as anti-inflammatory and anticytokine therapies, our ability to actively interrupt and reverse the progression of the inflammatory cascade will be enhanced. As yet, ARDS continues to be a challenging disease process to both fully understand and successfully treat in our critically ill patients.

Humans↗
PubMed1997

The role of radiopharmacological imaging in streamlining the drug development process.

Radioimaging techniques have found a place in clinical diagnosis, but there has been a hesitancy to use this approach in drug development. This reluctance may have been due to the availability of ligands, the time and cost of synthesis and the number of centres and, although these perceived problems have been largely overcome, for many the benefits are not evident. The use in drug development is potentially large since tomography can measure drug levels, specific binding, blood flow and activity within the human body. In drug discovery, combinational chemistry and high throughput screening, the synthesis of candidate drugs with specific binding properties are dependent on understanding the disease and using appropriate in vitro or animal models. Using small animal tomographs, these can be validated using radioimaging. Pharmacokinetics and metabolic problems, such as the distribution of inhaled gases, drug targeting into tumours of the brain or specific gastrointestinal absorption sites can be investigated within the human rather than relying on animals. The high specific activity allows low doses to be administered to man with limited safety studies, permitting kinetic and metabolic studies to be undertaken early in development. Safety studies and ensuing toxicological endpoints in animals rely on histopathology for gross degenerative in physiological function. Where concern exists, radioimaging could detect early in situ changes in humans, for example hepatic toxicity, before they become hazardous. In clinical studies, the action of drugs can be measured directly at the effector site prior to undertaking longer studies, which is important for many diseases, but particularly for those such as Alzheimer's disease, where improvements may be slow or subtle.

Animals↗
PubMed1996

Extrapolation from animals to man. The integration of pharmacokinetics and pharmacodynamics.

This paper has focused on the difficulties of extrapolating toxicological or pharmacological data obtained from animals to those expected in man. For some drugs, under certain conditions, there may be no problem, but for many, this is clearly not the case. Differences in apparent activity are impossible to reconcile without "normalizing" the dose for differences in pharmacokinetics and metabolism. The increasing use of artificial intelligence and expert systems in drug investigations may provide a greater insight into why these differences may occur and allow prediction but, in the end, they must be tested in the experiments undertaken. The use of kinetic dynamic relationships in different species will certainly help in this regard and, wherever possible, should be included in experimental design to build up a database of experience since such information is sadly lacking. But we must interpret with caution the data produced by those that continue to extrapolate animal data to humans without some attempt to discuss in detail the validity of their assumptions.

Animals↗
PubMed1996

Responses to novelty stress in female F344 rats: effects of age and d-fenfluramine treatment.

To elucidate some of the mechanisms underlying the neuroendocrine and neurochemical changes associated with age in female rats, we administered the serotonin (5-HT) releaser and reuptake inhibitor, d-fenfluramine (d-FEN; 0.0 or 0.6 mg/kg/day, PO) for 30-38 days to young (4 month) and old (21 month) F-344 female rats. Animals were placed into a novel open field (OF) for 20 min before sacrifice. Control animals were sacrificed immediately upon removal from their home cage (HC). Old rats exhibited significantly (p < 0.05) less exploratory behavior and a smaller CORT response to OF than young animals. d-FEN treatment had no effect on plasma ACTH and CORT levels or exploratory behavior. The old HC rats had significantly (p < 0.05) higher plasma levels of prolactin (PRL) than the young HC rats. A stress induced increase in PRL secretion was observed in the old rats only, which was attenuated by d-FEN treatment. In the OF groups, both the young and old rats showed elevated medial frontal cortex (MFC) dopamine turnover (DOPAC/DA ratio), but only the young rats exhibited an elevation in norepinephrine (NE) turnover (MHPG/NE ratio). d-FEN treatment blocked the stress-induced increase in NE turnover in the young rats and the increase in DA turnover in the old rats. These data suggest that 5-HT activity could be involved in the age-related changes in the MFC catecholamine and PRL responses to stress in female rats.

Adrenocorticotropic Hormone↗