Vitamin D3 Repletion Improves Vascular Function, as Measured by Cardiorenal Biomarkers in a High-Risk African American Cohort.

Background: 25-hydroxy vitamin D (Vit D)-deficiency is common among patients with chronic kidney disease (CKD) and contributes to cardiovascular disease (CVD). African Americans (AAs) suffer disproportionately from CKD and CVD, and 80% of AAs are Vit D-deficient. The impact of Vit D repletion on cardio-renal biomarkers in AAs is unknown. We examined Vit D repletion on full-length osteopontin (flOPN), c-terminal fibroblast growth factor-23 (FGF-23), and plasminogen activator inhibitor-1 (PAI-1), which are implicated in vascular and kidney pathology. Methods: We performed a randomized, placebo-controlled study of high-risk AAs with Vit D deficiency, treated with 100,000 IU Vit D3 (cholecalciferol; n = 65) or placebo (n = 65) every 4 weeks for 12 weeks. We measured kidney function (CKD-EPI eGFR), protein-to-creatinine ratio, vascular function (pulse wave velocity; PWV), augmentation index, waist circumference, sitting, and 24-h-ambulatory blood pressure (BP), intact parathyroid hormone (iPTH) and serum calcium at baseline and study end, and compared Vit D levels with laboratory variables. We quantified plasma FGF-23, PAI-1, and flOPN by enzyme-linked immunosorbent assay. Multiple regression analyzed the relationship between log flOPN, FGF-23, and PAI-1 with vascular and renal risk factors. Results: Compared to placebo, Vit D3 repletion increased Vit D3 2-fold (p < 0.0001), decreased iPTH by 12% (p < 0.01) and was significantly correlated with PWV (p < 0.009). Log flOPN decreased (p = 0.03), log FGF-23 increased (p = 0.04), but log PAI-1 did not change. Multiple regression indicated association between log flOPN and PWV (p = 0.04) and diastolic BP (p = 0.02), while log FGF-23 was associated with diastolic BP (p = 0.05), and a trend with eGFR (p = 0.06). Conclusion: Vit D3 repletion may reduce flOPN and improve vascular function in high risk AAs with Vit D deficiency.

The Role of Vitamin D and Oxidative Stress in Chronic Kidney Disease.

Chronic kidney disease (CKD) is a major non-communicable disease associated with high rates of premature morbidity and mortality. The prevalence of hypovitaminosis D (deficiency of 25(OH)D or 25D) is greater in racial/ethnic minorities and in patients with CKD than the general population. Low 25D is associated with bone and mineral disorders as well as immune, cardiometabolic and cardiovascular (CV) diseases. Thus, it has been suggested that low 25D contributes to the poor outcomes in patients with CKD. The prevalence of hypovitaminosis D rises progressively with advancing severity of kidney disease with over 30% of patients with CKD stage 3 and 70% patients with CKD stage 5 estimated to have low levels of 25D. This report describes several of the abnormal physiologic and counter-regulatory actions related to low 25D in CKD such as those in oxidative stress and inflammatory systems, and some of the preclinical and clinical evidence, or lack thereof, of normalizing serum 25D levels to improve outcomes in patients with CKD, and especially for the high risk subset of racial/ethnic minorities who suffer from higher rates of advanced CKD and hypovitaminosis D.

Rationale and design of a placebo controlled randomized trial to assess short term, high-dose oral cholecalciferol on select laboratory and genomic responses in African Americans with hypovitaminosis D.

Cardiovascular Disease (CVD) and related disorders remain a leading cause of health disparities and premature death for African Americans. Hypovitaminosis D is disproportionately prevalent in African Americans and has been linked to CVD and CVD risk factors including hypertension, diabetes and obesity. Thus, hypovitaminosis D may represent a common pathway influencing CV risk factors in a select subgroup of persons. The purpose of this paper is to report the study design of a prospective eight week prospective double-blind randomized, placebo-controlled trial (n = 330 allocated 2:1 to intervention vs. control) to assess the effect of placebo vs. high-dose oral cholecalciferol (100,000 IU vitamin D3 at baseline and week 2) on 6-week change of select biologic cardiometabolic risk factors (including parathyroid hormone to assess biologic activity, pro-inflammatory/pro-thrombotic/fibrotic markers, insulin sensitivity and vitamin D metabolites) and their relationship to vitamin D administration and modification by vitamin D receptor polymorphisms in overweight, hypertensive African Americans with hypovitaminosis D. Findings from this trial will present insights into potential causal links between vitamin D repletion and mechanistic pathways of CV disease, including established and novel genomic markers.

Highly and moderately aggressive mouse ovarian cancer cell lines exhibit differential gene expression.

Patients with advanced epithelial ovarian cancer often experience disease recurrence after standard therapies, a critical factor in determining their five-year survival rate. Recent reports indicated that long-term or short-term survival is associated with varied gene expression of cancer cells. Thus, identification of novel prognostic biomarkers should be considered. Since the mouse genome is similar to the human genome, we explored potential prognostic biomarkers using two groups of mouse ovarian cancer cell lines (group 1: IG-10, IG-10pw, and IG-10pw/agar; group 2: IG-10 clones 2, 3, and 11) which display highly and moderately aggressive phenotypes in vivo. Mice injected with these cell lines have different survival time and rates, capacities of tumor, and ascites formations, reflecting different prognostic potentials. Using an Affymetrix Mouse Genome 430 2.0 Array, a total of 181 genes were differentially expressed (P < 0.01) by at least twofold between two groups of the cell lines. Of the 181 genes, 109 and 72 genes were overexpressed in highly and moderately aggressive cell lines, respectively. Analysis of the 109 and 72 genes using Ingenuity Pathway Analysis (IPA) tool revealed two cancer-related gene networks. One was associated with the highly aggressive cell lines and affiliated with MYC gene, and another was associated with the moderately aggressive cell lines and affiliated with the androgen receptor (AR). Finally, the gene enrichment analysis indicated that the overexpressed 89 genes (out of 109 genes) in highly aggressive cell lines had a function annotation in the David database. The cancer-relevant significant gene ontology (GO) terms included Cell cycle, DNA metabolic process, and Programmed cell death. None of the genes from a set of the 72 genes overexpressed in the moderately aggressive cell lines had a function annotation in the David database. Our results suggested that the overexpressed MYC and 109 gene set represented highly aggressive ovarian cancer potential biomarkers while overexpressed AR and 72 gene set represented moderately aggressive ovarian cancer potential biomarkers. Based on our knowledge, the current study is first time to report the potential biomarkers relevant to different aggressive ovarian cancer. These potential biomarkers provide important information for investigating human ovarian cancer prognosis.

The Effect of Short Term Vitamin D Supplementation on the Inflammatory and Oxidative Mediators of Arterial Stiffness.

BACKGROUND: Vitamin D deficiency has been implicated as a potential risk factor for cardiovascular disease. The high rate of vitamin D deficiency (<30 ng/ml) exhibited by African Americans may account for some of the excess prevalence of cardiovascular morbidity and mortality in this vulnerable US population. Vitamin D supplementation may reduce the risk of cardiovascular disease by ameliorating the onset and progression of arterial stiffness, a strong predictor of cardiovascular mortality, usually assessed by pulse wave velocity and augmentation index. Very few prospective studies have evaluated the effect of vitamin D supplementation on the inflammatory and oxidative stress mediators of arterial stiffness. METHOD: In a double blind randomized placebo controlled study we evaluated the effect of a monthly dose of 100,000IU of vitamin D3 for three months on the level of serum 25(OH)D, intact parathyroid hormone (PTH), urinary isoprostane, adipocyte cytokine expression and arterial stiffness among 130 overweight and obese (BMI > 25) African Americans with elevated blood pressure (130 - 150/85 - 100 mmHg) and low serum vitamin D level (10 - 25 ng/ml). RESULTS: There was a significant increase in the serum 25(OH)D levels to a mean level of 34.5 ng/ml (SD = 7.1) with the intervention (p < 0.001). The increase in 25(OH)D levels was associated with a significant decrease in the serum level of intact PTH (p = 0.02), mean urinary isoprostane (p = 0.02) and adipocyte cytokine expression. Although the increase in the 25(OH)D levels was not associated with any significant change in the Pulse Wave Velocity (PWV) in the overall study sample, it was associated with a significant decrease in the augmentation index among the participants with the highest tertile of urinary isoprostane (p = 0.007). CONCLUSION: We concluded that vitamin D supplementation increased serum 25(OH)D levels, decreased intact PTH level and the levels of select inflammatory and oxidative stress mediators of arterial stiffness. Longer term prospective studies are warranted to evaluate the effect of high dose vitamin D supplementation on arterial stiffness.

Association between Vitamin D and Adiponectin and Its Relationship with Body Mass Index: The META-Health Study.

BACKGROUND: Low vitamin D and adiponectin levels are both associated with obesity and cardiovascular disease. Previous studies have indicated that vitamin D levels are directly associated with adiponectin, and that this association varies across body mass index (BMI) categories; stronger with increasing BMI. Few studies examined this association in African-Americans (AA), known to have lower levels of vitamin D and adiponectin, and in whites. METHODS: We assessed whether serum vitamin D is associated with serum adiponectin in a biracial population-based sample. Cross-sectional analyses were performed on 426 non-diabetic participants (218 whites and 208 AA) from the META-Health Study, a random sample from the metro Atlanta. Age-adjusted correlations and multivariable linear regression were used for analyses. We investigated the effect modification of the BMI categories of lean, overweight, and obese as defined by standard cut-points (25 and 30 kg/m(2)). RESULTS: The mean (SD) age of our study sample was 50.5 (9) years. The mean (SD) levels of vitamin D were 27.4 (9.8) ng/mL in white women, 25.5 (9.3) ng/mL in white men, 16.9 (7.3) ng/mL in AA women, and 18.8 (7.3) ng/mL in AA men. The mean (SD) levels of adiponectin were 17.0 (17.1) µg/mL in white women, 9.9 (11.3) µg/mL in white men, 6.6 (4.8) µg/mL in AA women, and 9.4 (11.6) µg/mL in AA men. Among lean white women (n = 63), there was a significant direct association between vitamin D and adiponectin (ß = 0.02, p = 0.04) after adjustment for age, systolic blood pressure, HDL-cholesterol, triglycerides, income, and season of blood drawing. On the contrary, in lean AA women (n = 23), there was a significant inverse association (ß = -0.06, p = 0.01). CONCLUSION: The association of vitamin D and adiponectin is dependent on race, gender, and BMI category. Among lean white women, there was a significant direct association, whereas in lean AA women the association was inverse. No association was present among obese individuals.

A rare form of melanoma masquerading as a diabetic foot ulcer: a case report.

Background. Acral lentiginous melanoma (ALM) is a less-common form of melanoma in US, and it accounts for about 5% of all diagnosed melanomas in US. ALM is often overlooked until it is well advanced because of the lesion's location and its atypical appearance in the early stages. We present a case of ALM initially presented as a diabetic foot ulcer. Case Report. An 81-year-old man initially presented to the primary care clinic with a right foot diabetic ulcer. There was a large plantar, dark-colored ulcer that bled easy. Initial excision biopsy revealed Clark's Level IV ALM. Subsequent definitive wide excision and sentinel node biopsy confirmed ALM with metastasis to inguinal lymph nodes (stage IIIb). The treatment included wide margin excision of the lesion with en bloc amputations of 4th and 5th toes, followed by adjuvant chemotherapy. Discussion. The development of ALM may potentially relate to diabetes as a reported higher prevalence of diabetes with ALM patients. Conclusion. The difficulty in early diagnosing of ALM remains as a formidable challenge particularly in diabetic patients who commonly develop plantar foot ulcers due to the diabetic neuropathy. This case reiterates the importance of a thorough foot exam in such patients.

Interaction of sleep quality and psychosocial stress on obesity in African Americans: the Cardiovascular Health Epidemiology Study (CHES).

BACKGROUND: Compared with whites, sleep disturbance and sleep deprivation appear more prevalent in African Americans (AA). Long-term sleep deprivation may increase the risk of obesity through multiple metabolic and endocrine alterations. Previous studies have reported contradictory results on the association between habitual sleep duration and obesity. Accordingly, we aimed to assess whether sleep quality and duration are inversely associated with body mass index (BMI) and obesity and test whether these associations are modified by psychosocial stress, known to influence sleep quality. METHODS: A sample of 1,515 AA residents of metropolitan Atlanta, aged 30-65 years, was recruited by a random-digit-dialing method in 2007-08. The outcome obesity was defined by BMI (kg/m²) continuously and categorically (BMI ≥ 30 versus BMI < 30). Global sleep quality (GSQ) score was computed as the sum of response values for the seven components of the Pittsburgh Sleep Quality Index (PSQI) scale. GSQ score was defined as a continuous variable (range 0-21) and as tertiles. The general perceived stress (GPS), derived from the validated Cohen scale, was categorized into tertiles to test the interaction. Chi-square tests, correlation coefficients and weighted multiple linear and logistic regression were used to assess the associations of GSQ, GPS and obesity. RESULTS: The mean (standard deviation) age was 47.5 (17.0) years, and 1,096 (72%) were women. GSQ score categorized into tertiles was associated with BMI. Among women, after multivariable adjustment that included age, gender, physical activity, smoking status, education, total family income, financial stress and history of hypertension, hypercholesterolemia, diabetes and myocardial infarction, obesity was associated with sleep quality as assessed by GSQ continuous score, [odds ratio, OR (95% C.I.): 1.08 (1.03 - 1.12)], and with a worse sleep disturbance subcomponent score [OR (95% C.I.): 1.48 (1.16 - 1.89)]. Among all participants, stress modified the association between obesity and sleep quality; there was an increased likelihood of obesity in the medium stress category, OR (95% C.I.): 1.09 (1.02 - 1.17). CONCLUSION: Sleep quality was associated with obesity in women. The association of sleep quality with obesity was modified by perceived stress. Our results indicate the need for simultaneous assessment of sleep and stress.

Effectiveness of an intervention to improve the documentation required for diagnosis of metabolic syndrome in clinics serving African-American patients.

BACKGROUND AND AIMS: The metabolic syndrome (MetS) is a clustering of cardio-metabolic risk factors for cardiovascular disease. It is important to identify individuals with the MetS early and initiate interventions long before adverse conditions occur. Our previous studies found that missing or incomplete data that should be entered into the electronic health record (EHR) by nursing staff could lead to the under-diagnosis of the MetS. This study aimed to determine whether a five-component intervention to improve EHR data entry would increase the completeness of data, particularly height, weight, and blood pressure, needed to diagnose the MetS. DESIGN: Quasi-experimental design with pre-test, intervention, and post-test sessions. SETTING: Two family medicine residency training clinics serving mainly African-American patients in Atlanta, Georgia, United States. SUBJECTS AND METHODS: Four nurses and four certified medical assistants attended pre-test, intervention, and post-test sessions. Data of 279 patients at pre-test and 246 patients at post-test were collected and analysed. The pre-test and post-test data completion rates of data entry were compared using rates and Wald chi(2)-test. MAIN OUTCOME MEASURES: Rate of patients with information documented in the EHR on blood pressure, weight, and height at pre-test and post-test. RESULTS: There was a statistically significant increase in the recording of height from pre-test to post-test (46.6% versus 96.7%, P <0.001) and the recording of blood pressure from pre-test to post-test (96.8% versus 99.2%, P <0.05). CONCLUSIONS: The intervention led to an improvement in the entry of pertinent EHR data among nurses and medical assistants in this primary care setting. This increase improved the ability to identify patients who met the criteria for the MetS.

Does the association of the triglyceride to high-density lipoprotein cholesterol ratio with fasting serum insulin differ by race/ethnicity?

BACKGROUND: The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio has been reported to be as closely correlated with insulin resistance as is the fasting serum insulin concentration (FSI), and therefore it is seen as a clinically useful way to identify the concomitant presence of insulin resistance and dyslipidemia. However, conflicting findings exist for the association of the TG/HDL-C ratio with FSI by race/ethnicity. METHODS: The associations of FSI concentration, serum triglyceride concentrations, and HDL-C were analyzed using log-binomial regression analyses and receiver operating characteristic (ROC) curve analysis among nondiabetic adults (n = 2652, aged > or = 20 years, 51.2% men) in the United States. RESULTS: After adjustment for potential confounding effects, the prevalence ratio of hyperinsulinemia was 2.16 (95% confidence interval [CI], 1.74 to 2.08) when using a single cutoff point of 3.5, and 2.23 (95% CI, 1.83 to 2.72) when using race/ethnicity-specific cutoff points of 3.0 for non-Hispanic whites and Mexican Americans and 2.0 for non-Hispanic blacks for the TG/HDL-C ratio. The area under the ROC curve of the TG/HDL-C ratio for predicting hyperinsulinemia was 0.77 (95% CI, 0.74 to 0.79), 0.75 (95% CI, 0.69 to 0.77), and 0.74 (95% CI, 0.69 to 0.76) for non-Hispanic whites, non-Hispanic blacks, and Mexican Americans, respectively. CONCLUSION: There was a significant association between the TG/HDL-C ratio and FSI among three major racial/ethnic groups in the United States. Our results add further support to the notion that the TG/HDL-C ratio may be a clinically simple and useful indicator for hyperinsulinemia among nondiabetic adults regardless of race/ethnicity.

Association of C-reactive protein with surrogate measures of insulin resistance among nondiabetic US from National Health and Nutrition Examination Survey 1999-2002.

BACKGROUND: Increased C-reactive protein (CRP) concentration and insulin resistance (IR) are associated with increased rates of adverse cardiovascular events. We sought to examine the relationship of CRP with surrogate measures of IR among nondiabetic adults in the US. METHODS: We conducted analyses using data from the National Health and Nutrition Examination Survey 1999-2002. We analyzed a nationally representative sample of 2514 men and nonpregnant women age > or = 20 years who were non-Hispanic white, non-Hispanic black, or Mexican American. RESULTS: After adjustment for age, sex, race/ethnicity, smoking status, systolic blood pressure, and serum concentrations of HDL cholesterol, LDL cholesterol, and triglyceride, CRP was significantly associated with 10 IR measures (all P values <0.01). The strength of the association attenuated after further adjustment for waist circumference (change in adjusted regression coefficients ranging from 60.0% to 75.1%). The association of CRP with each IR surrogate was similar (standardized regression coefficient ranges from 0.06 to 0.09). The association of CRP (>3 vs <1 mg/L) with the homeostasis model for assessment of IR (> or = 75th vs <75th percentile) was statistically significant among people with a body mass index > or = 30 kg/m(2) (odds ratio, 2.6; 95% CI, 1.3-5.1) or with a body mass index <25 kg/m(2) (odds ratio, 2.5; 95% CI, 1.5-4.2). CONCLUSIONS: CRP was significantly associated with the surrogate measures of IR among nondiabetic adults. Obesity may play an important role in the association of CRP with IR in this nationally representative sample.

Molecular characterization of strains of Human herpesvirus 8 from Japan, Argentina and Kuwait.

Current genotyping systems for Human herpesvirus 8 (HHV-8) are based on the highly variable gene encoding the K1 glycoprotein. Most strains collected worldwide cluster into two subtypes (I/A and II/C). Sequenced African strains have belonged to subtypes I/A and IV/B. Members of all three of these subtypes can have either the M or P allele at the right-hand side (RHS) of the genome. Strains obtained predominantly from aboriginal or relatively isolated populations have formed clades that branch at a distance from subtypes I/A and II/C, all being of the RHS P allele. The characterization is reported here of 16 Japanese, two Kuwaiti and five Argentine HHV-8 strains obtained from human immunodeficiency virus-infected and non-infected patients with Kaposi's sarcoma (KS), primary effusion lymphoma, multicentric Castleman's disease or renal transplants. K1 sequences of five Japanese, one Kuwaiti and two Argentine strains were identified as subtype I/A and eight Japanese, one Kuwaiti and three Argentine strains were subtype II/C. Three strains from elderly classic KS patients originally from Hokkaido, a northern Japanese island, were relatively closely related to strains of subtypes III/D and E. Consistent with previous observations, both the M and P alleles were identified at the RHS of subgroup I/A and II/C genomes; only the P allele was detected among the three Hokkaido strains. Distances among the Hokkaido strains were similar to the distance between subtypes I/A and II/C, suggesting that the Hokkaido strains may represent two distinct subtypes and that, as more strains are analysed, the currently recognized III/D subgroups will probably emerge as independent subtypes.