Circulating angiopoietins-1 and -2, angiopoietin receptor Tie-2 and vascular endothelial growth factor-A as biomarkers of acute myocardial infarction: a prospective nested case-control study.

BACKGROUND: Angiogenesis is up-regulated in myocardial ischemia. However, limited data exist assessing the value of circulating angiogenic biomarkers in predicting future incidence of acute myocardial infarction (AMI). Our aim was to examine the association between circulating levels of markers of angiogenesis with risk of incident acute myocardial infarction (AMI) in men and women. METHODS: We performed a case-control study (nested within a large cohort of persons receiving care within Kaiser Permanente of Northern California) including 695 AMI cases and 690 controls individually matched on age, gender and race/ethnicity. RESULTS: Median [inter-quartile range] serum concentrations of vascular endothelial growth factor-A (VEGF-A; 260 [252] vs. 235 [224] pg/mL; p = 0.01) and angiopoietin-2 (Ang-2; 1.18 [0.66] vs. 1.05 [0.58] ng/mL; p < 0.0001) were significantly higher in AMI cases than in controls. By contrast, endothelium-specific receptor tyrosine kinase (Tie-2; 14.2 [3.7] vs. 14.0 [3.1] ng/mL; p = 0.07) and angiopoietin-1 levels (Ang-1; 33.1 [13.6] vs. 32.5 [12.7] ng/mL; p = 0.52) did not differ significantly by case-control status. After adjustment for educational attainment, hypertension, diabetes, smoking, alcohol consumption, body mass index, LDL-C, HDL-C, triglycerides and C-reactive protein, each increment of 1 unit of Ang-2 as a Z score was associated with 1.17-fold (95 percent confidence interval, 1.02 to 1.35) increased odds of AMI, and the upper quartile of Ang-2, relative to the lowest quartile, was associated with 1.63-fold (95 percent confidence interval, 1.09 to 2.45) increased odds of AMI. CONCLUSIONS: Our data support a role of Ang-2 as a biomarker of incident AMI independent of traditional risk factors.

Insulin-like growth factors, their binding proteins, and prostate cancer risk: analysis of individual patient data from 12 prospective studies.

BACKGROUND: Some, but not all, published results have shown an association between circulating blood levels of some insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) and the subsequent risk for prostate cancer. PURPOSE: To assess the association between levels of IGFs and IGFBPs and the subsequent risk for prostate cancer. DATA SOURCES: Studies identified in PubMed, Web of Science, and CancerLit. STUDY SELECTION: The principal investigators of all studies that published data on circulating concentrations of sex steroids, IGFs, or IGFBPs and prostate cancer risk using prospectively collected blood samples were invited to collaborate. DATA EXTRACTION: Investigators provided individual participant data on circulating concentrations of IGF-I, IGF-II, IGFBP-II, and IGFBP-III and participant characteristics to a central data set in Oxford, United Kingdom. DATA SYNTHESIS: The study included data on 3700 men with prostate cancer and 5200 control participants. On average, case patients were 61.5 years of age at blood collection and received a diagnosis of prostate cancer 5 years after blood collection. The greater the serum IGF-I concentration, the greater the subsequent risk for prostate cancer (odds ratio [OR] in the highest vs. lowest quintile, 1.38 [95% CI, 1.19 to 1.60]; P < 0.001 for trend). Neither IGF-II nor IGFBP-II concentrations were associated with prostate cancer risk, but statistical power was limited. Insulin-like growth factor I and IGFBP-III were correlated (r = 0.58), and although IGFBP-III concentration seemed to be associated with prostate cancer risk, this was secondary to its association with IGF-I levels. Insulin-like growth factor I concentrations seemed to be more positively associated with low-grade than high-grade disease; otherwise, the association between IGFs and IGFBPs and prostate cancer risk had no statistically significant heterogeneity related to stage or grade of disease, time between blood collection and diagnosis, age and year of diagnosis, prostate-specific antigen level at recruitment, body mass index, smoking, or alcohol intake. LIMITATIONS: Insulin-like growth factor concentrations were measured in only 1 sample for each participant, and the laboratory methods to measure IGFs differed in each study. Not all patients had disease stage or grade information, and the diagnosis of prostate cancer may differ among the studies. CONCLUSION: High circulating IGF-I concentrations are associated with a moderately increased risk for prostate cancer.

Helicobacter pylori infection and development of pancreatic cancer.

BACKGROUND: Infection with Helicobacter pylori is an established risk factor for gastric cancer. Results from two studies suggest that it may also be a risk factor for pancreatic cancer. METHODS: We conducted a nested case control study among 128,992 adult subscribers to the Kaiser Permanente Medical Care Program who had been enrolled in a multiphasic health checkup from 1964 to 1969. Serum collected during the checkup was maintained frozen, and subjects were followed for cancer. Cases consisted of 104 randomly selected subjects among 507 who developed pancreatic cancer in the cohort. Controls consisted of 262 pancreatic cancer-free subjects from a pool of 730 controls previously tested for studies conducted on this cohort. Controls were individually matched to cases on age, gender, race, site, and date of multiphasic health checkup. Control sera were compared with cases for antibodies to H. pylori and the CagA protein. The effects of smoking, alcohol consumption, obesity, and years of education were also investigated. RESULTS: Neither H. pylori [odds ratio (OR), 0.85; 95% confidence interval (95% CI), 0.49-1.48] nor its CagA protein (OR, 0.96; 95% CI, 0.48-1.92) was associated with subsequent development of pancreatic cancer. Smoking (OR, 2.09; 95% CI, 1.17-3.74) and greater number of years of education (OR, 2.13; 95% CI, 1.23-3.69) were risk factors for pancreatic cancer, whereas alcohol consumption and obesity were not. CONCLUSION: Our results suggest that H. pylori infection is not associated with development of pancreatic cancer.

Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up.

OBJECTIVE: To determine whether serum titers of anti-Epstein-Barr virus (EBV) antibodies are elevated in blood specimens collected up to 30 years prior to onset of multiple sclerosis (MS). METHODS: Individuals with MS were identified among members of the Kaiser Permanente Northern California health plan who participated in the multiphasic examinations administered between 1965 and 1974. Stored serum samples were used to compare anti-EBV antibody titers in 42 individuals who developed MS with age-matched and sex-matched controls. RESULTS: The geometric mean titers of antibodies to the Epstein-Barr nuclear antigen (EBNA) complex and its component EBNA-1 were significantly higher in the MS cases when compared with matched controls. The relative risk of MS associated with a 4-fold increase in antibody titers was 2.1 (95% confidence interval, 1.1-3.8) for the EBNA complex and 1.8 (95% confidence interval, 1.1-2.9) for EBNA-1. Elevations of antibody titers to the EBNA complex and EBNA-1 among MS cases first occurred between 15 to 20 years before the onset of symptoms and persisted thereafter. CONCLUSION: The elevation of anti-EBV titers is probably an early event in the pathogenesis of MS and is unlikely to be the result of an aspecific immune dysregulation.

C-reactive protein, Helicobacter pylori, Chlamydia pneumoniae, cytomegalovirus and risk for myocardial infarction.

PURPOSE: C-reactive protein (CRP), Chlamydia pneumonia, Helicobacter pylori, and cytomegalovirus (CMV) have each been associated with atherosclerosis. We assessed how infection and CRP related to risk for subsequent myocardial infarction (MI). METHODS: Using a nested case-control design, we assessed how these factors independently and jointly affected risk for myocardial infarction (MI). Cases of first MI (N = 121) were identified from among participants in a multiphasic health check-up cohort. Controls without MI (N = 204) were matched to cases by gender, age, race, and date of serum collection. Sera collected at enrollment were tested for antibodies to infection and for CRP. RESULTS: In multivariate analysis (mean follow-up of 5.1 years), CRP was associated with MI only in subjects older than 51 years (p = 0.004). Although H. pylori infection increased risk for MI, this association was modest (OR = 1.90, 95% CI = 0.97-3.71) and was not evident in non-smokers or when adjusted for education. No association between C. pneumoniae or cytomegalovirus and MI was observed, nor was the association between CRP and MI explained by these infections. CONCLUSIONS: Elevated CRP is a risk factor for subsequent MI in older individuals. The relationship between Hp and MI may be due to confounding or co-linearity with socioeconomic status.

Association of prediagnostic serum vitamin D levels with the development of basal cell carcinoma.

We investigated the association between serum 25-hydroxyvitamin D (25(OH)D) levels and basal cell carcinoma (BCC) risk in a nested case-control study at Kaiser Permanente Northern California (KPNC). A total of 220 case patients with BCC diagnosed after serum collection were matched to 220 control subjects. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression. Fully adjusted models included body mass index (BMI), smoking, education, sun-exposure variables, X-ray exposure, and personal history of cancer. For each measure of serum 25(OH)D (continuous, clinically relevant tertiles, quintiles), we found an increased risk of BCC in unadjusted models (OR=1.03, 95% CI 1.00-1.05, P<0.05; OR=3.98, 95% CI: 1.31-12.31, deficient vs. sufficient, test for trend P-value <0.01; OR=2.32, 95% CI: 1.20-4.50, 1st vs. 5th quintile, test for trend P-value 0.03). In fully adjusted models, the values attenuated slightly (OR=1.02, 95% CI 1.00-1.05, P<0.05; OR=3.61, 95% CI: 1.00-13.10, deficient vs. sufficient, t-trend P=0.03; OR=2.09 1st vs. 5th quintile, 95% CI: 0.95-4.58, t-trend P=0.11). Our findings suggest that higher prediagnostic serum 25(OH)D levels may be associated with increased risk of subsequent BCC. Further studies to evaluate the effect of sun exposure on BCC and serum 25(OH)D levels may be warranted.

Serum ghrelin levels and risk of subsequent adenocarcinoma of the esophagus.

OBJECTIVE: Several large studies have shown a negative association between Helicobacter pylori (H. pylori) infection and esophageal adenocarcinoma. Diminution of gastric ghrelin secretion by H. pylori could protect against esophageal malignancy by decreasing appetite, food intake, and acid production, thereby decreasing weight and gastroesophageal reflux. METHODS: We evaluated the association of ghrelin with esophageal adenocarcinoma using a population from a previous nested case-control study. Among 128,992 enrolled in a multiphasic health checkup (MHC) between 1964 and 1969, 52 patients developed esophageal adenocarcinoma by the year 2000. Three random controls from the MHC cohort were matched to each case by age, sex, race, and the date and site of their MHC. Serum samples collected at the MHC had been previously tested for IgG antibodies against H. pylori and the CagA protein. Serum ghrelin concentrations were determined by a commercial EIA on 52% of the initial subjects (31 cases and 79 controls). RESULTS: A concentration of ghrelin greater than 3,200 pg/mL at MHC (fourth quartile) was associated with a lower risk of esophageal cancer (H. pylori and body mass index [BMI] adjusted OR=0.18 [CI 0.04-0.78]). This inverse association was seen only in overweight subjects (BMI>or=25, P value for interaction=0.09). The effects of H. pylori and ghrelin were independent. CONCLUSION: Contrary to the original hypothesis, high rather than low serum ghrelin was associated with protection against esophageal adenocarcinoma but only among overweight subjects.

Does the association between serum endostatin, an endogenous anti-angiogenic protein, and acute myocardial infarction differ by race?

Endostatin, an endogenous anti-angiogenic protein, has been linked to reduced atherosclerosis in animal models. We conducted a nested case-control study to ascertain whether decreased circulating endostatin might be associated with increased odds of acute myocardial infarction (AMI) and whether this association varied by sex or race. Cases were 211 subjects who subsequently developed AMI, and controls were 173 subjects free of cardiovascular disease matched on age, sex, race and follow-up time. In conditional logistic regression adjusting for traditional risk factors, the odds ratio of AMI per 1 SD increment in endostatin was 0.85 (95% confidence interval, 0.73-1.00). This association varied by race (but not by sex) such that a statistically significant inverse relation was found among Asians and white individuals and a significant positive relation among black individuals. Further research is needed to replicate these findings and to elucidate potential mechanisms for these race/ethnic differences.

Helicobacter pylori infection and the risk of development of esophageal adenocarcinoma.

BACKGROUND: An increase in the incidence of esophageal adenocarcinoma has coincided with a decrease in the prevalence of Helicobacter pylori infection. Whether these 2 phenomena are associated is unknown. METHODS: We conducted a nested case-control study of 128,992 members of an integrated health care system who had participated in a multiphasic health checkup (MHC) during 1964-1969. During follow-up, 52 patients developed esophageal adenocarcinoma. Three randomly chosen control subjects from the MHC cohort were matched to each case subject, on the basis of age at the MHC, sex, race, and the date and site of the MHC. Data on cigarette smoking, alcohol consumption, body mass index (BMI), and education level were obtained at the MHC. Serum samples collected at the MHC were tested for IgG antibodies to H. pylori and to the H. pylori CagA protein. RESULTS: Subjects with H. pylori infections were less likely than uninfected subjects to develop esophageal adenocarcinoma (odds ratio [OR], 0.37 [95% confidence interval (CI), 0.16-0.88]). This significant association was restricted to case subjects and control subjects <50 years old at the MHC (OR, 0.20 [95% CI, 0.06-0.68]). In patients with H. pylori infections, the OR for those who tested positive for IgG antibodies to the CagA protein was similar to that for those who tested negative for it. BMI >/=25 and cigarette smoking were strong independent risk factors for development of esophageal adenocarcinoma. CONCLUSION: The absence of H. pylori infection, independent of cigarette smoking and BMI, is associated with a markedly increased risk of development of esophageal adenocarcinoma.

Transplants from balding and hairy androgenetic alopecia scalp regrow hair comparably well on immunodeficient mice.

Human hair follicles were grafted onto 2 strains of immunodeficient mice to compare the regeneration potential of vellus (miniaturized, balding) and terminal (hairy, nonbalding) follicles from males and a female exhibiting pattern baldness. Each mouse had transplants of both types of follicles from a single donor for direct comparison. Grafted follicles from 2 male donors resulted in nonsignificant differences in mean length (52 mm vs 54 mm) and mean diameter (99 microm vs 93 microm) at 22 weeks for hairs originating from balding and hairy scalp, respectively, corresponding to 400% versus 62% of the mean pretransplantation diameters. Follicles from the female donor transplanted to several mice also resulted in nonsignificant differences in length (43 mm vs 37 mm) for hairs from balding and hairy scalp, respectively, during a period of 22 weeks. The mean diameter of the originally vellus hairs increased 3-fold, whereas the terminal hairs plateaued at approximately 50% of pretransplantation diameter, resulting in a final balding hair volume double that of the nonbalding hairs. This report shows that miniaturized hair follicles of pattern alopecia can quickly regenerate once removed from the human scalp and can grow as well as or better than terminal follicles from the same individual.

CagA status of Helicobacter pylori infection and p53 gene mutations in gastric adenocarcinoma.

Infection with Helicobacter pylori (H. pylori) increases stomach cancer risk. Helicobacter pylori strains with the cag pathogenicity island (PAI) induce more severe inflammation in the gastric epithelium and are more strongly associated with stomach cancer risk than strains lacking the PAI. We examined whether the prevalence of somatic p53 mutation in gastric adenocarcinoma differed between subjects with and without infection with CagA(+) (a marker for the PAI) H. pylori strains. DNA from 105 microdissected tumor specimens was analyzed for mutation in exons 5-8 of the p53 gene by polymerase chain reaction-based single-strand conformation polymorphism followed by direct DNA sequencing. Enzyme-linked immunosorbent assays for IgG antibodies against H. pylori and CagA were performed on sera collected 2-31 years prior to cancer diagnosis. Tumors from CagA(+) subjects were significantly more likely to have p53 mutations than tumors from CagA(-) subjects (including H. pylori- and H. pylori(+)/CagA(-)): odds ratio = 3.72; 95% confidence interval, 1.06-13.07 after adjustment for histologic type and anatomic subsite of tumor and age at diagnosis and sex of subjects. Mutations were predominantly insertions and deletions (43%) as well as transition mutations at CpG dinucleotides (33%). The data suggest that CagA(+) H. pylori infection, when compared with CagA(-) infection or the absence of H. pylori infection, is associated with a higher prevalence of p53 mutation in gastric adenocarcinoma.