Denise J. Roe

Outcomes of Rapid Defibrillation by Security Officers after Cardiac Arrest in Casinos

BACKGROUND The use of automated external defibrillators by persons other than paramedics and emergency medical technicians is advocated by the American Heart Association and other organizations. However, there are few data on the outcomes when the devices are used by nonmedical personnel for out-of-hospital cardiac arrest. METHODS We studied a prospective series of cases of sudden cardiac arrest in casinos. Casino security officers were instructed in the use of automated external defibrillators. The locations where the defibrillators were stored in the casinos were chosen to make possible a target interval of three minutes or less from collapse to the first defibrillation. Our protocol called for a defibrillation first (if feasible), followed by manual cardiopulmonary resuscitation. The primary outcome was survival to discharge from the hospital. RESULTS Automated external defibrillators were used, 105 patients whose initial cardiac rhythm was ventricular fibrillation. Fifty-six of the patients 153 percent) survived to discharge from the hospital. Among the 90 patients whose collapse was witnessed (86 percent), the clinically relevant time intervals were a mean (+/-SD) of 3.5+/-2.9 minutes from collapse to attachment of the defibrillator, 4.4+/-2.9 minutes from collapse to the delivery of the first defibrillation shock, and 9.8+/-4.3 minutes from collapse to The arrival of the paramedics. The survival rate was 74 percent for those who received their first defibrillation no later than three minutes after a witnessed collapse and 49 percent for those who received their first defibrillation after more than three minutes. CONCLUSIONS Rapid defibrillation by nonmedical personnel using an automated external defibrillator can improve survival after out-of-hospital cardiac arrest due to ventricular fibrillation. Intervals of no more than three minutes from collapse to defibrillation are necessary to achieve the highest survival rates.

Lack of Effect of a High-Fiber Cereal Supplement on the Recurrence of Colorectal Adenomas

BACKGROUND The risks of colorectal cancer and adenoma, the precursor lesion, are believed to be influenced by dietary factors. Epidemiologic evidence that cereal fiber protects against colorectal cancer is equivocal. We conducted a randomized trial to determine whether dietary supplementation with wheat-bran fiber reduces the rate of recurrence of colorectal adenomas. METHODS We randomly assigned 1429 men and women who were 40 to 80 years of age and who had had one or more histologically confirmed colorectal adenomas removed within three months before recruitment began to a supervised program of dietary supplementation with either high amounts (13.5 g per day) or low amounts (2 g per day) of wheat-bran fiber. The primary end point was the presence or absence of new adenomas at the time of follow-up colonoscopy. Subjects and physicians, including colonoscopists, were unaware of the group assignments. RESULTS Of the 1303 subjects who completed the study, 719 had been randomly assigned to the high-fiber group and 584 to the low-fiber group. The median times from randomization to the last follow-up colonoscopy were 34 months in the high-fiber group and 36 months in the low-fiber group. By the time of the last follow-up colonoscopy, at least one adenoma had been identified in 338 subjects in the high-fiber group (47.0 percent) and in 299 subjects in the low-fiber group (51.2 percent). The multivariate adjusted odds ratio for recurrent adenoma in tile high-fiber group, as compared with the low-fiber group, was 0.88 (95 percent confidence interval, 0.70 to 1.11; P=0.28), and the relative risk of recurrence according to the number of adenomas, in the high-fiber group as compared with the low-fiber group, was 0.99 (95 percent confidence interval, 0.71 to 1.36; P=0.93). CONCLUSIONS As used in this study, a dietary supplement of wheat-bran fiber does not protect against recurrent colorectal adenomas.

Estimating Effectiveness of Cardiac Arrest Interventions A Logistic Regression Survival Model

BACKGROUND The study objective was to develop a simple, generalizable predictive model for survival after out-of-hospital cardiac arrest due to ventricular fibrillation. METHODS AND RESULTS Logistic regression analysis of two retrospective series (n=205 and n=1667, respectively) of out-of-hospital cardiac arrests was performed on data sets from a Southwestern city (population, 415,000; area, 406 km2) and a Northwestern county (population, 1,038,000; area, 1399 km2). Both are served by similar two-tiered emergency response systems. All arrests were witnessed and occurred before the arrival of emergency responders, and the initial cardiac rhythm observed was ventricular fibrillation. The main outcome measure was survival to hospital discharge. Patient age, initiation of CPR by bystanders, interval from collapse to CPR, interval from collapse to defibrillation, bystander CPR/collapse-to-CPR interval interaction, and collapse-to-CPR/collapse-to-defibrillation interval interaction were significantly associated with survival. There was not a significant difference between observed survival rates at the two sites after control for significant predictors. A simplified predictive model retaining only collapse to CPR and collapse to defibrillation intervals performed comparably to the more complicated explanatory model. CONCLUSIONS The effectiveness of prehospital interventions for out-of-hospital cardiac arrest may be estimated from their influence on collapse to CPR and collapse to defibrillation intervals. A model derived from combined data from two geographically distinct populations did not identify site as a predictor of survival if clinically relevant predictor variables were controlled for. This model can be generalized to other US populations and used to project the local effectiveness of interventions to improve cardiac arrest survival.

Bicarbonate Increases Tumor pH and Inhibits Spontaneous Metastases

The external pH of solid tumors is acidic as a consequence of increased metabolism of glucose and poor perfusion. Acid pH has been shown to stimulate tumor cell invasion and metastasis in vitro and in cells before tail vein injection in vivo. The present study investigates whether inhibition of this tumor acidity will reduce the incidence of in vivo metastases. Here, we show that oral NaHCO(3) selectively increased the pH of tumors and reduced the formation of spontaneous metastases in mouse models of metastatic breast cancer. This treatment regimen was shown to significantly increase the extracellular pH, but not the intracellular pH, of tumors by (31)P magnetic resonance spectroscopy and the export of acid from growing tumors by fluorescence microscopy of tumors grown in window chambers. NaHCO(3) therapy also reduced the rate of lymph node involvement, yet did not affect the levels of circulating tumor cells, suggesting that reduced organ metastases were not due to increased intravasation. In contrast, NaHCO(3) therapy significantly reduced the formation of hepatic metastases following intrasplenic injection, suggesting that it did inhibit extravasation and colonization. In tail vein injections of alternative cancer models, bicarbonate had mixed results, inhibiting the formation of metastases from PC3M prostate cancer cells, but not those of B16 melanoma. Although the mechanism of this therapy is not known with certainty, low pH was shown to increase the release of active cathepsin B, an important matrix remodeling protease.

Incidence, Prevalence, and Clearance of Type-Specific Human Papillomavirus Infections: The Young Women’s Health Study

The natural history of type-specific human papillomavirus (HPV) infections was examined in a cohort of 331 women aged 18-35 years who self-referred for routine gynecological care. Participants underwent a gynecological examination at baseline and at approximately 4 and approximately 10 months after baseline. Cervical samples were collected for HPV testing and genotyping at each visit, as was information on reproductive, sexual, and medical histories. The rate of new HPV infections was 2.9% per month; the highest rates were observed for HPV types 16, 39, 84, and 51. Among women who tested negative for HPV at baseline, the cumulative probability of acquiring an oncogenic HPV strain during a 12-month follow-up period was 0.32, compared with 0.18 for nononcogenic strains. Women who had had >/=1 new male sex partner in the recent past were significantly more likely to acquire a new HPV infection (relative hazard, 2.39; 95% confidence interval, 1.20-4.76). The median time to clearance of infection was significantly longer for oncogenic strains (9.8 months) than for nononcogenic strains (4.3 months).

Enhancement of chemotherapy by manipulation of tumour pH.

SummaryThe extracellular (interstitial) pH (pHe) of solid tumours is significantly more acidic compared to normal tissues. In-vitro, low pH reduces the uptake of weakly basic chemotherapeutic drugs and, hence, reduces their cytotoxicity. This phenomenon has been postulated to contribute to a ‘physiological’ resistance to weakly basic drugs in vivo. Doxorubicin is a weak base chemotherapeutic agent that is commonly used in combination chemotherapy to clinically treat breast cancers. This report demonstrates that MCF-7 human breast cancer cells in vitro are more susceptible to doxorubicin toxicity at pH 7.4, compared to pH 6.8. Furthermore 31P-magnetic resonance spectroscopy (MRS) has shown that the pHe of MCF-7 human breast cancer xenografts can be effectively and significantly raised with sodium bicarbonate in drinking water. The bicarbonate-induced extracellular alkalinization leads to significant improvements in the therapeutic effectiveness of doxorubicin against MCF-7 xenografts in vivo. Although physiological resistance to weakly basic chemotherapeutics is well-documented in vitro and in theory, these data represent the first in vivo demonstration of this important phenomenon.

Inhibitory effect of selenomethionine on the growth of three selected human tumor cell lines

Selenium supplementation has been shown for many years to work as an anticarcinogenic agent both in epidemiology and in in vitro studies. Selenium supplementation has recently been shown to decrease total cancer incidence. However, the mechanism of action of selenium as an anticarcinogenic agent has yet to be elucidated. Selenomethionine was the predominant form of selenium in the dietary supplement in the study by Clark et al. (Clark, L.C., Combs, G.F., Turnbull, W.B., Slate, E.H., Chalker, D.K., Chow, J., Davis, L.S., Glover, R.A., Graham, G.F., Gross, E.G., Krongrad, A., Lesher, J.L., Park, H.K., Sanders, B.B., Smith, C.L., Taylor, J.R. and The Nutritional Prevention of Cancer Study Group (1996) Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: a randomized controlled trial. J. Am. Med. Assoc., 276 (24), 1957-1963) and therefore we evaluated the growth inhibitory effects of selenomethionine against human tumor cells. Selenomethionine was tested against each of three human tumor cell lines (MCF-7/S breast carcinoma, DU-145 prostate cancer cells and UACC-375 melanoma) and against normal human diploid fibroblasts. All cell lines demonstrated a dose-dependent manner of growth inhibition by selenomethionine. Selenomethionine inhibited the growth of all of the human tumor cell lines in the micromolar (microM) range (ranging from 45 to 130 microM) while growth inhibition of normal diploid fibroblasts required 1 mM selenomethionine, approximately 1000-fold higher than for the cancer cell lines. In short, normal diploid fibroblasts were less sensitive than the cancer cell lines to the growth inhibitory effects of selenomethionine. Furthermore, we show that selenomethionine administration to these cancer cell lines results in apoptotic cell death and aberrant mitoses. These results demonstrate the differential sensitivity of tumor cells and normal cells to selenomethionine.

Different mechanisms of decreased drug accumulation in doxorubicin and mitoxantrone resistant variants of the MCF7 human breast cancer cell line.

We selected two drug resistant variants of the MCF7 human breast cancer cell line by chronic in vitro exposure to doxorubicin (MCF7/D40 cell line) and mitoxantrone (MCF7/Mitox cell line), respectively. The cell lines are similar in growth characteristics including doubling time, DNA synthetic phase and cell size. Resistance to mitoxantrone conferred only partial resistance to doxorubicin; whereas resistance selected for doxorubicin appeared to confer complete resistance to mitoxantrone. Both agents selected for cross resistance to the Vinca alkaloids. MCF7/D40 cells display a classic-multi-drug resistance phenotype with expression of P-glycoprotein, decreased drug accumulation relative to the parental line and reversal of drug accumulation and drug resistance by verapamil. MCF7/Mitox cells likewise display resistance to multiple drugs, but in contrast to MCF7/D40 cells do not express P-glycoprotein by immunoblot or RNA blot analysis. Net drug accumulation in MCF7/Mitox cells was decreased relative to the parental cells but there was no selective modulation of drug accumulation or in vitro drug resistance by the addition of verapamil. Efflux of mitoxantrone was enhanced in both the MCF7/D40 and MCF7/Mitox cell lines relative to the MCF7/S cell line. We conclude that the two drug resistant cell lines have different mechanisms of decreased drug accumulation.

Concentrations and plasma‐tissue‐diet relationships of carotenoids, retinoids, and tocopherols in humans

Micronutrients, such as beta-carotene and vitamins A and E, are potential chemopreventive agents; however, their concentrations in human target tissues are largely unknown. Because these micronutrients may exert their action at the site of target tissues, the tissue concentrations of the micronutrients need to be determined. In this cross-sectional study, we have measured the concentrations of seven carotenoids, two retinoids, and two tocopherols in paired plasma, buccal mucosal cells (BMC), and skin samples from 96 healthy subjects (ages 26-82 yrs). The plasma-tissue, as well as the diet-plasma and diet-tissue relationships of the micronutrients, and the impact of various potential confounders on the micronutrient concentrations were evaluated. The micronutrient concentrations of plasma and BMC used in the evaluation were the average of three measurements over a one-month period. Our data indicated that 1) the correlations between the plasma and BMC (Spearman r = 0.40-0.91, p < 0.05) and the plasma and skin (r = 0.24-0.75, p < 0.05) concentrations of most micronutrients were significant in all subjects, suggesting that the status of these micronutrients in the BMC and skin may be estimated from their plasma concentrations; 2) the correlations between the diet and plasma/tissue concentrations of the micronutrients were generally not as strong as the plasma-tissue relationships; the diet-plasma and diet-tissue relationships of the carotenoids were particularly poor in the smokers; 3) the plasma and tissue concentrations of most micronutrients were lower in smokers than in nonsmokers and higher in vitamin supplement users than in nonsupplement users; the differences remained significant after adjustment for age, gender, and diet intake estimates; 4) among the seven carotenoids examined, lycopene was unique, because its concentration was not lower in smokers or higher in supplement users but was inversely associated with age.

Factors prognostic for survival in patients with malignant melanoma spread to the regional lymph nodes.

To establish clinical and histologic determinants of survival, records of all UCLA patients with resectable melanoma metastatic to the lymph nodes during the years 1954-1976 were reviewed. These 150 patients were treated first with wide excision, lymphadenectomy, and with radiation/chemotherapy and/or additional surgery only if further recurrences developed. None received adjuvant immunotherapy or chemotherapy. In 97 of 139 patients with identified primary tumors, slides of the primary lesion were reviewed. Putative prognostic factors included age, sex, parity, site of primary tumor, presence of satellitosis, clinical status of nodes, histologic characteristics of primary lesion (Clarks level, thickness of tumor, presence/width of ulceration, and number of mitoses/HPF), time from biopsy of primary tumor to lymphadenectomy, and number of positive nodes. kaplan-Meier estimates of survival for the entire group at one, two, five, and ten years were 73, 55, 37, and 33%, respectively. Median follow-up period of survivors was four years. Univariate analyses using the log-rank test showed that thickness of the primary lesion (p less than 0.001), width of ulceration (p = 0.003), absence of ulceration (p = 0.024), and number of positive nodes (p = 0,.033) were prognostic for survival. In multivariate analysis by the Cox procedure, thickness of the primary (p = 0.001) and number of melanoma-containing nodes (p = 0.043) were prognostic for survival. Location of the primary tumor became marginally significant (p = 0.12) in the multrivariate model. These findings demonstrate the prognostic importance of characteristics of both the primary lesion and extent of regional dissemination. Future prospective randomized trials for (adjuvant) therapy of Stage II melanoma should be stratified by these variables.