Biomedical subjects

D E Clark

Publications and source records attributed to D E Clark.

At least 19 recordsLinked to original sources

PubMed2006

A constitutively active ERBB4/HER4 allele with enhanced transcriptional coactivation and cell-killing activities.

In the normal breast, ERBB4 regulates epithelial differentiation and functions as a nuclear chaperone for signal transducer and activator of transcription (STAT) 5A, thereby stimulating milk-gene expression. In addition, ERBB4 functions as a proapoptotic protein, suppressing the growth of malignant cells. We hypothesize that these ERBB4 activities can be marshaled to suppress the growth of breast tumors. To this end, we have created an ERBB4 allele harboring an activating transmembrane mutation (ERBB4-CA) by substituting isoleucine 658 for glutamic acid. This base substitution forms a valine-glutamic acid-glycine activation domain first identified in oncogenic ERBB2/HER2/Neu. Ectopic expression of ERBB4-CA in HEK293T cells resulted in a fivefold increase in receptor tyrosine phosphorylation. Functionally, ERBB4-CA exhibited higher levels of nuclear translocation than wild-type ERBB4, leading to significantly enhanced ERBB4-induced STAT5A simulation of the beta-casein promoter. Activated ERBB4 has been demonstrated to induce cell killing of breast tumor cells. Significantly, ERBB4-CA potentiated the proapoptotic function of ERBB4 in each breast, prostate and ovarian cancer cell line tested. Untransformed cell lines were resistant to both ERBB4 and ERBB4-CA-mediated apoptosis underscoring the potential utility of active ERBB4 signaling for the therapeutic intervention of human cancer.

Alleles↗

PubMed2006

Estimating injury severity using the Barell matrix.

OBJECTIVE: To determine whether the Barell matrix (Inj Prev 2002;8:91-6) could effectively categorize injuries by severity. METHODS: Injury diagnoses of cases in the 2002 US Nationwide Inpatient Sample were classified according to the Barell matrix. For each cell of the matrix, the authors used ICDMAP-90 to determine the predominant Abbreviated Injury Score (AIS) and body region, and calculated the weighted proportion surviving (bPScell) among patients with any diagnosis in that cell. These findings were used to estimate maximum AIS (bAISmax), ISS (bISS), and the minimum or product of bPScell (bPSmin, bPSprod) for injured patients in the 1996-2000 US National Hospital Discharge Surveys. Case survival was determined for different scores, and outcome models using age, sex, comorbidity, mechanism, and bISS or bPSmin were compared to models using ISS calculated from ICDMAP-90 (mISS) or using ICISS. RESULTS: Case survival decreased with increasing bAISmax or bISS; survival was closely approximated by bPSmin, and also increased monotonically with bPSprod. Outcome models using bISS or bPSmin were similar to those using mISS or ICISS. An Abbreviated Barell Categorization, with only four groups, was also effective. CONCLUSION: Barell matrix categorization of administrative data allows severity scoring similar to that obtainable with ICDMAP-90 or ICISS.

Hospital Mortality↗

PubMed2005

The serine/threonine protein kinase, p90 ribosomal S6 kinase, is an important regulator of prostate cancer cell proliferation.

An increase in the activity of mitogen-activated protein kinase (MAPK) has been correlated with the progression of prostate cancer to advanced disease in humans. The serine/threonine protein kinase p90-kDa ribosomal S6 kinase (RSK) is an important downstream effector of MAPK but its role in prostate cancer has not previously been examined. Increasing RSK isoform 2 (RSK2) levels in the human prostate cancer line, LNCaP, enhanced prostate-specific antigen (PSA) expression, an important diagnostic marker for prostate cancer, whereas inhibiting RSK activity using a RSK-specific inhibitor, 3Ac-SL0101, decreased PSA expression. The RSK2 regulation of PSA expression occurred via a mechanism involving both RSK2 kinase activity and its ability to associate with the coactivator, p300. RNA interference of the androgen receptor (AR) showed that the AR was important in the RSK2-mediated increase in PSA expression. RSK levels are higher in approximately 50% of human prostate cancers compared with normal prostate tissue, which suggests that increased RSK levels may participate in the rise in PSA expression that occurs in prostate cancer. Furthermore, 3Ac-SL0101 inhibited proliferation of the LNCaP line and the androgen-independent human prostate cancer line, PC-3. These results suggest that proliferation of some prostate cancer cells is dependent on RSK activity and support the hypothesis that RSK may be an important chemotherapeutic target for prostate cancer.

Cell Growth Processes↗

PubMed2005

[Fractures in the elderly--a challenge for prevention and health promotion--results from the KORA fracture study Augsburg].

Fractures of the appendicular bones are frequent and can cause a loss of the ability for independent living, depending on age and fracture localisation. They affect both sexes at different times and in different ways. The basic epidemiology for Germany of this injury resp. disease and knowledge regarding medium-term health-related consequences has been provided by work done in the context of the KORA Augsburg Fracture Study 1998, a follow-up of older participants of the third MONICA Augsburg survey S3 (1994/95) and through further research in the past years. Results of a validation study support the value of questionnaire-based patients recall of fractures and their location. It could be shown that age, gender, time since fracture and impaired walking have the greatest predictive value among a number of factors. Limitations of physical function are apparent especially during the first two years after a fragility fracture. After five years functional capacity of survivors equals the functional capacity of control persons of the same age. These population-representative and validated data support model-based cost-effective strategies of population-orientated disease prevention and health promotion. An age and gender-specific approach (gender mainstreaming) is mandatory.

Age Distribution↗

PubMed2004

Practical introduction to record linkage for injury research.

The frequency of early fatality and the transient nature of emergency medical care mean that a single database will rarely suffice for population based injury research. Linking records from multiple data sources is therefore a promising method for injury surveillance or trauma system evaluation. The purpose of this article is to review the historical development of record linkage, provide a basic mathematical foundation, discuss some practical issues, and consider some ethical concerns. Clerical or computer assisted deterministic record linkage methods may suffice for some applications, but probabilistic methods are particularly useful for larger studies. The probabilistic method attempts to simulate human reasoning by comparing each of several elements from the two records. The basic mathematical specifications are derived algebraically from fundamental concepts of probability, although the theory can be extended to include more advanced mathematics. Probabilistic, deterministic, and clerical techniques may be combined in different ways depending upon the goal of the record linkage project. If a population parameter is being estimated for a purely statistical study, a completely probabilistic approach may be most efficient; for other applications, where the purpose is to make inferences about specific individuals based upon their data contained in two or more files, the need for a high positive predictive value would favor a deterministic method or a probabilistic method with careful clerical review. Whatever techniques are used, researchers must realize that the combination of data sources entails additional ethical obligations beyond the use of each source alone.

Databases, Factual↗

PubMed2003

Trends in hospitalization after injury: older women are displacing young men.

OBJECTIVE: To evaluate trends in hospitalization after injuries in the USA. DESIGN: National Hospital Discharge Survey data from 1979 to 2000 were evaluated annually by age group, sex, injury severity score (ISS), length of stay, and discharge destination. SETTING AND SUBJECTS: National probability sample of hospitalized patients. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Incidence, duration, outcome, and population based rates of hospital admission after injuries. RESULTS: The number of young males admitted to hospitals after injuries has decreased dramatically; older females are now the group most frequently admitted. Total days in the hospital have decreased in all age groups, but have declined less in the older population than in the younger population; furthermore, most patients aged 65 and over were formerly discharged home, but now most are discharged to long term care facilities. Overall hospitalization rates after injury have decreased in all age groups, but have declined less in the older population; furthermore, male and female hospitalization rates for serious injury (ISS at least 9, excluding isolated hip fracture) are decreasing in younger age groups while increasing in older age groups. CONCLUSIONS: Older patients comprise a growing proportion of injuries requiring hospitalization. Trauma systems must address this change, and preventing injuries in older people is increasingly important.

Adolescent↗

PubMed2002

Independent living after fractures in the elderly.

Although fractures are an important source of disability among the growing elderly populations of industrialized societies, patient-centered multidimensional outcome information is scarce. The purpose of this study was to quantify the natural history of recovery from fractures of the upper and lower extremities. From the 1994/95 WHO MONICA survey in Augsburg, Germany, we selected all persons aged 58-78 years who had experienced a fracture during the preceeding 10 years, along with a control population twice as large. The Health Assessment Questionnaire (HAQ) and the Medical Outcomes Study Short Form 36 (SF-36) were administered to these subjects in 1998. Patients' recollection of fracture type and location were validated against medical records. The most recent fracture was in the upper extremity in 45 cases, lower extremity in 55 cases and elsewhere in 46 cases. Extremity fractures resulted in persistent and measurable impairment of the activities of daily living or general quality of life in patients 65 years or older, especially if the femur was involved. More than 40% of the interindividual variation of functional disability in the study group could be explained by age, sex, history of a fracture within 12 years and perceived difficulties walking. Existing generic and specific musculoskeletal outcome measurement instruments thus allow the assessment of functional recovery and health status after fractures in an elderly population. Geriatric assessment following fractures at higher age may improve ability to live independently. Difficulty walking deserves special attention, as it is associated with more general functional disability among the elderly.

Activities of Daily Living↗

PubMed2002

Willingness to pay for flood and ecological risk reduction in an urban watershed.

Urban watershed managers frequently must address alternative policy goals; flood control and ecological risk reduction. This study combines hydrologic models of flood control and biotic models of ecologic risk with economic models of willingness-to-pay and psychological models of risk processing and planned behavior to evaluate these two alternative policy objectives. The findings reveal that flood risk exposure, especially for those individuals who would remain outside the 100 year flood plain if the project were enacted, does influence the financial support that local residents would be willing to make to a flood control project. Other important determinants include demographic factors such as income, and attitudinal measures of the respondent. Expanding the scope of the project to include ecological risk reduction does not, however, appear to change the average willingness-to-pay for a project.

Demography↗

PubMed2001

Rsk2 allosterically activates estrogen receptor alpha by docking to the hormone-binding domain.

We describe a novel mechanism for transcriptional regulation, in which docking of p90 ribosomal S6 kinase 2 (Rsk2) to the hormone-binding domain (HBD) of estrogen receptor alpha (ERalpha) induces a conformational change that enhances the transcriptional activation function contained in the HBD. A constitutively active mutant of Rsk2 specifically enhances ERalpha-mediated transcription by phosphorylation of Ser167 in ERalpha and by physically associating with residues 326-394 of the ERalpha HBD. The anti-estrogen 4-hydroxytamoxifen blocks Rsk2-mediated activation of ERalpha, by inducing a conformation of ERalpha in which the Rsk2 docking site is masked. Transcriptional activation and docking are specific for ERalpha and do not occur with the related isoform, ERbeta. ERalpha phosphorylation, docking and transcriptional activation are regulated by the Rsk2 N-terminal kinase domain. The allosteric regulation of a target protein, independent of phosphorylation, may be paradigmatic of a general function for protein kinase docking sites.

Allosteric Regulation↗

PubMed2001

Hip fracture incidence in east and west germany: reassessement ten years after unification.

The rising incidence of hip fractures is of world wide concern. In addition to the demographically aging populations world wide a secular trend of hip fracture incidence has been reported for various populations. The objective of the current study was to reassess hip fracture incidence ten years following German reunification and compare incidence rates in former East and West Germany. Data from the German hospital discharge diagnosis registry were used to compare rates in former East and West Germany. A reassessment of a secular trend was done with directly age-standardized rates of the population 60 years old and over. Significant differences were found between incidence rates in the East and West German states with higher rates in the West. Compared to earlier studies for East Germany, rate in East Germany have increased by on average annually 6% since reunification. This is a steep increase compared to the annual rise by about 3% between 1974 and 1989. Hip fracture incidence in East Germany thereby has doubled during the 25-year period from 1971 to 1996. Although the observed acceleration of a secular trend in East Germany probably has multiple causes, evidence suggests a significant influence of Western life style on hip fracture incidence.

Age Distribution↗

PubMed2001

Motor vehicle crash fatalities in the elderly: rural versus urban.

BACKGROUND: The elderly contribute disproportionately to hospital trauma mortality and expense. This population and its traffic fatality rate are increasing. The purpose of this study was to determine how the effect of age on vehicle-related mortality is modified by population density. METHODS: FARS data for vehicle drivers and passengers were analyzed after linkage to census age-specific county population and area estimates. Characteristics of crash fatalities in the elderly (> or =65 years old) were compared with younger victims, for each quartile of county population density. RESULTS: There were 5905 fatalities among the elderly, and 26,159 among the younger population, yielding annual rates (per 100,000) of 17.6 and 11.4. Rates were higher in counties with lower population density, but always higher among the elderly. Elderly fatal crash victims in all county quartiles were less likely to be male, unrestrained, riding with an intoxicated driver, or traveling over 60 MPH; all these risk factors were more frequent at lower population densities, regardless of age. Fatal crashes at intersections were more likely in the elderly, especially at higher population densities. CONCLUSION: Older age and lower population density independently increase vehicle-related mortality. Differing characteristics in each category suggest different preventive strategies.

Accidents, Traffic↗

PubMed2001

Prediction of intestinal absorption and blood-brain barrier penetration by computational methods.

This review surveys the computational methods that have been developed with the aim of identifying drug candidates likely to fail later on the road to market. The specifications for such computational methods are outlined, including factors such as speed, interpretability, robustness and accuracy. Then, computational filters aimed at predicting "drug-likeness" in a general sense are discussed before methods for the prediction of more specific properties--intestinal absorption and blood-brain barrier penetration--are reviewed. Directions for future research are discussed and, in concluding, the impact of these methods on the drug discovery process, both now and in the future, is briefly considered.

Animals↗

PubMed2001

Distribution of vascular endothelial growth factor (VEGF) and its binding sites at the maternal-fetal interface during gestation in pigs.

Pigs show epitheliochorial placentation, in which the maternal uterine epithelium and the fetal trophectoderm become closely apposed. There is no invasion of trophoblast into the maternal tissue, and nutrient and waste exchange take place across two epithelial layers beneath which a complex network of capillaries forms. Later in gestation, the epithelial cells become indented by blood vessels, which greatly reduces the distance for diffusion between the two circulatory systems. Vascular endothelial growth factor is a secreted homodimeric angiogenic growth factor that is involved in physiological and pathological angiogenesis. Its receptors are generally restricted to endothelial cells. Ligand binding, in situ hybridization and immunohistochemistry were carried out in pig placenta throughout gestation to investigate the possible role of vascular endothelial growth factor and its receptors in non-invasive placentation. In situ hybridization and immunohistochemistry revealed that mRNA and immunoreactivity for vascular endothelial growth factor were localized in both maternal and fetal epithelial cells at the maternal-fetal interface and over the maternal glands, although the signal was generally weaker in the maternal glands. Ligand binding was used to localize for vascular endothelial growth factor receptors; no binding was observed over the maternal glands, but very strong binding was localized to the endometrial blood vessels. At the interface between maternal and fetal tissue, a similar pattern was observed whereby the numerous small capillaries at the bases of the two apposed epithelia bound vascular endothelial growth factor specifically. It is concluded that vascular endothelial growth factor produced by the maternal and fetal epithelial layers promotes the growth of capillaries locally, which would facilitate the development of two vascular networks for the efficient transfer of nutrients and waste products.

Animals↗

PubMed2000

Angiogenic growth factor expression in placenta.

New blood vessel growth is generally a rare event in the healthy adult. However, a notable exception to this is the female reproductive tract where cyclic angiogenesis occurs. Striking new vessel growth and remodeling also occurs during placentation; thus angiogenesis is essential for reproductive success. Vascular endothelial growth factor is a potent stimulator of this process and its production and action is tightly regulated. Indeed the placenta is a rich source of a soluble variant of the flt-1 receptor which seems to protect the placenta from the effects of excess vascular endothelial growth factor. The balance between new vessel growth (in the placental villi for example) and endothelial cell loss in the spiral arteries within the decidua is a delicate one. This is influenced by the local production of promotors and inhibitors of endothelial cell activation. Perturbation of this may lead to maternal pathology during pregnancy.

Angiogenesis Inducing Agents↗

PubMed2000

Violence and fear of violence in East and West Germany.

The purpose of this research was to assess the effect of major social changes in Germany since 1989 on mortality due to intentional injury. Mechanisms and types of fatal intentional injury in East and West Germany between 1970 and 1995 were determined from death certificates and compared with judicial data on violent crime convictions and recent public survey data on citizen fear of crime. The number of homicides among East German males increased between 1989 and 1991, and the homicide rate remains high when compared with West German males (although lower than that of American males). Homicide among German females is less common, presently about equally likely in East and West. Violent crime in general has become more frequent in Germany, and citizen fear of crime has increased markedly, especially in the East. Non-citizens are convicted for an increasing number of homicides and assaults. Rates of suicide were declining in East and West before reunification, and these rates have continued to decline. Social changes in Europe since 1989 have led to noticeable increases in violence and homicide in Germany, which in turn have reduced feelings of security among German citizens, especially in the East. Suicide rates have not been affected.

Adult↗

PubMed2000

Effective dose from radiation absorbed during a panoramic examination with a new generation machine.

OBJECTIVES: The purpose of this investigation was to measure the tissue-absorbed dose and to calculate the whole-body effective dose (E) for a new generation panoramic machine (Planmeca PM 2002 CC Proline), operating in the panoramic examination mode. Comparisons could then be made with historical panoramic and intraoral radiographic dose measurement values and effective dose estimates. STUDY DESIGN: Thermoluminescent dosimeters were embedded in a humanoid, tissue-equivalent phantom at anatomically significant sites, representing key tissues. Absorbed dose measurements were obtained after every 5 panoramic exposures of a 25-exposure total. The measured average tissue-absorbed doses from a single panoramic exposure were used in the calculation of the whole-body E. RESULTS: The whole-body E for the PM 2002 CC Proline panoramic examination is 3.85 microSv. This is below the panoramic average of 6.7 microSv. The PM 2002 CC Proline panoramic examination delivers approximately 5% to 12% of the E of a complete mouth intraoral radiographic examination. CONCLUSIONS: The effective dose from the PM 2002 CC Proline examination is at the low end of the range for other panoramic machines and is far below either a D-speed or E-speed film intraoral radiographic examination.

Body Burden↗

PubMed2000

Decreasing incidence of burn injury in a rural state.

OBJECTIVES: To determine changes in the incidence of burn injury since the regionalization of burn care and intensification of fire prevention initiatives that occurred in Maine during the 1970s. METHODS: Death certificate data from Maine and the United States for deaths due to fire or burns were obtained for 1960-98. Hospitalization and burn registry data were obtained for Maine from 1973-98. Frequencies and incidence rates were compared over time and, where possible, between Maine and the United States. RESULTS: During 1960-79, annual burn mortality in Maine averaged 5.1/100,000, with random variation. After this, the rate declined steadily to an average annual level of 1.4/100,000 during 1993-96. For the entire United States, average annual mortality declined from 4.2/100,000 during 1961-64 to 1.5/100,000 during 1993-96. Reduction in mortality has been principally due to prevention of dwelling fires. Hospitalization for burns in Maine was 34.8/100,000 during 1973-76 and declined to 10.6/100,000 during 1995-98. CONCLUSIONS: Burn prevention measures have dramatically reduced the incidence of death and hospitalization resulting from burns in Maine.

Adolescent↗

PubMed2000

Injury mortality in East Germany.

OBJECTIVES: This study determined the effects of social changes in East Germany since 1989 on patterns of injury mortality. METHODS: Death certificate data regarding injuries from 1980 through 1995 and police data regarding traffic injuries in East Germany from 1980 through 1998 were compared with similar data from West Germany. RESULTS: The number of motor vehicle-related injuries and deaths in East Germany increased dramatically between 1989 and 1991, whereas those in West Germany declined slightly. The increased mortality in the more rural East has especially involved young men driving automobiles on rural roads and has persisted since reunification of East and West Germany. Falls, other accidents, and suicides have shown no such effect. Homicide among East German men has increased but remains uncommon. CONCLUSIONS: Recent social changes in East Germany, including increased access to motor vehicles and decreased restrictions on personal freedom, have been associated with increased motor vehicle crashes and mortality, especially among young men and on rural roads.

Accidental Falls↗