Genomic approaches to identifying targets for treating ß hemoglobinopathies.

Sickle cell disease and ß thalassemia are common severe diseases with little effective pathophysiologically-based treatment. Their phenotypic heterogeneity prompted genomic approaches to identify modifiers that ultimately might be exploited therapeutically. Fetal hemoglobin (HbF) is the major modulator of the phenotype of the ß hemoglobinopathies. HbF inhibits deoxyHbS polymerization and in ß thalassemia compensates for the reduction of HbA. The major success of genomics has been a better understanding the genetic regulation of HbF by identifying the major quantitative trait loci for this trait. If the targets identified can lead to means of increasing HbF to therapeutic levels in sufficient numbers of sickle or ß-thalassemia erythrocytes, the pathophysiology of these diseases would be reversed. The availability of new target loci, high-throughput drug screening, and recent advances in genome editing provide the opportunity for new approaches to therapeutically increasing HbF production.

Using state-issued identification cards for obesity tracking.

Obesity prevention has emerged as one of public health's top priorities. Public health agencies need reliable data on population health status to guide prevention efforts. Existing survey data sources provide county-level estimates; obtaining sub-county estimates from survey data can be prohibitively expensive. State-issued identification cards are an alternate data source for community-level obesity estimates. We computed body mass index for 3.2 million adult Oregonians who were issued a driver license or identification card between 2003 and 2010. Statewide estimates of obesity prevalence and average body mass index were compared to the Oregon Behavioral Risk Factor Surveillance System (BRFSS). After geocoding addresses we calculated average adult body mass index for every census tract and block group in the state. Sub-county estimates reveal striking patterns in the population's weight status. Annual obesity prevalence estimates from identification cards averaged 18% lower than the BRFSS for men and 31% lower for women. Body mass index estimates averaged 2% lower than the BRFSS for men and 5% lower for women. Identification card records are a promising data source to augment tracking of obesity. People do tend to misrepresent their weight, but the consistent bias does not obscure patterns and trends. Large numbers of records allow for stable estimates for small geographic areas.

Sexual orientation and sex differences in adult chronic conditions, health risk factors, and protective health practices, Oregon, 2005-2008.

INTRODUCTION: Research on lesbian, gay, and bisexual (LGB) individuals' health and health practices has primarily consisted of convenience studies focused on HIV/AIDS, substance use, or mental illness. We examined health-related disparities among Oregon LGB men and women compared with heterosexual men and women using data from a population-based survey. METHODS: Data from the 2005 through 2008 Oregon Behavioral Risk Factor Surveillance System were used to examine associations between sexual orientation and chronic conditions, health limitations, health risk factors, and protective health practices. RESULTS: Compared with heterosexual women, lesbian and bisexual women were significantly more likely to smoke cigarettes, be obese, binge drink, and have chronic conditions, and less likely to engage in protective health practices. Compared with heterosexual men, gay men were significantly less likely to be obese, more likely to binge drink, and more likely to engage in protective health practices. Compared with heterosexual men, bisexual men were significantly more likely to have a physical disability, smoke cigarettes, binge drink, and more likely to get an HIV test. CONCLUSIONS: Health disparities among Oregon LGB individuals were most prominent among lesbian and bisexual women. Gay men had the most protective health practices, but they were more likely than heterosexual men to engage in risky behaviors that lead to chronic diseases later in life. Targeted public health interventions should be provided in environments that avoid stigmatizing and discriminating against LGB individuals where they live, work, learn, and socialize.

Fetal hemoglobin in sickle cell anemia: genetic studies of the Arab-Indian haplotype.

Sickle cell anemia is common in the Middle East and India where the HbS gene is sometimes associated with the Arab-Indian (AI) ß-globin gene (HBB) cluster haplotype. In this haplotype of sickle cell anemia, fetal hemoglobin (HbF) levels are 3-4 fold higher than those found in patients with HbS haplotypes of African origin. Little is known about the genetic elements that modulate HbF in AI haplotype patients. We therefore studied Saudi HbS homozygotes with the AI haplotype (mean HbF 19.2±7.0%, range 3.6 to 39.6%) and employed targeted genotyping of polymorphic sites to explore cis- and trans- acting elements associated with high HbF expression. We also described sequences which appear to be unique to the AI haplotype for which future functional studies are needed to further define their role in HbF modulation. All cases, regardless of HbF concentration, were homozygous for AI haplotype-specific elements cis to HBB. SNPs in BCL11A and HBS1L-MYB that were associated with HbF in other populations explained only 8.8% of the variation in HbF. KLF1 polymorphisms associated previously with high HbF were not present in the 44 patients tested. More than 90% of the HbF variance in sickle cell patients with the AI haplotype remains unexplained by the genetic loci that we studied. The dispersion of HbF levels among AI haplotype patients suggests that other genetic elements modulate the effects of the known cis- and trans-acting regulators. These regulatory elements, which remain to be discovered, might be specific in the Saudi and some other populations where HbF levels are especially high.

Fetal haemoglobin levels and haematological characteristics of compound heterozygotes for haemoglobin S and deletional hereditary persistence of fetal haemoglobin.

Compound heterozygotes for sickle haemoglobin (HbS) and hereditary persistence of fetal haemoglobin (HPFH) have high fetal haemoglobin (HbF) levels but few, if any, sickle cell disease-related complications. We studied 30 cases of HbS-HPFH (types 1 and 2), confirmed by molecular analysis, and report the haematological features and change in HbF levels over time. These results were compared to those of patients with sickle cell anaemia or HbS-ß(0) thalassaemia, including a subgroup of patients carrying the XmnI polymorphism, known to be associated with elevated HbF. Among the HbS-HPFH patients, HbF level was 50-90% during infancy and declined steeply within the first few years of life, stabilizing between ages 3 and 5years, at approximately 30%. Mean HbF of individuals age 5 or older was 31±3%, average haemoglobin concentration was 130±10g/l and average mean corpuscular volume (MCV) was 75±4 fl. Univariate and multivariate regression analyses significantly associated HbF with age, haemoglobin concentration, and MCV (P<0·001). There was a strong inverse association between HbF and age (r=-0·9, P<0·001). Despite having a much higher HbF level, patients with HbS-HPFH have a similar age-related pattern of HbF decline and associations as patients with sickle cell anaemia or HbS-ß(0) thalassaemia.

Fetal hemoglobin in sickle cell anemia: molecular characterization of the unusually high fetal hemoglobin phenotype in African Americans.

Fetal hemoglobin (HbF) is a major modifier of disease severity in sickle cell anemia (SCA). Three major HbF quantitative trait loci (QTL) are known: the Xmn I site upstream of (G)γ- globin gene (HBG2) on chromosome 11p15, BCL11A on chromosome 2p16, and HBS1L-MYB intergenic polymorphism (HMIP) on chromosome 6q23. However, the roles of these QTLs in patients with SCA with uncharacteristically high HbF are not known. We studied 20 African American patients with SCA with markedly elevated HbF (mean 17.2%). They had significantly higher minor allele frequencies (MAF) in two HbF QTLs, BCL11A, and HMIP, compared with those with low HbF. A 3-bp (TAC) deletion in complete linkage disequilibrium (LD) with the minor allele of rs9399137 in HMIP was also present significantly more often in these patients. To further explore other genetic loci that might be responsible for this high HbF, we sequenced a 14.1 kb DNA fragment between the (A)γ-(HBG1) and δ-globin genes (HBD). Thirty-eight SNPs were found. Four SNPs had significantly higher major allele frequencies in the unusually high HbF group. In silico analyses of these four polymorphisms predicted alteration in transcription factor binding sites in 3.

Fetal hemoglobin in sickle cell anemia.

Fetal hemoglobin (HbF) is the major genetic modulator of the hematologic and clinical features of sickle cell disease, an effect mediated by its exclusion from the sickle hemoglobin polymer. Fetal hemoglobin genes are genetically regulated, and the level of HbF and its distribution among sickle erythrocytes is highly variable. Some patients with sickle cell disease have exceptionally high levels of HbF that are associated with the Senegal and Saudi-Indian haplotype of the HBB-like gene cluster; some patients with different haplotypes can have similarly high HbF. In these patients, high HbF is associated with generally milder but not asymptomatic disease. Studying these persons might provide additional insights into HbF gene regulation. HbF appears to benefit some complications of disease more than others. This might be related to the premature destruction of erythrocytes that do not contain HbF, even though the total HbF concentration is high. Recent insights into HbF regulation have spurred new efforts to induce high HbF levels in sickle cell disease beyond those achievable with the current limited repertory of HbF inducers.

Differences in health and health behaviors between state employees and other employed adults in Oregon, 2007.

INTRODUCTION: Worksite health promotion and interventions have gained popularity among state agencies. We studied the health behaviors and health characteristics of adults employed in state agencies in Oregon and compared those state employees with the statewide population of employed, insured adults. METHODS: We used data from the Oregon Behavioral Risk Factor Surveillance System (BRFSS) and a modified BRFSS survey administered to state employees. State employees were compared with employed, insured BRFSS respondents in total and then separately for men and women. RESULTS: The prevalence of healthy weight was lower among state employees compared with the statewide population of employed, insured adults (29% vs 35%), and the prevalence of obesity was higher (35% vs 26%). State employees were also less likely to meet physical activity recommendations (44% vs 56%). Diabetes prevalence was higher among state employees (7% vs 5%), and self-reported excellent or very good health status was lower (54% vs 64%). CONCLUSION: State employees differ from the statewide population of employed, insured adults on a number of health behaviors and conditions. These differences suggest obesity prevention and diabetes control as priority areas for state agency worksite interventions.

Arthritic pain among Latinos: results from a community-based survey.

OBJECTIVE: To examine factors associated with pain among Latinos with arthritis, identify common coping strategies and potentially effective interventions, and determine whether pain levels affect the level of interest in potentially useful programs. METHODS: Using a convenience sampling approach and a combination of face-to-face and telephone surveys, 588 Latino adults in Oregon with arthritis were interviewed. The intensity of pain during a typical day was assessed using a scale ranging from 0 (no pain) to 10 (worst pain). A score of >or=7 was defined as severe pain. RESULTS: More than 60% of Latinos reported severe pain. Results from an ordinary least square regression indicated that among Latinos with arthritis, women, those with lower levels of education, and those reporting poor or fair self-rated health and functional limitations had higher levels of pain, after controlling for confounders. Those with severe pain were more likely than those with lower levels of pain to use over the counter medicine and home remedies to manage their arthritis. In addition, Latinos with greater pain were more likely to be interested in arthritis management programs. CONCLUSION: These findings have important implications for public health policy. The strong interest of Latinos in various arthritis and joint pain management programs could prove to be an important avenue for supporting a population with high levels of arthritic pain and lack of health insurance. These pain management programs are all the more appealing, given the availability of a number of evidence-based, low-cost interventions.

Prohibitin and the SWI/SNF ATPase subunit BRG1 are required for effective androgen antagonist-mediated transcriptional repression of androgen receptor-regulated genes.

Androgen antagonists or androgen deprivation are the primary therapeutic modalities for the treatment of prostate cancer. Invariably, however, the disease becomes progressive and unresponsive to androgen ablation therapy (hormone refractory). The molecular mechanisms by which androgen antagonists inhibit prostate cancer proliferation are not fully defined. In this study, we identify two molecules which are required for effective prostate cancer cell responsiveness to androgen antagonists. We establish that androgen receptor (AR)-dependent transcriptional suppression by androgen antagonists requires the tumor suppressor prohibitin. This requirement for prohibitin was demonstrated using structurally-distinct androgen antagonists, stable and transient knockdown of prohibitin and transfected and endogenous AR-responsive genes. The SWI-SNF complex core ATPase BRG1, but not its closely-related counterpart ATPase BRM, is required for this repressive action of prohibitin on AR-responsive promoters. Androgen antagonists induce recruitment of prohibitin and BRG1 to endogenous AR-responsive promoters and induce a physical association between AR and prohibitin and BRG1. The recruitment of prohibitin to endogenous AR-responsive promoters is dependent upon antagonist-bound AR. Prohibitin binding in the prostate-specific antigen (PSA) promoter results in the recruitment of BRG1 and the dissociation of p300 from the PSA promoter. These findings suggest that prohibitin may function through BRG1-mediated local chromatin remodeling activity and the removal of p300-mediated acetylation to produce androgen antagonist-mediated transcriptional repression. Furthermore, in addition to its necessary role in AR-mediated transcriptional repression, we demonstrate that prohibitin is required for full and efficient androgen antagonist-mediated growth suppression of prostate cancer cells.

Sirtuin 1 is required for antagonist-induced transcriptional repression of androgen-responsive genes by the androgen receptor.

Androgen antagonists or androgen deprivation is a primary therapeutic modality for the treatment of prostate cancer. Invariably, however, the disease becomes progressive and unresponsive to androgen ablation therapy (hormone refractory). The molecular mechanisms by which the androgen antagonists inhibit prostate cancer proliferation are not fully defined. In this report, we demonstrate that sirtuin 1 (SIRT1), a nicotinamide adenosine dinucleotide-dependent histone deacetylase (HDAC) linked to the regulation of longevity, is required for androgen antagonist-mediated transcriptional repression and growth suppression. Androgen antagonist-bound androgen receptor (AR) recruits SIRT1 and nuclear receptor corepressor to AR-responsive promoters and deacetylates histone H3 locally at the prostate-specific antigen promoter. Furthermore, SIRT1 down-regulation by small interfering RNA or by pharmacological means increased the sensitivity of androgen-responsive genes to androgen stimulation, enhanced the sensitivity of prostate cancer cell proliferative responses to androgens, and decreased the sensitivity of prostate cancer cells to androgen antagonists. In this study, we demonstrate the ligand-dependent recruitment of a class III HDAC into a corepressor transcriptional complex and a necessary functional role for a class III HDAC as a transcriptional corepressor in AR antagonist-induced transcriptional repression. Collectively, these findings identify SIRT1 as a corepressor of AR and elucidate a new molecular pathway relevant to prostate cancer growth and approaches to therapy.

Medical hyperspectral imaging to facilitate residual tumor identification during surgery.

INTRODUCTION: Adequate evaluation of breast tumor resection at surgery continues to be an important issue in surgical care, as over 30% of postoperative tumors recur locally unless radiation is used to destroy remaining tumor cells in the field. Medical Hyperspectral Imaging (MHSI) delivers near-real time images of biomarkers in tissue, providing an assessment of pathophysiology and the potential to distinguish different tissues based on spectral characteristics. METHODS: We have used an experimental DMBA-induced rat breast tumor model to examine the intraoperative utility of MHSI, in distinguishing tumor from normal breast and other tissues. Rats bearing tumors underwent surgical exposure and MHSI imaging, followed by partial resection of the tumors, then MHSI imaging of the resection bed, and finally total resection of tumors and of grossly normal-appearing glands. Resected tissue underwent gross examination, MHSI imaging, and histopathological evaluation. RESULTS: An algorithm based on spectral characteristics of tissue types was developed to distinguish between tumor and normal tissues. Tissues including tumor, blood vessels, muscle, and connective tissue were clearly identified and differentiated by MHSI. Fragments of residual tumor 0.5-1 mm in size intentionally left in the operative bed were readily identified. MHSI demonstrated a sensitivity of 89% and a specificity of 94% for detection of residual tumor, comparable to that of histopathological examination of the tumor bed (85% and 92%, respectively). CONCLUSION: We conclude that MHSI may be useful in identifying small residual tumor in a tumor resection bed and for indicating areas requiring more extensive resection and more effective biopsy locations to the surgeon.

Breast cancer risk factors and mammographic breast density in women over age 70.

BACKGROUND: Breast density is a strong risk factor for breast cancer, but little is known about factors associated with breast density in women over 70. METHODS: Percent breast density, sex hormone levels and breast cancer risk factor data were obtained on 239 women ages 70-92 recruited from 1986 to 1988 in the United States. Multivariable linear regression was used to develop a model to describe factors associated with percent density. RESULTS: Median (range) percent density among women was 23.7% (0-85%). Body mass index (beta=-0.345, p<0.001 adjusted for age and parity) and parity (beta=-0.277, p<0.001 adjusted for age and BMI) were significantly and inversely associated with percent breast density. After adjusting for parity and BMI, age was not associated with breast density (beta=0.05, p=0.45). Parous women had lower percent density than nulliparous women (23.7 versus 34.7%, p=0.005). Women who had undergone surgical menopause had greater breast density than those who had had a natural menopause (33.4 versus 24.8%, p=0.048), as did women who were not current smokers (26.0 versus 17.3% for smokers, p=0.02). Breast density was not associated with age at menarche, age at menopause, age at first birth, breastfeeding, estrogen levels or androgen levels. In a multivariable model, 24% of the variance in percent breast density was explained by BMI (beta=-0.35), parity (beta=-0.29), surgical menopause (beta=0.13) and current smoking (beta=-0.12). CONCLUSION: Factors associated with breast density in older, post-menopausal women differ from traditional breast cancer risk factors and from factors associated with breast density in pre-menopausal and younger post-menopausal women.

Agreement between self-reported information and medical claims data on diagnosed diabetes in Oregon's Medicaid population.

Recent trends in Oregon indicated that diabetes is on the rise. Medicaid self-reported data estimated about 11 percent are affected by diabetes, which is twice the prevalence of the general population in Oregon. Little is known about the agreement between self-reported information and medical claims data in the Medicaid population. This study provides an opportunity to compare prevalence of diabetes when the estimates are computed from the two different data sources. A sample of 2,154 Medicaid adults in Oregon (18 to 64 years old) were identified in both the Medicaid claims and self-report survey. The result reported a strong agreement of diabetes definition between the Medicaid claim data and the self-reported survey.

Diabetes preventive care in Oregon's Medicaid population.

The purpose of this study was to estimate the prevalence of diabetes in Oregon's adult Medicaid population and to compare the level of diabetes-related preventive care with the state's general population. Responses to telephone interviews conducted in 1999 among 2,770 randomly selected adult Medicaid beneficiaries and 7,229 Oregon residents were compared. Diabetes prevalence among adult Medicaid recipients (11.1% [95% Cl, 9.9% to 12.2%]) was more than twice that in the general population (4.7% [95% Cl, 4.2% to 5.3%]). During the year prior to the interview, adults with diabetes in the Medicaid and general populations reported performing the following preventive care, respectively: > or = 2 diabetes care visits (80%, 77%); foot examination (74%, 74%); dilated eye examination (73%, 68%); influenza vaccine (65%, 61%); self-monitored blood glucose daily (63%, 61%); pneumococcal vaccine (51%, 47%); regular aspirin use (48%, 53%); and awareness of Hemoglobin A1c (34%, 39%). Although the reported prevalence of diabetes in Oregon's Medicaid population is high, the prevalence of diabetes preventive care activities was similar to the state's general population. Nonetheless, specific services in both populations could be improved.

Public health surveillance approaches in Oregon's Medicaid population.

The development of methods for public health surveillance in Medicaid populations is an important goal for public health practice. In Oregon, we developed approaches to case finding using claims and self-reported data obtained from the Medicaid beneficiary population. Disease rosters, derived from claims data, form the basis for analyses pertaining to particular health conditions. Self-reported information obtained through a telephone survey forms the basis for analyses pertaining to behavioral risk factors, disease history, and other information not available in claims data. We also describe some projects in which we plan to use combined claims and survey data. We describe our experiences with using these techniques and provide examples from projects in progress or planned. Our initial experiences suggest that these approaches enhance our ability to conduct public health surveillance in Oregon's Medicaid population.