Norma S. Ketchum

Serum dioxin and diabetes mellitus in veterans of Operation Ranch Hand.

We studied diabetes mellitus and glucose and insulin levels in Air Force veterans exposed to Agent Orange and its contaminant, 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (dioxin), during the Vietnam War. The index subjects of the Air Forces ongoing 20‐year prospective epidemiologic study are veterans of Operation Ranch Hand (N = 989), the unit responsible for aerial herbicide spraying in Vietnam from 1962 to 1971. Other Air Force veterans who served in Southeast Asia during the same period but were not involved with spraying herbicides serve as Comparisons (N = 1,276). The median serum dioxin level in the Ranch Hand group was 12.2 parts per trillion (ppt) (range = 0–617.8 ppt), and the median dioxin level in the Comparison group was 4.0 ppt (range = 0–10 ppt). We found that glucose abnormalities [relative risk = 1.4; 95% confidence limits (CL) = 1.1, 1.8], diabetes prevalence (relative risk = 1.5; 95% CL = 1.2, 2.0), and the use of oral medications to control diabetes (relative risk = 2.3; 95% CL = 1.3, 3.9) increased, whereas time‐to‐diabetes‐onset decreased with dioxin exposure. Serum insulin abnormalities (relative risk = 3.4; 95% CL = 1.9, 6.1) increased with dioxin exposure in nondiabetics. These results indicate an adverse relation between dioxin exposure and diabetes mellitus, glucose metabolism, and insulin production.

Cancer in US Air Force veterans of the Vietnam War.

Cancer incidence and mortality were summarized in Air Force veterans of the Vietnam War. The index subjects were Operation Ranch Hand veterans who sprayed 2,3,7,8 tetrachlorodibenzo-p-dioxin (dioxin)-contaminated herbicides in Vietnam. Comparisons served in Southeast Asia during the same period but did not spray herbicides. We assessed cancer incidence and mortality using national rates and contrasted cancer risk in each of three Ranch Hand dioxin exposure categories relative to comparisons. The incidence of melanoma and prostate cancer was increased among white Ranch Hand veterans relative to national rates. Among veterans who spent at most 2 years in Southeast Asia, the risk of cancer at any site, of prostate cancer and of melanoma was increased in the highest dioxin exposure category. These results appear consistent with an association between cancer and dioxin exposure.

Diabetes mellitus and 2,3,7,8-tetrachlorodibenzo-p-dioxin elimination in veterans of Operation Ranch Hand.

Using multivariate statistical models, no significant relationship was found between the rate of 2,3,7,8-tetrachlorodibenzo-p-dioxin ( TCDD) elimination and the occurrence or time to onset of diabetes in 343 veterans of Operation Ranch Hand, the unit responsible for the aerial spraying of Agent Orange and other TCDD-contaminated herbicides during the Vietnam War. Without adjustment for age, body mass index, family history of diabetes, and smoking history, the time to onset of diabetes decreased and the risk of diabetes increased with a diminished elimination rate. However, after adjustment, diabetes time to onset and occurrence were not significantly associated with TCDD elimination. Analyses of covariance found no significant difference between the average elimination rates of diabetic and nondiabetic veterans, without or with adjustment for risk factors. To our knowledge, this is the only study to date to examine TCDD elimination and diabetes.

Identification of microRNAs associated with hyperthermia-induced cellular stress response

MicroRNAs (miRNAs) are a class of small RNAs that play a critical role in the coordination of fundamental cellular processes. Recent studies suggest that miRNAs participate in the cellular stress response (CSR), but their specific involvement remains unclear. In this study, we identify a group of thermally regulated miRNAs (TRMs) that are associated with the CSR. Using miRNA microarrays, we show that dermal fibroblasts differentially express 123 miRNAs when exposed to hyperthermia. Interestingly, only 27 of these miRNAs are annotated in the current Sanger registry. We validated the expression of the annotated miRNAs using qPCR techniques, and we found that the qPCR and microarray data was in well agreement. Computational target-prediction studies revealed that putative targets for the TRMs are heat shock proteins and Argonaute-2—the core functional unit of RNA silencing. These results indicate that cells express a specific group of miRNAs when exposed to hyperthermia, and these miRNAs may function in the regulation of the CSR. Future studies will be conducted to determine if other cells lines differentially express these miRNAs when exposed to hyperthermia.

Dioxin and diabetes mellitus: an analysis of the combined NIOSH and Ranch Hand data

OBJECTIVES To reanalyze in a similar manner the two principal studies of TCDD (tetrachlorodibenzo-p-dioxin) and diabetes in an attempt to reconcile disparate results. METHODS Data from 990 United States Air Force veterans (Ranch Hand) and 1275 referents were reanalyzed, and a NIOSH population of 267 chemical workers and 227 referents. The Ranch Hand veterans had lower concentrations of lipid adjusted serum TCDD (median 12 parts per trillion (ppt)) than the NIOSH workers (median 75 ppt) when examined in the late 1980s. An analysis was conducted of the combined data sets, adopting a uniform approach to outcome definition, data analysis, and covariate control. RESULTS The combined exposed groups did not differ markedly from the combined non-exposed groups for prevalence of diabetes (odds ratio (OR) 1.17, 95% confidence interval (95% CI) 0.92 to 1.48), with no evidence of heterogeneity of exposure effect between studies. Also virtually no difference was found between combined exposed and non-exposed groups in mean fasting serum glucose (difference in log serum glucose 0.002, 95% CI −0.006 to 0.010), and there was little evidence in either study of a dose-response trend for fasting serum glucose. An increasing trend was found (p=0.0001) in prevalence of diabetes with increased TCDD (at the time of examination or at time of last exposure) among the Ranch Hand population, with excess risk largely confined to the highest 8% of the exposed group (>78 ppt serum TCDD), which had an OR of 3.21 (95% CI 1.81 to 5.72) versus those with <10 ppt TCDD. However, no such positive dose-response was found in the NIOSH population. CONCLUSIONS There was little overall evidence that the exposed workers were at higher risk than the non-exposed workers of diabetes or abnormal fasting glucose. However, the Ranch Hand subjects showed a positive dose-response for diabetes, whereas the more highly exposed NIOSH subjects did not. The reason for the difference in diabetes dose-response trends between the two studies is unknown.

Serum Dioxin, Testosterone, and Subsequent Risk of Benign Prostatic Hyperplasia: A Prospective Cohort Study of Air Force Veterans

Background Operation Ranch Hand veterans were involved in spraying herbicides, including Agent Orange, during the Vietnam War in 1962–1971; Agent Orange was contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). It has been hypothesized that dioxins may be partially responsible for an increase of male reproductive tract disorders such as testicular cancer, cryptorchidism, and hypospadias. Objectives In this study, our objective was to assess the effect of serum TCDD concentration on the risk of development of benign prostatic hyperplasia (BPH) and on serum testosterone levels. Methods This study was a longitudinal, prospective cohort study made up of U.S. Air Force veterans involved in Operation Ranch Hand. Other Air Force veterans who did not spray herbicides were included as comparisons. BPH was determined by medical record review and by medical examinations conducted during the study. Data were available for 971 Ranch Hand and 1,266 comparison veterans. We investigated the relationship between BPH and serum TCDD level using the Cox proportional hazards models adjusted for testosterone levels, body mass index (BMI), and the percentage change in BMI per year. Results In univariate and multivariate analyses, the risk of BPH decreased with increasing serum TCDD in the comparison group. The multivariate risk ratio for BPH in the comparison group was 0.84 (95% confidence interval, 0.73–0.98). Excluding men with prostate cancer, inflammatory or other prostatic diseases did not substantially alter the association. Serum testosterone levels were inversely associated with serum TCDD levels in both Ranch Hand and comparison groups. Conclusions TCDD exposure at general population levels is associated with a decreasing risk of BPH with higher exposure levels. TCDD exposure is also negatively associated with serum testosterone levels.

Utilization of evidence-based psychotherapies in Veterans Affairs posttraumatic stress disorder outpatient clinics

In response to the growing numbers of veterans with posttraumatic stress disorder (PTSD), the Department of Veterans Affairs (VA) has sought to make evidence-based psychotherapies for PTSD available at every VA facility. We conducted a national survey of providers within VA PTSD clinical teams (PCTs) to describe utilization of prolonged exposure (PE) and cognitive processing therapy (CPT) and to identify individual and organizational factors associated with treatment uptake and adherence. Participants (N = 128) completed an electronic survey assessing reported utilization of PE and CPT treatments, adherence to treatment manuals, and characteristics of the provider and workplace environment. Participants reported conducting a weekly mean of 4.5 hours of PE, 3.9 hours of CPT (individual format), 1.3 hours of CPT (group format), and 13.4 hours of supportive care. Perceived effectiveness of PE and CPT were significantly associated with utilization of and adherence to those treatments. Reported number of hours conducting supportive care was positively associated with feeling the clinic was not sufficiently staffed (p = .05). Adherence to the PE treatment manual was positively associated with receiving emotional support from coworkers (p < .01). Provider attitudes and organizational factors such as staffing and work relationships may have an important impact on treatment selection and the quality of PTSD care provided in VA PCTs.

Did TCDD exposure or service in Southeast Asia increase the risk of cancer in air force Vietnam veterans who did not spray agent orange

Objective: We sought to examine cancer incidence in 1482 Air Force veterans who served in Southeast Asia (SEA) and who were not occupationally exposed to herbicides. Methods: Cancer incidence between 1982 and 2003 was determined by record review and Cox proportional hazards models were used to estimate risk ratios across serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and years served in SEA categories. Results: All sites cancer risk increased with TCDD (relative risk = 1.6, 95% confidence interval = 1.2–2.2). The risk of prostate cancer increased with years of SEA service but not with TCDD. TCDD and years of SEA service interacted with all sites cancer; the risk was greatest in those with the highest TCDD levels and the longest time served in SEA. Conclusions: These results suggest nonoccupational exposures to TCDD or other factors while in SEA may contribute to cancer risk in these veterans.

Prostate cancer in US Air Force veterans of the Vietnam war

US Air Force veterans of Operation Ranch Hand sprayed herbicides contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in Vietnam from 1962 to 1971. Comparisons served in Southeast Asia (SEA) during the same time period but did not spray herbicides. Here we investigate a potential association between exposure to TCDD and prostate cancer. Data were available for 2516 veterans (1019 Ranch Hand and 1497 Comparison) who participated in at least one of six physical examinations starting in 1982 and had a measurement of serum TCDD. We assigned Ranch Hands to two exposure categories: Lower and Higher, based on their median 20-year cumulative TCDD level. In total, 81 Comparison and 59 Ranch Hand prostate cancers were identified between 1 January 1982 and 31 December 2003. We found no overall increase in the risk of prostate cancer in Ranch Hand veterans versus the Comparisons. There was a positive association in Ranch Hand veterans in the Higher TCDD category who served in SEA before 1969 (RR=2.27, 95% CI 1.11–4.66) when more contaminated herbicides were used, but the number of cases was small (n=15). A within-group comparison found that in Comparison veterans, time served in SEA was associated with an increased risk of prostate cancer (RR=2.18, 95% CI 1.27–3.76, >789 days versus ≤789 days). No increase in the risk of prostate cancer was observed within the Ranch Hand group in association with TCDD or time served in SEA. These analyses suggest that a longer service in SEA and exposures other than TCDD may have increased the risk of prostate cancer in Comparison veterans.

Prospective evaluation of operating characteristics of prostate cancer detection biomarkers

PURPOSE We assessed the independent predictive values of the serum markers free prostate specific antigen, proenzyme prostate specific antigen, neuroendocrine marker and Dickkopf-1 compared to serum prostate specific antigen and other standard risk factors for early prostate cancer detection. MATERIALS AND METHODS From the prospectively collected SABOR cohort 250 prostate cancer cases, and 250 mean age matched and proportion of African-American race/ethnicity matched controls were selected who had a prior available prostate specific antigen and digital rectal examination. Serum samples were obtained, and free prostate specific antigen, [-2]proenzyme prostate specific antigen, Dickkopf-1 and neuroendocrine marker were measured. AUC, sensitivities and specificities were calculated, and multivariable logistic regression was used to assess the independent predictive value compared to prostate specific antigen, digital rectal examination, family history, prior biopsy history, race/ethnicity and age. RESULTS The AUCs (95% CI) were 0.76 (0.71, 0.8) for free prostate specific antigen, 0.72 (0.67, 0.76) for [-2]proenzyme prostate specific antigen, 0.76 (0.72, 0.8) for %free prostate specific antigen, 0.61 (0.56, 0.66) for %[-2]proenzyme prostate specific antigen, 0.73 (0.68, 0.77) for prostate health index, 0.53 (0.48, 0.58) for Dickkopf-1 and 0.53 (0.48, 0.59) for neuroendocrine marker. In the 2 to 10 ng/ml prostate specific antigen range the AUCs (95% CI) were 0.58 (0.49, 0.67) for free prostate specific antigen, 0.53 (0.44, 0.62) for [-2]proenzyme prostate specific antigen, 0.67 (0.59, 0.75) for %free prostate specific antigen, 0.57 (0.49, 0.65) for %[-2]proenzyme prostate specific antigen and 0.59 (0.51, 0.67) for phi. Only %free prostate specific antigen retained independent predictive value compared to the traditional risk factors. CONCLUSIONS Free prostate specific antigen retained independent diagnostic usefulness for prostate cancers detected through prostate specific antigen and digital rectal examination screening. Prostate specific antigen isoforms are highly correlated with prostate specific antigen. Future research is needed to identify new markers associated with prostate cancer through different mechanisms.