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Biomedical subjects

C G Miles

Publications and source records attributed to C G Miles.

14 recordsLinked to original sources
PubMed2005

Gonadal effects of a mouse Denys-Drash syndrome mutation.

Gonadal effects of the Denys-Drash syndrome (DDS) mutation Wt1(tmT396 )were examined in chimaeric and heterozygous mice. Since the only heterozygote was 41,XXY, Sertoli cell function was assessed by comparison with age-matched control XXY testes. Control XXY Sertoli cells showed immuno-expression of WT1 and androgen receptor (AR) indistinguishable from wild-type (40,XY), but expressed anti-Mullerian hormone (AMH). In contrast, DDS Sertoli cells showed only faint immuno-expression of WT1 and did not express AR or AMH. While XY<-->XY DDS chimaeras were male, XX<-->XY chimaeras were predominantly female. In the rare XX<-->XY DDS males the Sertoli cell lineage was largely derived from Wt1 mutant XY cells. We conclude that DDS mutant cells can form Sertoli cells, that the dominant mutation does not cause male sex reversal in mice but distorts the sex ratio of XX<-->XY chimaeras, and that there may be a link between WT1, AMH and AR expression by Sertoli cells in vivo.

Animals↗
PubMed1997

Risk factors for hip fracture in men. Hip Fracture Study Group.

To identify risk factors for hip fracture in men, the authors conducted a case-control study involving 20 hospitals in Philadelphia, Pennsylvania, and 14 hospitals in Kaiser Permanente Medical Care Program of northern California. The 356 enrolled men had been admitted with a radiologically confirmed first hip fracture. The 402 control men either were from the Philadelphia area or were members of Kaiser Permanente and were frequency matched to the cases by age and ZIP code or telephone exchange. Information on potential risk factors was obtained through personal interviews. Men in the lowest quintile of body mass had a greatly increased risk of hip fracture compared with men in the heaviest quintile (odds ratio (OR) 3.8, 95% confidence interval (CI) 2.3-6.4). Premorbid lower limb dysfunction was associated with increased risks for hip fracture (OR 3.4, 95% CI 2.1-5.4). Increased risks were also observed with the use of cimetidine (OR 2.5, 95% CI 1.4-4.6) and psychotropic drugs (OR 2.2, 95% CI 1.4-3.3). Smoking cigarettes or a pipe increased the risk of hip fracture, and this association was independent of body mass. Finally, previous physical activity was markedly protective. Factors thought to affect bone density as well as factors identified as risk factors for falls appear to be important determinants of the risk of hip fracture in men. Physical activity may be a particularly promising preventive measure for men. Additional studies of the use of cimetidine on osteoporosis and osteoporotic fractures are indicated.

Activities of Daily Living↗
PubMed1996

Injuries among inner-city minority women: a population-based longitudinal study.

Active emergency department-based surveillance was conducted to determine the incidence of fatal and nonfatal injuries in an urban, female African American population from 1987 through 1990. Nearly 40% of the women studied sustained one or more injuries that required emergency care or resulted in death. By 1989, violence had surpassed falls as the leading cause of injuries, the rate increased by 55% over the study period. Injury rates were highest among young women for nearly every major cause of injury. The rate of death due to injuries was also highest among young women, for whom violence was the leading cause of death. In summary, injuries to women in this inner-city minority community were extremely common and increased significantly from 1987 to 1990. Injuries in young inner-city minority women should be considered a priority health problem in the United States.

Adult↗
PubMed1995

Altered cytokine expression in T lymphocytes from human immunodeficiency virus Tat transgenic mice.

Examination of the interaction between human immunodeficiency virus (HIV) regulatory gene products and the host immune system is fundamental to understanding the pathogenesis of HIV and could reveal possible targets for therapeutic intervention in the treatment of AIDS. The HIV Tat gene is a potential candidate for this type of strategy. Transgenic mice can be used to investigate the in vivo effects of Tat on the developing and dynamic immune system and on cellular gene expression. Thus, we have generated transgenic mice that harbor the HIV type 1 Tat gene under the transcriptional control of the human CD2 gene regulatory elements. This expression cassette results in high-level, tissue-specific transcription of the transgene within the T-cell compartment. In this report, we demonstrate the effects of Tat on the in vivo immune system. CD2-Tat transgenic mice show no signs of aberrant thymic development and have normal levels of T-cell subsets in the thymus and peripheral lymphoid organs. However, activated T cells from transgenic mice contain increased levels of tumor necrosis factor beta mRNA as well as biologically active tumor necrosis factor protein and express elevated levels of transforming growth factor beta and interleukin-4 receptor mRNA. These increased cytokine levels do not appear to alter mitogen- or antigen-stimulated responses or induce the formation of dermal lesions in ageing mice. Such investigations should provide insight into the combination of host immune factors mediating pathogenesis in HIV infection.

Aging↗
PubMed1994

A longitudinal study of injury morbidity in an African-American population.

OBJECTIVE: To improve understanding of the patterns of injury morbidity and mortality in an urban African-American population. DESIGN: Prospective survey of emergency department records for a geographically defined population from 1987 through 1990. SETTING: Eleven hospital emergency departments in Philadelphia, Pa. PARTICIPANTS: The approximately 68,000 people living in 17 census tracts in western Philadelphia. RESULTS: A total of 46,260 injury events were identified in the survey (168.8 events per 1000 population annually). Half of the population made an emergency department visit for one or more injuries during the 4 years of study. There were 2796 hospital admissions (10.2/1000 population) and 403 deaths (1.5/1000 population) as a result of these injuries. Although in 1987 falls were the most frequent type of injury resulting in an emergency department visit, by 1989 the number of interpersonal intentional injury events exceeded the number of falls. Interpersonal intentional injuries accounted for 31.2% of hospital admissions and 42.7% of deaths. Of men 20 through 29 years old, 94.3% visited an emergency department at least once in the 4 years because of an injury, and 40.9% of men in this age group sought treatment for one or more interpersonal intentional injuries. The likelihood of future interpersonal intentional injury-related visits increased with the number of previous injuries of this type. CONCLUSIONS: Interpersonal intentional injury occurs frequently in this population. More attention needs to be paid to prevention and intervention to reduce the toll of this violence. The high prevalence of injury in certain age strata may make general, population-based efforts for injury prevention more efficient than efforts targeted to subgroups.

Accidental Falls↗
PubMed1994

Specific ablation of human immunodeficiency virus Tat-expressing cells by conditionally toxic retroviruses.

The identification of human immunodeficiency virus (HIV) as the etiologic agent of AIDS has led to the proposal of novel intervention strategies to block HIV infection and viral replication or eliminate HIV-infected cells. We have produced recombinant retroviruses for a molecular ablation system, whereby a toxin gene can be delivered to hematopoietic cells for the specific elimination of HIV Tat-expressing cells. For this cell-specific ablation, we have coupled the conditional toxin herpes simplex virus type 1 thymidine kinase (tk) gene to the HIV-2 promoter and Tat responsive region (TAR) in order that transcriptional activity be under the absolute control of HIV and simian immunodeficiency virus Tat trans-activator proteins. Since the HIV-2 promoter has a considerable level of basal expression in the absence of Tat, we constructed a number of modifications in the HIV-2 promoter to minimize the risk of cytotoxicity to cells not containing HIV Tat. We demonstrate that certain promoter modifications reduce basal transcription while maintaining high trans-activated levels of expression when transfected or transduced by retroviral vectors into several different cell lines. In mouse and human cells infected with HIV-2 tk retroviruses, we show that Tat-induced expression from the HIV-2 promoter results in differential ablation and a massive reduction in Tat-positive cells after ganciclovir treatment. Thus, the retroviruses produced in these studies may be applicable to HIV ablative therapy.

Antiviral Agents↗
PubMed1993

CD4 cell surface downregulation in HIV-1 Nef transgenic mice is a consequence of intracellular sequestration.

The Nef gene product is a regulatory protein of HIV whose biological function is poorly understood. Nef has been thought to have a negative effect on viral replication in vitro but has been shown in studies with SIV to be necessary in the establishment of viraemia in vivo. In vitro studies in various human cell lines have shown that Nef downregulates the expression of cell surface CD4 and thus could have effects on the immune response. We have generated four transgenic mouse lines, with constructs containing two different Nef alleles under the control of CD2 regulatory elements to examine the interaction of Nef with the host immune system in vivo. In adult transgenic mice we have found marked downregulation in the level of CD4 on the surface of double positive thymocytes and a decrease in the number of CD4+ T cells in the thymus. Functional analyses have revealed a decrease in the total activation of transgenic thymocytes by anti-CD3 epsilon antibody. By specific intracellular staining of T cells in such mice we have found CD4 colocalizing with a Golgi-specific marker. These results strongly suggest a Nef mediated effect on developing CD4 thymocytes resulting from interference of Nef in the intracellular trafficking or post-translational modification of CD4.

Animals↗
PubMed1993

Studies of HIV-2 promoter activity and cell specific ablation.

We have a developed a retroviral mediated molecular ablation method to specifically eliminate HIV Tat-expressing cells. This approach utilizes the Tat-inducible HIV-2 promoter and a conditional toxin gene. The Herpes Simplex Virus thymidine kinase gene product is toxic to mammalian cells only after treatment with Ganciclovir (GCV) or other nucleoside analogues. We demonstrate here that certain promoter modifications can decrease basal expression while retaining the ability to be transactivated. Furthermore, we show that a HIV-2 promoter thymidine kinase gene cassette transduced via retroviral vectors into tissue culture cells can specifically promote the ablation of HIV-Tat expressing cells in the presence GCV. We also show that there is a large differential in HIV-thymidine kinase gene transcription and lethal drug dose between Tat-expressing cells and Tat-negative cells.

Base Sequence↗
PubMed1986

Financial cost as an obstacle to hypertension therapy.

A home health interview, including blood pressure measurements, was conducted on 4,688 adults representing the noninstitutionalized population of Georgia. Subjects with diastolic blood pressure greater than or equal to 90 mm Hg or on antihypertensive medication were considered hypertensive. The prevalence of uncontrolled moderate or severe hypertension (diastolic greater than or equal to 105 mm Hg) was 1.9 per cent. With the exception of White women, all race-sex groups with uncontrolled moderate or severe hypertension reported substantially lower per capita income than their mild or controlled hypertensive counterparts. A larger percentage of the uncontrolled moderate to severe hypertensives on medication, as compared to their mild or controlled counterparts, reported economic barriers to pharmacologic and medical care on cost of medicines (36 per cent vs 22 per cent); refills (36 per cent vs 16 per cent); and office visits (26 per cent vs 16 per cent). Black women reported these barriers more than Whites. These findings suggest that costs of antihypertensive care may be an obstacle in blood pressure control for certain population subgroups.

Adult↗
PubMed1980

Marihuana and work performance: results from an experiment.

Determining the relationship between marihuana and economic activity is an important factor in establishing social policy in this area. The effects of marihuana availability and consumption on production, hours worked, and output per hour are reported from an experimental microeconomy involving resident volunteer human subjects. The statistical analysis shows no effect of marihuana on total output or total hours worked for experimental as compared to control conditions, although marihuana use was generally associated with a simultaneous decision to engage in passive leisure activities in the period immediately following smoking. These results suggest a hypothesis about the general relationship between marihuana and economic activity that is used to integrate the results of several other studies with those reported here.

Adolescent↗
PubMed1970

The effect of a fading procedure upon the acquisition of control by an overshadowed auditory feature.

Pigeons' key-pecking responses were reinforced in the presence of a compound stimulus that consisted of an auditory feature (a tone) and a visual feature (a light) and non-reinforced in the presence of a compound stimulus that was either a noise and a dark key, or noise and a light. In the condition where reinforcement trials differed from non-reinforcement trials on the basis of both auditory and visual features, the tone exerted very little control over responding on test. In the condition where reinforcement differed from non-reinforcement trials solely on the basis of the auditory features, an abrupt and a gradual introduction of the visual feature of the negative stimulus, a light, were compared for their effect upon control in the compounds. The tone acquired strong control in both cases. Evidence indicated that the tone had acquired control in the gradual condition without the occurrence of responses to the negative stimulus. An incidental finding was that when the negative stimulus consisted of a noise and a light, which was introduced abruptly, responding over the light dimension with tone, on test, was peaked at a point other than that light value used as positive and negative during training.

Journal Article↗