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PubMed2005

Side effects and cancer-related stress determine quality of life in long-term survivors of testicular cancer.

PURPOSE: The prevalence of long-term survivors after treatment for testicular cancer (TC) is increasing, and most studies display normal or only slightly reduced quality of life (QOL) in TC survivors (TCSs). Impaired QOL is claimed to be associated with treatment modality and its side effects, although most studies in this field can be criticized for various methodologic shortcomings. We wanted to examine variation in long-term QOL in TCSs in relation to TC treatment modality, side effects, and TC-related stress in a large population. PATIENTS AND METHODS: QOL, side effects, and TC-related stress were self-rated by a questionnaire at a mean of 11 years of follow-up in 1,409 TCSs treated from 1980 to 1994. Norm data was obtained from 2,678 males who were representative of the general population. QOL was measured with the Short Form-36 (SF-36), and TC-related stress was measured with the Impact of Event Scale. RESULTS: There were no clinically relevant differences in QOL between TCSs and age-adjusted norm data, although there was a slightly lowered SF-36 Physical Component Summary Score in TCSs. Variation of QOL in TCSs was related to self-reported side effects and TC-related stress but not to TC treatment modality. A significant association was found between side effects and TC-related stress. CONCLUSION: TCSs do not suffer long term from reduced QOL, and only minor differences in QOL were found between different treatment modalities. TCSs who report more side effects or TC-related stress have increased risk for reduced QOL, but these associations are not explained by TC treatment modalities. Further QOL research in this area should explore vulnerability factors for side effects and TC-related stress.

Adult↗
PubMed2005

Changing conclusions on secondhand smoke in a sudden infant death syndrome review funded by the tobacco industry.

BACKGROUND: Prenatal and postnatal exposure to tobacco smoke adversely affects maternal and child health. Secondhand smoke (SHS) has been linked causally with sudden infant death syndrome (SIDS) in major health reports. In 1992, the US Environmental Protection Agency (EPA) first noted an association between SHS and SIDS, and both prenatal exposure and postnatal SHS exposure were listed as independent risk factors for SIDS in a 1997 California EPA report (republished in 1999 by the National Cancer Institute) and a 2004 US Surgeon General report. The tobacco industry has used scientific consultants to attack the evidence that SHS causes disease, most often lung cancer. Little is known about the industry's strategies to contest the evidence on maternal and child health. In 2001, a review was published on SIDS that acknowledged funding from the Philip Morris (PM) tobacco company. Tobacco industry documents related to this review were examined to identify the company's influence on the content and conclusions of this review. METHODS: Tobacco industry documents include 40 million pages of internal memos and reports made available to the public as a result of litigation settlements against the tobacco industry in the United States. Between November 2003 and January 2004, we searched tobacco industry document Internet sites from the University of California Legacy Tobacco Documents Library and the Tobacco Documents Online website. Key terms included "SIDS" and names of key persons. Two authors conducted independent searches with similar key terms, reviewed the documents, and agreed on relevancy through consensus. Thirty documents were identified as relevant. Two drafts (an early version and a final version) of an industry-funded review article on SIDS were identified, and 2 authors independently compared these drafts with the final publication. Formal comments by PM executives made in response to the first draft were also reviewed. We used Science Citation Index in July 2004 to determine citation patterns for the referenced SIDS reviews. RESULTS: PM executives feared that SHS and maternal and child health issues would create a powerful and emotional impetus for smoke-free areas in the home, public areas, and the workplace. In response to the 1992 US EPA report on SHS, the Science and Technology Department of PM's Switzerland subsidiary, Fabriques de Tabac Reunies, searched for "independent" consultants to publish articles addressing SHS. The first industry-funded article was a literature review focusing on smoking and SIDS, conducted by consultant Peter Lee and co-author Allison Thornton, which stated that the association between parental smoking and SIDS could have been attributable to the failure to control fully for confounders. That first review has only been cited once, in the subsequent industry-funded review. In 1997, PM commissioned a consultant, Frank Sullivan, to write a review, with coauthor Susan Barlow, of all possible risk factors for SIDS. The first draft concluded that prenatal and postnatal smoking exposures are both independent risk factors for SIDS. After receiving comments and meeting with PM scientific executives, Sullivan changed his original conclusions on smoking and SIDS. The final draft was changed to emphasize the effects of prenatal maternal smoking and to conclude that postnatal SHS effects were "less well established." Changes in the draft to support this new conclusion included descriptions of Peter Lee's industry-funded review, a 1999 negative but underpowered study of SIDS risk and urinary cotinine levels, and criticisms of the conclusions of the National Cancer Institute report that SHS was causally associated with SIDS. In April 2001, the Sullivan review was published in the United Kingdom journal Paediatric and Perinatal Epidemiology, with a disclosure statement that acknowledged financial support from PM but did not acknowledge contributions from PM executives in the preparation of the review. By 2004, the Sullivan SIDS review had been cited at least 19 times in the medical literature. CONCLUSIONS: PM executives responded to corporate concerns about the possible adverse effects of SHS on maternal and child health by commissioning consultants to write review articles for publication in the medical literature. PM executives successfully encouraged one author to change his original conclusion that SHS is an independent risk factor for SIDS to state that the role of SHS is "less well established." These statements are consistent with PM's corporate position that active smoking causes disease but only public health officials conclude the same for SHS. The author's disclosure of industry funding did not reveal the full extent of PM's involvement in shaping the content of the article. This analysis suggests that accepting tobacco industry funds can disrupt the integrity of the scientific process. The background of this SIDS review is relevant for institutions engaged in the debate about accepting or eschewing funding from the tobacco industry. Those who support acceptance of tobacco industry funds argue that academic authors retain the right to publish their work and maintain final approval of the written product, but this argument fails to recognize that the tobacco industry funds work to ensure that messages favorable to the industry are published and disseminated. Clinicians, parents, and public health officials are most vulnerable to the changed conclusions of the SIDS review. The national SIDS "Back to Sleep" campaign has been very successful in reducing SIDS rates. However, estimates of SIDS risk from SHS (odds ratios range from 1.4 to 5.1) have considerable overlap with estimates of risk from prone sleep positioning (odds ratios range from 1.7 to 12.9). With the Back to Sleep campaign well underway, efforts to address parental smoking behavior in both the prenatal and postnatal periods should be intensified. The tobacco industry's disinformation campaign on SHS and maternal and child health can be counteracted within clinicians' offices.

Causality↗
PubMed2001

Intermediate-effect biomarkers in prevention of skin cancer.

Skin cancers, both non-melanoma and melanoma, usually progress through sequential steps towards malignant transformation, leading to mutant clones and precancerous lesions. Prevention of skin cancers relies on reduction of exposure to solar radiation and may be evaluated by measuring induction of intermediate-effect biomarkers such as sunburn cells or p53 mutations in the epidermis, actinic (solar) keratoses, UV-induced immunosuppression or naevi. Sunburn cells (apoptotic keratinocytes) and p53 mutations are indicators of UV-induced DNA lesions as early steps of malignant transformation of epidermal keratinocytes. Actinic keratoses are premalignant sun-induced skin lesions, characterized as keratinized patches with aberrant cell differentiation and proliferation; they represent risk factors for basal-cell carcinoma and melanoma and are precursors of squamous-cell carcinoma. Studies in humans have investigated UV-induced immunosuppression and its modulation by topical sunscreen application, focusing on contact hypersensitivity as measured by immunization or response to haptens, or on modulation of stimulation of allogeneic lymphocytes by epidermal cells, or local release of immunomodulatory molecules such as cis-urocanic acid or interleukin-10. Naevi are focal collections of melanocytes, usually found at the junction of the epidermis and dermis or at various depths in the dermis. Common acquired naevi arise after birth both spontaneously and in response to sun exposure. Most acquired naevi are clonal, while most melanocytes in non-naeval areas are not. Although it is not yet certain whether naevi represent premalignant lesions or risk factors, many melanomas arise in acquired naevi, and the number of naevi constitutes the best predictor of individual risk of melanoma. The presence of large (i.e., >5 mm) or atypical naevi (i.e., large naevi with non-uniform colour and irregular borders) is associated with elevated melanoma risk, independently of the number of smaller naevi. Children seem particularly vulnerable to sun-induced biological events involved in the genesis of melanoma, and the greatest increase in naevus numbers per unit of skin surface occurs before adolescence. Therefore, the distribution of naevi and their development in children are relevant to understanding melanoma occurrence in adults.

Biomarkers, Tumor↗
PubMed2002

Environmental and occupational medicine and injury prevention: education and impact, classroom and community.

The core value guiding the work of physicians and health workers, including those in Environmental and Occupational Epidemiology and Medicine and Injury Prevention, is to protect the health of the public, especially its most vulnerable individuals. In these fields, we emphasize teaching the use of epidemiology, the core discipline of public health, as a tool for early detection and prevention of disease and injury, as well as an instrument for hypothesis testing. The classic core topics are toxic and physical exposures and their effects, and strategies for their prevention; emerging issues are child labor, mass violence, and democide. In environmental health, students need to be prepared for the reality that the most important and severe problems are often the most difficult to investigate, solve, and evaluate. The following are some recommendations for producing graduates who are effective in protecting communities from environmental hazards and risks: (1) Teach the precautionary principle and its application; (2) Evaluate programs for teaching environmental and occupational health, medicine and epidemiology in schools of public health by their impact on the WHO health indicators and their impact on measures of ecosystem sustainability; (3) Develop problem-oriented projects and give academic credit for projects with definable public health impact and redefine the role of the health officer as the chief resident for Schools of Public Health and Community Medicine; (4) Teach the abuses of child labor and working conditions of women in the workplace and how to prevent the hazards and risks from the more common types of child work; (5) Upgrade teaching of injury prevention and prevention of deaths from external causes; (6) Teach students to recognize the insensitivity of epidemiology as a tool for early detection of true risk; (7) Teach the importance of context in the use of tests of statistical significance; (8) Teach the epidemiologic importance of short latency periods from high exposures as sentinel events for later group risk for cancer and stating the case for action; (9) Protect students and colleagues who are whistleblowers in environmental health from harassment and punishment; (10) Develop curricula and workshops that promote the use of epidemiologic tools for preventing genocide, democide, and their precursors. Schools of Public Health and Community Medicine are at the interface between the resources of academic power and the major problems of community health. Implementing the above recommendations will strengthen academic investigation and impact.

Curriculum↗
PubMed2000

Clinical and pathologic aspects of spontaneous canine prostate carcinoma: a retrospective analysis of 76 cases.

BACKGROUND: Pet dogs and men share a vulnerability for the development of prostate carcinoma. The purpose of this study was to further characterize the clinical and pathologic features of spontaneous canine prostate carcinoma. METHODS: A multiinstitutional, retrospective study was conducted using 76 dogs with prostate carcinoma that underwent postmortem evaluation. For each case, clinical and pathologic data were tabulated and hematoxylin/eosin-stained tissue sections from the primary tumor and metastatic lesions were evaluated. Prostatic carcinomas were subclassified based upon the presence of glandular, urothelial, squamoid, or sarcomatoid differentiation. We focused our analysis on dogs that differed with respect to morphologic features of the primary tumor, lifetime duration of testicular hormone exposure, and presence of skeletal metastases. RESULTS: The vast majority of canine prostate carcinomas affected elderly sexually intact dogs or dogs that underwent surgical castration after sexual maturity. Adenocarcinoma was the most frequent histologic type, although more than half of canine prostate carcinomas exhibited intratumoral heterogeneity. In many cases, primary tumors showed mixed morphology, characterized by two or more types of differentiation. Duration of testicular hormone exposure was significantly different between dogs with adenocarcinoma and dogs with mixed morphology tumor, but did not appear to influence the frequency or pattern of metastases. Overall, gross metastases were present in 80% of dogs with prostate carcinoma. Skeletal metastases were present in 22% of cases, and the predominantly axial skeletal distribution of these lesions was similar to that reported in men with prostate carcinoma. Young dogs were at highest risk for development of skeletal metastases. CONCLUSIONS: This study provides a more complete characterization of spontaneous prostate carcinoma of dogs in terms of morphologic heterogeneity, skeletal metastases, and the influence of testicular hormones. Prostate carcinoma in pet dogs provides an immunocompetent, autochthonous tumor system that mimics certain aspects of human prostate cancer. This spontaneous model may contribute to our understanding of the factors that regulate carcinogenesis within the aged prostate, and to the development of chemoprevention strategies or bone-targeted therapies.

Adenocarcinoma↗
PubMed2005

P-glycoprotein and breast cancer resistance protein expression in human placentae of various gestational ages.

Placental efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) protect the developing fetus from exposure to potentially toxic xenobiotics. However, little is known about the expression of these transporters in human placentae of different gestational ages. Therefore, we quantified the expression of P-gp and BCRP in human placentae of different gestational ages. We also measured the expression of various nuclear regulatory factors such as the pregnane xenobiotic factor to determine whether their expression also changes with gestational age. Syncitial microvillous plasma membranes were isolated from human placentae of various gestational ages (60-90 days, 90-120 days, and full-term C-section placentae). P-gp and BCRP expression (protein) in these preparations were measured by Western blot analysis followed by an ELISA. Expression (mRNA) of P-gp, BCRP, and nuclear regulatory factors in the placentae were quantified by quantitative real-time PCR. P-gp expression (relative to that of alkaline phosphatase) was significantly (P < 0.05) higher (44.8-fold as protein; 6.5-fold as mRNA) in early gestational age human placentae (60-90 days) vs. term placentae. In contrast, BCRP (protein and mRNA) and nuclear regulatory factors (mRNA) expression in placental tissue did not change significantly with gestational age. However, placental expression of P-gp and human chorionic gonadotropin-beta (hCG-beta) transcripts was highly correlated (r = 0.73; P < 0.0001; Spearman rank correlation). Expression of P-gp, but not BCRP, decreases dramatically with gestational age in human placentae. This decrease in P-gp expression is not caused by a change in expression of nuclear receptor transcripts but appears to be related to hCG-beta expression. The placental P-gp expression appears to be upregulated in early pregnancy to protect the fetus from xenobiotic toxicity at a time when it is most vulnerable to such toxicity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Development of a comprehensive women's health program in an academic medical center: experiences of the Indiana University National Center of Excellence in Women's Health.

BACKGROUND: The IU National Cancer of Excellence (CoE) in Women's Health was funded by the Office on Women's Health, Department of Health and Human Services, in 1997 as part of the "second generation" of CoEs. The purpose of this paper is to describe the changes that the existence of this Center have wrought within the IU School of Medicine. METHODS: This paper describes the creation, mission, and function of the IU CoE, as well as some of its accomplishments to date. RESULTS: Through its missions targeting clinical care, research, education, community outreach, and leadership development, the IU CoE has significantly changed the delivery of care to and by women at this institution. CONCLUSIONS: The IU CoE has been responsible for major changes in the concepts of women's health from a clinical, research, education, and leadership perspective at the IU School of Medicine. Similar cases can be made for most of the other CoEs around the country. The challenges being faced continue to be sustained and sufficient funding for these valuable Centers.

Academic Medical Centers↗
PubMed2026

Genomic and transcriptomic features of relapsed small cell lung cancer.

BACKGROUND: Relapsed small cell lung cancer is characterized by treatment resistance and poor outcomes. Genomic and transcriptomic alterations in relapsed SCLC have not been characterized well. We comprehensively profiled relapsed SCLC samples along with patient-matched treatment-naive samples, when available, using whole-exome (WES), whole-genome (WGS), and RNA-sequencing (RNA-seq) to describe the molecular landscape of relapsed SCLC. Our goal is to identify potential novel pathways for additional functional validation and eventually novel therapeutic options. METHODS: We analyzed 54 relapsed and 27 treatment-naive SCLC samples using WES (with 26 patient-matched paired samples). A subset of the samples was also analyzed by WGS (n=28) and RNA-seq (n=31). Differences in mutational signatures, gene expression, structural variants, splicing, and neoantigen profiles at diagnosis and relapse were investigated. RESULTS: Relapsed SCLC samples demonstrated mutation signatures characteristic of platinum and APOBEC mutagenesis. Furthermore, these samples were characterized by MYC, MYCL and MYCN amplifications. Both treatment-naive and relapsed SCLC samples showed high prevalence of mutation-associated neoantigens (median= 86 in treatment-naive and 90 in relapsed SCLC; p=0.8) and TP53 was the most frequently altered gene to result in a neoantigen (48% of analyzed samples). Potential mechanisms of immune evasion, including amplification of CD24, overexpression of IDO1, increased M2 macrophage presence, and upregulation of HLA-E were also observed in relapse samples. Differences in alternative splicing patterns were observed between treatment-naive and relapsed small cell samples. Retained intron events were significantly enriched in treatment-naive samples and affected genes involved in DNA repair, metabolism, and WNT and MYC pathways. CONCLUSIONS: This study highlights the genomic and transcriptomic features of relapsed SCLC. These samples were characterized by genomic instability, WNT and MYC dysregulation, and splicing aberrations. Additional studies targeting the splicing machinery, WNT signaling, and immune evasion pathways could identify novel therapeutic vulnerabilities in SCLC.

Journal Article↗
PubMed2003

Retention of under-served women in clinical trials: a focus group study.

More information is needed to understand how women view their participation in clinical trials. As part of the formative evaluation phase of a 4-year National Cancer Institute funded study, researchers associated with the "Community Retention Intervention Study" (CRIS) conducted focus groups to identify additional data on the underlying issues regarding the retention and compliance of under-served women in clinical trials. Six focus groups were conducted: 3 were age-based, and 3 involved participants of the Women's Health Initiative (WHI) clinical trial component in Birmingham, Alabama. A total of 62 women, between 18 and 87 years of age, participated in the sessions: 79% were African-American and 52% reported incomes below dollar 20,000. The qualitative data analysis revealed that women were more inclined to participate in a clinical trial if they, or a family member, would benefit. Non-compliance with study protocols was generally a result of complications or unwanted side effects of treatments. Focus group data were used to develop retention and compliance strategies for the CRIS study. Findings suggest that focus group data can be used effectively to develop retention and compliance strategies specific to under-served women.

Adolescent↗
PubMed2003

[Mutation analysis of hMSH2 and hMLH1 genes in Chinese hereditary nonpolyposis colorectal cancer families].

OBJECTIVES: To determine the germ-line mutations of hMSH2 and hMLH1 genes in Chinese hereditary nonpolyposis colorectal cancer (HNPCC) families' probands or in patients fulfilling different clinical criteria or guidelines; to clarify the nature and distribution of the mutations; to evaluate the sensitivity of different clinical criteria in mutation prediction. METHODS: The entire coding regions (35 exons including exon-intron boundaries) of hMSH2 and hMLH1 genes were directly sequenced in 24 Amsterdam criteria (AC) probands, 15 Japanese criteria (JC) probands (except AC kindreds) and 19 Bethesda guidelines (BG) patients (except two former groups). All available affected and unaffected members from families of those with mutations were screened for mutation. RESULTS: In 16 unrelated families selected by the different clinical criteria, 17 germ-line mutations were found with 11 (64.7%) of hMLH1 and 6 (35.3%) of hMSH2. Two mutations were identified in one of the families. Among the 17 germ-line mutations, 12 had not been reported previously. A diversified mutation spectrum was found, but 6 hMLH1 mutations were found to be concentrated in the region encompassing exon 14, 15 and 16. There was a wide spectrum of mutation type including frame shift, nonsense, splice site mutation, in frame insertion or deletion and missense mutations. The mutation detection rate of hMSH2 and hMLH1 in the AC group was significantly higher than that in the JC group (12/24 vs. 3/15). On the other hand, a low mutation rate (1/19) was detected in 19 BG patients. The mutation cosegregated with disease. Besides, three different genotypes in tumors from probands of mutation-positive families were found. CONCLUSIONS: hMSH2 and hMLH1 mutations in Chinese HNPCC families show a wide spectrum. It seems that hMLH1 gene is involved more frequently than hMSH2 gene in Chinese HNPCC families. Different clinical criteria predict mutations with different sensitivities. The Amsterdam Criteria are most sensitive, while Japanese Criteria are highly practical and the Bethesda Guidelines are also practical to some extent. Gene mutations cosegregate with the disease phenotype. Carriers with no symptom in HNPCC families are most vulnerable groups, follow-ups are required for this group to get early diagnosis and to prevent the development of CRCs.

Adaptor Proteins, Signal Transducing↗
PubMed1992

Mitochondrial DNA alterations as ageing-associated molecular events.

Mitochondrial DNA (mtDNA) is a naked double-stranded circular extrachromosomal genetic element continuously exposed to the matrix that contains great amounts of reactive oxygen species and free radicals. The age-dependent decline in the capability and capacity of mitochondria to dispose these oxy-radicals will render mtDNA more vulnerable to mutations during the ageing process. During the past 3 years, more than 10 different types of deletions have been identified in the mtDNA of various tissues of old humans. Some of them were found only in a certain tissue but some others appeared in more than one organ or tissue. The 4977-bp deletion is the most prevalent and abundant one among these deletions. Skeletal muscle is the target tissue of most ageing-associated mtDNA deletions and has often been found to carry multiple deletions. The onset age of the various deletions in mtDNA varies greatly with individual and type of the deletion. The 4977-bp deletion has been independently demonstrated to occur in the mtDNA of various tissues of the human in the early third decade of life. However, the 7436-bp deletion was only detected in the heart mtDNA of human subjects in their late thirties. The others appeared only in older humans over 40 years old. No apparent sex difference was found in the onset age of these ageing-associated mtDNA deletions. The various ageing-associated deletions could be classified into two groups. Most of the deletions belong to the first group, in which the 5'- and 3'-end breakpoints of the deletion are flanked by 4-bp or longer direct repeats. The deletion in the second group occurs less frequently and shows no distinct repeat sequences flanking the deletion sites. These two groups of mtDNA deletions may occur by different mechanisms. The first group is most probably caused by internal recombination or slippage mispairing during replication of mtDNA by the D-loop mechanism. The deleted mtDNA and the deleted DNA fragment may be further degraded or escape from the mitochondria and get translocated into the nucleus. The latter route has been substantiated by many observations of inserted mtDNA sequences in the nuclear DNA. Thus, the fragments of migrating mtDNA may change the information content and expression level of certain nuclear genes and thereby promote the ageing process or cause cancer. Similar ageing-associated alterations of mtDNA have also been observed in aged animals and plants. I suggest that mtDNA deletions and other mutations to be discovered are molecular events generally associated with the ageing process.

Aging↗
PubMed2006

Smoking, not smoking: how important is where you live?

ISSUE ADDRESSED: To explore and describe the social-environmental influence upon the likelihood of smoking tobacco for the Australian experience, in particular, Victoria. METHODS: A multilevel (hierarchically structured regression) method was used. The micro-level units (characteristics of individuals) came from the annual surveys conducted by the Cancer Council of Victoria from 1990-97. The dependent variable was smoking status. The socio-demographic variables of age, marital status, education, employment status and ethnicity of individuals were used. The macro-level units (partitioned by postcode) came from the Australian Bureau of Statistics' Socioeconomic Index for Areas, split into quartiles. RESULTS: Residential neighbourhood had a unique but modest influence in the likelihood of smoking for both men and women. Also as the level of disadvantage increased within the residential area so did the odds of smoking for both men and women; however, the effect was not consistent. The odds of smoking were highest in the most disadvantaged areas for men, contrasting with women for whom the highest odds were in areas of more but not most disadvantage. CONCLUSIONS: The level of disadvantage of the residential neighbourhood has a unique, statistically significant influence, but not to the same degree as previously published Australian research. The effect is consistent across individual characteristics such as age and level of education for men. The effect is small and less consistent for women. Indeed, area of residence seems less important for women as a whole, suggesting differential influences according to gender.

Adolescent↗
PubMed2003

Cerebral perfusion and metabolism in resuscitated patients with severe post-hypoxic encephalopathy.

Positron emission tomography (PET) was used for the study of regional cerebral perfusion and metabolism in eight patients with severe post-hypoxic encephalopathy, caused by cardiac arrest and resulting in a coma lasting for at least 24 h. Using this method, we aimed to identify regional vulnerability, which was hypothesized to provide (i) insight in pathogenic mechanisms and (ii) early prognostic parameters. On day 1 post-resuscitation, 18-Fluor deoxyglucose ([F18]-FDG) indicated a marked decrease of cerebral metabolic activity. Gray matter glucose consumption was 54% of normal values, whereas white matter uptake was 70% of normal. Regional differences followed a pattern of neuronal density rather than specific patterns of functionally or biochemically defined regions or of vascular territories. In contrast to [F18]-FDG, the distribution of 15-oxygen labeled water ([O-15]-water) showed a better demarcation between gray and white matter, whereas focal deficit was not observed. In some patients, hyperperfusion relative to regional glucose consumption was observed in the occipital poles and basal ganglia. This suggests loss of vascular tone, i.e. vascular paralysis, in the basilar artery territory. CT and MRI scanning did not show any major change with respect to the hypoxic injury. In the small group studied, all patients had a poor outcome. The comparison between survivors and nonsurvivors did not reveal obvious differences in PET data, suggesting that this technique does not provide major prognostic clues adding to the prognostic information derived from serial neurological assessment in the restricted patient group characterized by prolonged coma.

Adolescent↗
PubMed2006

REACH-Meharry community-campus partnership: developing culturally competent health care providers.

An important national health care effort is elimination of racial and ethnic disparities in six specific conditions: infant mortality, cancer screening and management, cardiovascular disease, diabetes, human immunodeficiency virus infection, and child and adult immunizations. To address this concern, several health entities in Nashville, Tennessee responded to a grant initiative from the Centers for Disease Control and Prevention to develop a Racial and Ethnic Approaches to Community Health (REACH) demonstration project. The resulting award is the Nashville REACH 2010 Project, charged to develop sustainable methods to reduce and, in time, eliminate racial and ethnic disparities in cardiovascular disease and diabetes in the North Nashville community, where mortality rates of these diseases are substantially higher than in other parts of the county. As one of its many interests, the project included potential health care providers to receive and disseminate messages about disease prevention and health education. The present paper describes the community-campus partnership between the Nashville REACH 2010 project and the post-baccalaureate program of Meharry Medical College, a partnership that enfolded Meharry's pre-professional health care students into the community-based participatory service research project to increase the awareness and sensitivity of future minority health care providers to issues in minority and poor, underserved populations and to increase potential providers' familiarity with the processes involved in community-based participatory research.

Black or African American↗
PubMed2006

Disease and disadvantage in the United States and in England.

CONTEXT: The United States spends considerably more money on health care than the United Kingdom, but whether that translates to better health outcomes is unknown. OBJECTIVE: To assess the relative heath status of older individuals in England and the United States, especially how their health status varies by important indicators of socioeconomic position. DESIGN, SETTING, AND PARTICIPANTS: We analyzed representative samples of residents aged 55 to 64 years from both countries using 2002 data from the US Health and Retirement Survey (n = 4386) and the English Longitudinal Study of Aging (n = 3681), which were designed to have directly comparable measures of health, income, and education. This analysis is supplemented by samples of those aged 40 to 70 years from the 1999-2002 waves of National Health and Nutrition Examination Survey (n = 2097) and the 2003 wave of the Health Survey for England (n = 5526). These surveys contain extensive and comparable biological disease markers on respondents, which are used to determine whether differential propensities to report illness can explain these health differences. To ensure that health differences are not solely due to health issues in the black or Latino populations in the United States, the analysis is limited to non-Hispanic whites in both countries. MAIN OUTCOME MEASURE: Self-reported prevalence rates of several chronic diseases related to diabetes and heart disease, adjusted for age and health behavior risk factors, were compared between the 2 countries and across education and income classes within each country. RESULTS: The US population in late middle age is less healthy than the equivalent British population for diabetes, hypertension, heart disease, myocardial infarction, stroke, lung disease, and cancer. Within each country, there exists a pronounced negative socioeconomic status (SES) gradient with self-reported disease so that health disparities are largest at the bottom of the education or income variants of the SES hierarchy. This conclusion is generally robust to control for a standard set of behavioral risk factors, including smoking, overweight, obesity, and alcohol drinking, which explain very little of these health differences. These differences between countries or across SES groups within each country are not due to biases in self-reported disease because biological markers of disease exhibit exactly the same patterns. To illustrate, among those aged 55 to 64 years, diabetes prevalence is twice as high in the United States and only one fifth of this difference can be explained by a common set of risk factors. Similarly, among middle-aged adults, mean levels of C-reactive protein are 20% higher in the United States compared with England and mean high-density lipoprotein cholesterol levels are 14% lower. These differences are not solely driven by the bottom of the SES distribution. In many diseases, the top of the SES distribution is less healthy in the United States as well. CONCLUSION: Based on self-reported illnesses and biological markers of disease, US residents are much less healthy than their English counterparts and these differences exist at all points of the SES distribution.

Aged↗
PubMed2004

The WISEWOMAN projects: lessons learned from three states.

BACKGROUND: The WISEWOMAN program provides chronic disease risk factor screening, lifestyle interventions, and referrals to financially disadvantaged women who participate in the National Breast and Cervical Cancer Early Detection Program (NBCCEDP). Three states (Arizona, Massachusetts, and North Carolina) participated in Phase One (1995-1998). METHODS: Using a case study approach, we reviewed documents and conducted telephone interviews to compare the three projects' design and execution. The interviews, carried out in mid-2002, involved a convenience sample of project coordinators, project directors, researchers, and one CDC project officer (n = 9). RESULTS: Many providers were overwhelmed by WISEWOMAN's research component and disliked its lack of flexibility. Researchers emphasized that high-quality evaluation requires resources and attention. Informants described the challenges of integrating WISEWOMAN with state BCCEDP programs that are in varying development stages and recommended changes in organizational culture and provider practices. Regarding implementation, informants emphasized the need for adequate and appropriate planning, buy-in, training, professional support, and outreach. Our sample also noted that WISEWOMAN projects tend to be labor intensive. CONCLUSIONS: WISEWOMAN projects face challenges of integrating clinical and lifestyle interventions, reaching beyond a focus on individuals, marshaling substantial resources, and introducing complex interventions into stretched healthcare environments. The three Phase One projects were deemed successful in reaching underserved women, developing a more comprehensive women's health model, strengthening linkages to primary healthcare, experimenting with innovative behavioral interventions, and tapping into women's roles as social support providers and family/community gatekeepers.

Adult↗
PubMed2006

Chromatin structural elements and chromosomal translocations in leukemia.

Recurring chromosome abnormalities are strongly associated with certain subtypes of leukemia, lymphoma and sarcomas. More recently, their potential involvement in carcinomas, i.e. prostate cancer, has been recognized. They are among the most important factors in determining disease prognosis, and in many cases, identification of these chromosome abnormalities is crucial in selecting appropriate treatment protocols. Chromosome translocations are frequently observed in both de novo and therapy-related acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The mechanisms that result in such chromosome translocations in leukemia and other cancers are largely unknown. Genomic breakpoints in all the common chromosome translocations in leukemia, including t(4;11), t(9;11), t(8;21), inv(16), t(15;17), t(12;21), t(1;19) and t(9;22), have been cloned. Genomic breakpoints tend to cluster in certain intronic regions of the relevant genes including MLL, AF4, AF9, AML1, ETO, CBFB, MYHI1, PML, RARA, TEL, E2A, PBX1, BCR and ABL. However, whereas the genomic breakpoints in MLL tend to cluster in the 5' portion of the 8.3 kb breakpoint cluster region (BCR) in de novo and adult patients and in the 3' portion in infant leukemia patients and t-AML patients, those in both the AML1 and ETO genes occur in the same clustered regions in both de novo and t-AML patients. These differences may reflect differences in the mechanisms involved in the formation of the translocations. Specific chromatin structural elements, such as in vivo topoisomerase II (topo II) cleavage sites, DNase I hypersensitive sites and scaffold attachment regions (SARs) have been mapped in the breakpoint regions of the relevant genes. Strong in vivo topo II cleavage sites and DNase I hypersensitive sites often co-localize with each other and also with many of the BCRs in most of these genes, whereas SARs are associated with BCRs in MLL, AF4, AF9, AML1, ETO and ABL, but not in the BCR gene. In addition, the BCRs in MLL, AML1 and ETO have the lowest free energy level for unwinding double strand DNA. Virtually all chromosome translocations in leukemia that have been analyzed to date show no consistent homologous sequences at the breakpoints, whereas a strong non-homologous end joining (NHEJ) repair signature exists at all of these chromosome translocation breakpoint junctions; this includes small deletions and duplications in each breakpoint, and micro-homologies and non-template insertions at genomic junctions of each chromosome translocation. Surprisingly, the size of these deletions and duplications in the same translocation is much larger in de novo leukemia than in therapy-related leukemia. We propose a non-homologous chromosome recombination model as one of the mechanisms that results in chromosome translocations in leukemia. The topo II cleavage sites at open chromatin regions (DNase I hypersensitive sites), SARs or the regions with low energy level are vulnerable to certain genotoxic or other agents and become the initial breakage sites, which are followed by an excision end joining repair process.

Chromatin↗
PubMed2006

Ethnicity coding in a regional cancer registry and in Hospital Episode Statistics.

BACKGROUND: The collection of ethnicity information as part of cancer datasets is important for planning services and ensuring equal access, and for epidemiological studies. However, ethnicity has generally not been well recorded in cancer registries in the UK. The aim of this study was to determine the completeness of ethnicity coding in the Thames Cancer Registry (TCR) database and within the Hospital Episode Statistics (HES) data as held by the London Health Observatory, and to investigate factors associated with ethnicity being recorded. METHODS: Records for 111821 hospital admissions of London residents with a malignant cancer as a primary diagnosis between April 2002 and March 2003 and records for 25581 London residents diagnosed with cancer in 2002 were examined. Data on sex, age, cancer network of residence, deprivation, proportion of non-whites in the local authority population, and site of cancer were available. The proportion of patients in each group with a valid ethnicity code was calculated. In the TCR data proportions were also calculated adjusted for all other variables. RESULTS: Ethnicity was recorded for 90661 (81.1%) of the hospital admissions in the HES data and 5796 (22.7%) patients on the TCR database. Patients resident in areas with a higher proportion of non-white residents and the most deprived populations were more likely to have an ethnic code on the TCR database, though this pattern was not seen in the HES data. Adjustment did not materially affect the association between deprivation and ethnicity being recorded in the TCR data. CONCLUSION: There was a large difference in completeness of ethnicity between the data sources. In order to improve the level of recording in TCR data there needs to be better recording of ethnicity in sources TCR data collection staff have access to, or use of information from other sources e.g. electronic data feeds from hospitals or pathology laboratories, or HES data itself supplied directly to TCR. Efforts to collect ethnicity data should be encouraged in all healthcare settings. Future research should explore where the difficulties collecting ethnicity information lie, whether with patients, healthcare professionals or the recording procedure, and how such problems can be overcome.

Adolescent↗