Levetiracetam rectal administration in healthy dogs.

BACKGROUND: Levetiracetam is used to manage status epilepticus (SE) and cluster seizures (CS) in humans. The drug might be absorbed after rectal administration and could offer a practical adjunct to rectal administration of diazepam in managing SE and CS. HYPOTHESIS: Levetiracetam is rapidly absorbed after rectal administration in dogs and maintains target serum concentrations for at least 9 hours. ANIMALS: Six healthy privately owned dogs between 2 and 6 years of age and weighing 10-20 kg. METHODS: Levetiracetam (40 mg/kg) was administered rectally and blood samples were obtained immediately before (time zero) and at 10, 20, 40, 60, 90, 180, 360, and 540 minutes after drug administration. Dogs were observed for signs of adverse effects over a 24-hour period after drug administration. RESULTS: CLEV at 10 minutes was 15.3 ± 5.5 µg/mL (mean, SD) with concentrations in the target range (5-40 µg/mL) for all dogs throughout the sampling period. Cmax (36.0 ± 10.7 µg/mL) and Tmax (103 ± 31 minutes) values were calculated and 2 disparate groups were appreciated. Dogs with feces in the rectum at the time of drug administration had lower mean Cmax values (26.7 ± 3.4 µg/mL) compared with those without (45.2 ± 4.4 µg/mL). Mild sedation was observed between 60 and 90 minutes without other adverse effects noted. CONCLUSIONS AND CLINICAL IMPORTANCE: This study supports the use of rectally administered levetiracetam in future studies of clinical effectiveness in the management of epileptic dogs.

Threshold Amsler grid as a screening tool for asymptomatic patients on hydroxychloroquine therapy.

BACKGROUND/AIMS: Patients taking hydroxychloroquine (HCQ) are at risk of developing classic bull's eye maculopathy. Currently, the standard Amsler grid (AG) is one of the most useful methods to identify such lesions. However, AG is a suprathreshold target and may not detect relative central scotomas. The aim of this study was to determine if the threshold Amsler grid (TAG) test, which varies light transmission through two cross polarising filters, allows increased detection of scotomas caused by HCQ toxicity. METHODS: 56 rheumatological patients taking HCQ and 12 similar patients not taking HCQ were tested by AG, red Amsler grid (RAG), and TAG. RESULTS: No scotomas were observed in patients never treated with HCQ. Among patients who had been treated with HCQ, AG revealed scotomas in two of 56 (3.64%) patients; in contrast, six (10.7%) and 37 (66.1%) scotomas were identified by RAG and TAG testing respectively. Additionally, the average area of each scotoma detected by all three methods expanded from 34.5 square degrees of central field loss on AG testing to 71 square degrees on RAG and 117 on TAG. CONCLUSION: By decreasing the perceived luminance of the suprathreshold AG, TAG testing provides a novel alternative to detect shallow scotomas and areas of depressed retinal activity secondary to HCQ toxicity.

Ethnic differences in ovulatory function in nulliparous women.

African-American women have a long-standing approximately 20% higher breast cancer incidence rate than USA White women under age 40 while rates among Latinas are lower than those of Whites. The reasons for this are not clear, however they may be due to ethnic differences in circulating oestradiol and progesterone levels. In a cross-sectional study, we investigated whether anovulation frequency and circulating serum oestradiol and/or progesterone levels vary among normally cycling nulliparous African-American (n=60), Latina (n=112) and non-Latina White (n=69) women. Blood and urine specimens were collected over two menstrual cycles among healthy 17- to 34-year-old women. Frequency of anovulation was greater among White women (nine out of 63, 14.3%) than African-American women (four out of 56, 7.1%) or Latina women (seven out of 102, 6.9%), although these differences were not statistically significant. African-American women had 9.9% (P=0.26) higher follicular phase oestradiol concentrations than Latina women and 17.4% (P=0.13) higher levels than White women. African-American women also had considerably higher levels of luteal phase oestradiol (vs Latinas, +9.4%, P=0.14; vs Whites, +25.3%, P=0.003) and progesterone (vs Latinas, +15.4%, P=0.07; vs Whites, +36.4%, P=0.002). Latina women were also observed to have higher follicular oestradiol, and luteal oestradiol and progesterone levels than White women (follicular oestradiol: +6.8%, P=0.48; luteal oestradiol: +14.6%, P=0.04; luteal progesterone: +18.2%, P=0.06). These results suggest that exposure to endogenous steroid hormones may be greater for young African-American and Latina women than for Whites.

A randomized controlled trial using glycemic plus fetal ultrasound parameters versus glycemic parameters to determine insulin therapy in gestational diabetes with fasting hyperglycemia.

OBJECTIVE: To compare management based on maternal glycemic criteria with management based on relaxed glycemic criteria and fetal abdominal circumference (AC) measurements in order to select patients for insulin treatment of gestational diabetes mellitus (GDM) with fasting hyperglycemia. RESEARCH DESIGN AND METHODS: In a pilot study, 98 women with fasting plasma glucose (FPG) concentrations of 105-120 mg/dl were randomized. The standard group received insulin treatment. The experimental group received insulin if the AC, measured monthly, was > or =70th percentile and/or if any venous FPG measurement was >120 mg/dl. Power was projected to detect a 250-g difference in birth weights. RESULTS: Gestational ages, maternal glycemia, and AC percentiles were similar at randomization. After initiation of protocol, venous FPG (P = 0.003) and capillary blood glucose levels (P = 0.049) were significantly lower in the standard group. Birth weights (3,271 +/- 458 vs. 3,369 +/- 461 g), frequencies of birth weights >90th percentile (6.3 vs 8.3%), and neonatal morbidity (25 vs. 25%) did not differ significantly between the standard and experimental groups, respectively. The cesarean delivery rate was significantly lower (14.6 vs. 33.3%, P = 0.03) in the standard group; this difference was not explained by birth weights. In the experimental group, infants of women who did not receive insulin had lower birth weights than infants of mothers treated with insulin (3,180 +/- 425 vs. 3,482 +/- 451 g, P = 0.03). CONCLUSIONS: In women with GDM and fasting hyperglycemia, glucose plus fetal AC measurements identified pregnancies at low risk for macrosomia and resulted in the avoidance of insulin therapy in 38% of patients without increasing rates of neonatal morbidity.

Risk factors for penile cancer: results of a population-based case-control study in Los Angeles County (United States).

UNLABELLED: The etiology of penile cancer is poorly understood, with neonatal circumcision being one of the few recognized nondemographic risk factors. Multiple logistic regression was used to analyze interview data from 100 matched case-control pairs; cases of carcinoma in situ (CIS) and invasive carcinoma of the penis were analyzed separately as well as together. Phimosis was strongly associated with invasive carcinoma (adjusted odds ratio [OR] = 16; 95% confidence interval [CI] = 4.5-57) but not CIS (OR = 1.7; 95% CI = 0.32-7.8), and these associations persisted when the analyses were restricted to uncircumcised subjects. Neonatal circumcision was inversely associated with invasive carcinoma (OR = 0.41; 95% CI = 0.13-1.1) but not CIS, and the observed association with invasive carcinoma was weakened appreciably when the analysis was restricted to subjects with no history of phimosis (OR = 0.79; 95% CI = 0.29-2.6). Other factors positively associated with invasive carcinoma or CIS or both were injury to the penis, cigarette smoking, physical inactivity and, to a lesser extent, genital warts and other infections or inflammation of the penis. CONCLUSIONS: Although many effects were imprecisely estimated in this study, the protective effect of circumcision on invasive penile cancer appears to be mediated in large part by phimosis; furthermore, the effects of certain factors such as phimosis and circumcision appear to differ for CIS and invasive carcinoma.

Response of pancreatic beta-cells to improved insulin sensitivity in women at high risk for type 2 diabetes.

The purpose of this study was to examine the response of pancreatic beta-cells to changes in insulin sensitivity in women at high risk for type 2 diabetes. Oral glucose tolerance tests (OGTTs) and frequently sampled intravenous glucose tolerance tests (FSIGTs) were conducted on Latino women with impaired glucose tolerance and a history of gestational diabetes before and after 12 weeks of treatment with 400 mg/day troglitazone (n = 13) or placebo (n = 12). Insulin sensitivity was assessed by minimal model analysis, and beta-cell insulin release was assessed as acute insulin responses to glucose (AIRg) and tolbutamide (AIRt) during FSIGTs and as the 30-min incremental insulin response (30-min dINS) during OGTTs. Beta-cell compensation for insulin resistance was assessed as the product (disposition index) of minimal model insulin sensitivity and each of the 3 measures of beta-cell insulin release. In the placebo group, there was no significant change in insulin sensitivity or in any measure of insulin release, beta-cell compensation for insulin resistance, or glucose tolerance. Troglitazone treatment resulted in a significant increase in insulin sensitivity, as reported previously. In response, AIRg did not change significantly, so that the disposition index for AIRg increased significantly from baseline (P = 0.004) and compared with placebo (P = 0.02). AIRt (P = 0.001) and 30-min dINS (P = 0.02) fell with improved insulin sensitivity during troglitazone treatment, so that the disposition index for each of these measures of beta-cell function did not change significantly from baseline (P > 0.20) or compared with placebo (P > 0.3). Minimal model analysis revealed that 89% of the change from baseline in insulin sensitivity during troglitazone treatment was accounted for by lowered plasma insulin concentrations. Neither oral nor intravenous glucose tolerance changed significantly from baseline or compared with placebo during troglitazone treatment. The predominant response of beta-cells to improved insulin sensitivity in women at high risk for type 2 diabetes was a reduction in insulin release to maintain nearly constant glucose tolerance.

Antepartum predictors of the development of type 2 diabetes in Latino women 11-26 months after pregnancies complicated by gestational diabetes.

In this study, we sought to identify antepartum characteristics that predict the de novo development of diabetes 11-26 months after the index pregnancy in a carefully characterized cohort of women with gestational diabetes mellitus (GDM). Oral and frequently sampled intravenous glucose tolerance tests (OGTTs and FSIGTs), hyperinsulinemic-euglycemic clamps with labeled glucose, and body composition studies were performed on 91 islet cell antibody-negative Latino women with GDM during the third trimester of pregnancy. The women were documented to be diabetes-free within 6 months postpartum. Their diabetes status was ascertained again between 11 and 26 months postpartum. Logistic regression analysis was used to identify independent predictors of the development of diabetes within that interval. Fourteen of the women developed diabetes by World Health Organization criteria 11-26 months after delivery of the index pregnancy. Three antepartum variables were independent predictors of diabetes: the 1-h postchallenge plasma glucose concentration from the 100-g OGTT at which GDM was diagnosed (higher = increased risk; P = 0.003); an index of pancreatic beta-cell compensation for insulin resistance, defined as the product of the 30-min incremental plasma insulin:glucose ratio on a 75-g OGTT and the insulin sensitivity index from a hyperinsulinemic-euglycemic clamp (lower = increased risk, P = 0.009); and the basal glucose production rate after an overnight fast (higher = increased risk; P = 0.04). We conclude that postchallenge hyperglycemia, poor pancreatic beta-cell compensation for insulin resistance, and elevated endogenous glucose production during pregnancy precede the development of type 2 diabetes in young Latino women by at least 1-2 years.

Multiple metabolic defects during late pregnancy in women at high risk for type 2 diabetes.

Detailed metabolic studies were carried out to compare major regulatory steps in glucose metabolism in vivo between 25 normal pregnant Latino women without and 150 pregnant Latino women with gestational diabetes mellitus (GDM). The two groups were frequency-matched for age, BMI, and gestational age at testing in the third trimester. After an overnight fast, women with GDM had higher fasting plasma glucose (P = 0.0001) and immunoreactive insulin (P = 0.0003) concentrations and higher glucose production rates (P = 0.01) but lower glucose clearance rates (P = 0.001) compared with normal pregnant women. During steady-state hyperinsulinemia (approximately 600 pmol/l) and euglycemia (approximately 4.9 mmol/l), women with GDM had lower glucose clearance rates (P = 0.0001) but higher glucose production rates (P = 0.0001) and plasma free fatty acid (FFA) concentrations (P = 0.0002) than the normal women. These intergroup differences persisted when a subgroup of 116 women with GDM who were not diabetic < or = 6 months after pregnancy were used in the analysis. When all subjects were considered, there was a very close correlation between glucose production rates and plasma FFA concentrations throughout the glucose clamps in control (r = 0.996) and GDM (r = 0.995) groups. Slopes and intercepts of the relationships were nearly identical, suggesting that blunted suppression of FFA concentrations contributed to blunted suppression of glucose production in the GDM group. In addition to these defects in insulin action, women with GDM had a 67% impairment of pancreatic beta-cell compensation for insulin resistance compared with normal pregnant women. These results demonstrate that women with GDM have multiple defects in insulin action together with impaired compensation for insulin resistance. Our findings suggest that defects in the regulation of glucose clearance, glucose production, and plasma FFA concentrations, together with defects in pancreatic beta-cell function, precede the development of type 2 diabetes in these high-risk women.

Hormonal choices after gestational diabetes. Subsequent pregnancy, contraception, and hormone replacement.

The effects of subsequent states of excess hormone exposure, for example, subsequent pregnancy, hormonal contraception, and hormonal replacement therapy, on the development of diabetes in women with prior gestational diabetes were assessed. Current literature examining the effect of parity, hormonal contraception, and hormonal replacement therapy in healthy women and women with previous gestational diabetes and current diabetes was reviewed. Subsequent pregnancy in women with prior GDM appears to triple the risk of subsequent diabetes. Low-dose progestin and estrogen combination oral contraceptives do not appear to clinically increase the risk of diabetes. Hormonal replacement therapy appears to provide the greatest reduction in coronary artery disease to women at greatest risk, i.e., those who have developed diabetes. Careful follow-up and metabolic surveillance should be provided when prescribing hormonal contraception or replacement therapy. In women with prior gestational diabetes, exposure to repeat pregnancy poses a greater risk for subsequent diabetes than does either an exposure to low-dose progestin and estrogen combination oral contraceptives or to postmenopausal hormonal therapy, both of which do not appear to increase the risk of diabetes.

Utility of fetal measurements in the management of gestational diabetes mellitus.

The metabolic management of gestational diabetes mellitus (GDM) during pregnancy traditionally has focused on maintenance of circulating maternal glucose concentrations in all patients within a range that is associated with a low rate of perinatal morbidity, especially morbidity related to excessive fetal growth and macrosomia. Clinical data reviewed elsewhere in this supplement provide guidelines for glycemic targets that appear to eliminate the excess risk to the fetus. However, because only a minority of infants are at risk for perinatal morbidity over the range of glycemia generally encountered in patients with GDM, attainment of those strict glycemic targets in all women with GDM requires implementation of self-monitoring of glucose and exogenous insulin therapy in many pregnancies that are not at risk. In this article, we review management approaches that take into account not only maternal glycemia, but also fetal growth and metabolic parameters in selecting GDM pregnancies for intensive metabolic therapy. The approaches can reduce the number of women with mild GDM who require self-monitoring of glucose and/or exogenous insulin therapy, thereby providing the potential to improve cost-effectiveness of antepartum management of GDM.

Contraception and the risk of type 2 diabetes mellitus in Latina women with prior gestational diabetes mellitus.

CONTEXT: Effective contraception is essential in women with prior gestational diabetes mellitus (GDM) but should not increase their already substantial risk of developing type 2 diabetes. OBJECTIVE: To determine whether exposure to low-dose oral contraceptives increases the risk of developing type 2 diabetes mellitus in women with recent GDM. DESIGN: Retrospective cohort study of 904 Latinas with GDM who gave birth between January 1987 and March 1994, in whom postpartum diabetes was excluded at 4 to 16 weeks post partum. INTERVENTIONS: At their initial postpartum visit, 443 women selected a nonhormonal form of contraception, 383 received a low-dose, estrogen-progestin combination oral contraceptive (OC), and 78 breast-feeding women received the progestin-only OC. When breast-feeding ended, patients initially taking progestin-only OCs were switched to combination OCs. Patients were followed up periodically with oral glucose tolerance tests for up to 7 1/2 years. MAIN OUTCOME MEASURES: Person time was used to compute unadjusted average annual incidence rates of developing diabetes mellitus, as defined by the National Diabetes Data Group Criteria. Survival analysis was used to compute the unadjusted cumulative incidence rates and adjusted relative risks of diabetes mellitus. RESULTS: The unadjusted average annual incidence rates of type 2 diabetes mellitus were 8.7%, 10.4%, and 26.5%, respectively, for patients using nonhormonal forms of contraception, combination OCs, and progestin-only OCs. Cumulative incidence rates were virtually identical for patients with uninterrupted use of combination OCs and nonhormonal forms of contraception, but patients using progestin-only OCs developed diabetes mellitus more rapidly during the first 2 years of use. After adjustment for potential confounding factors, the use of progestin-only OCs almost tripled the risk of type 2 diabetes mellitus compared with equivalent use of low-dose combination OCs (adjusted relative risk, 2.87; 95% confidence interval, 1.57-5.27). The magnitude of this risk increased with duration of uninterrupted use. CONCLUSION: Progestin-only OCs were associated with an increased risk of diabetes in breast-feeding Latinas with recent GDM and probably should be prescribed with caution, if at all, in these women. Long-term use of low-dose combination OCs did not increase the risk of type 2 diabetes compared with use of nonhormonal contraception. Thus, combination OCs do not appear to increase the risk of diabetes in non-breast-feeding women with recent GDM.

Gestational diabetes: antepartum characteristics that predict postpartum glucose intolerance and type 2 diabetes in Latino women.

We examined antepartum clinical characteristics along with measures of glucose tolerance, insulin sensitivity, pancreatic beta-cell function, and body composition in Latino women with gestational diabetes mellitus (GDM) for their ability to predict type 2 diabetes or impaired glucose tolerance (IGT) within 6 months after delivery. A total of 122 islet cell antibody-negative women underwent oral and intravenous glucose tolerance tests (OGTT; IVGTT), hyperinsulinemic-euglycemic clamps, and measurement of body fat between 29 and 36 weeks' gestation and returned between 1 and 6 months postpartum for a 75-g OGTT. Logistic regression analysis was used to examine the relationship between antepartum variables and glucose tolerance status postpartum. At postpartum testing, 40% of the cohort had normal glucose tolerance, 50% had IGT, and 10% had diabetes by American Diabetes Association criteria. Independent antepartum predictors of postpartum diabetes were the 30-min incremental insulin:glucose ratio during a 75-g OGTT (P = 0.0002) and the total area under the diagnostic 100-g glucose tolerance curve (P = 0.003). Independent predictors of postpartum IGT were a low first-phase IVGTT insulin response (P = 0.0001), a diagnosis of GDM before 22 weeks' gestation (P = 0.003), and weight gain between prepregnancy and the postpartum examination (P = 0.03). All subjects had low insulin sensitivity during late pregnancy, but neither glucose clamp nor minimal model measures of insulin sensitivity in the 3rd trimester were associated with the risk of IGT or diabetes within 6 months' postpartum. These results highlight the importance of pancreatic beta-cell dysfunction, detectable under conditions of marked insulin resistance in late pregnancy, to predict abnormalities of glucose tolerance soon after delivery in pregnancies complicated by GDM. Moreover, the association of postpartum IGT with weight gain and an early gestational age at diagnosis of GDM suggests a role for chronic insulin resistance in mediating hyperglycemia outside the 3rd trimester in women with such a beta-cell defect.

TRIPOD (TRoglitazone In the Prevention Of Diabetes): a randomized, placebo-controlled trial of troglitazone in women with prior gestational diabetes mellitus.

The TRoglitazone In the Prevention Of Diabetes (TRIPOD) trial is a single-center, randomized, placebo-controlled, double-masked study. The primary aim of the TRIPOD trial is to test the hypothesis that chronic administration of troglitazone to nondiabetic women with prior gestational diabetes mellitus (GDM) will improve whole-body insulin sensitivity and reduce the incidence of non-insulin-dependent diabetes (NIDDM). Because troglitazone is already known to lower blood glucose concentrations in persons who have developed NIDDM, an additional aim of the project will be to determine whether early intervention with troglitazone will achieve better final glycemic control than can be achieved by later intervention. In addition, since troglitazone treatment is expected to improve insulin sensitivity and may prevent or delay a decline in glucose tolerance, we also plan to determine whether long-term troglitazone treatment alters the development or progression of atherosclerosis. In this article we describe the experiment's design, the study's endpoints and methods for determining those endpoints, methods for assessing quality of life, and proposed methods for statistical analyses. The unique two-phase study design of the TRIPOD trial will permit testing not only of the biological question about reversal of insulin resistance and prevention of diabetes, but also of the clinical question about whether early intervention is superior to late intervention. Results from this trial will have an important impact on the monitoring and treatment of patients at high risk for NIDDM.

Wood-dust exposures and cancer of the colon.

Previous studies of workers exposed to wood dusts have shown a decreased risk of cancer of the colon in these workers. However, none of these studies adequately controlled for potential confounders, such as physical activity, diet, and family history of colorectal cancer. The purpose of this case-control study was to evaluate the association between exposure to wood dust and risk for colon cancer after adjusting for potential confounders. Four hundred nineteen male cases of adenocarcinoma of the colon, identified from the Los Angeles County Cancer Surveillance Program, were individually matched to neighborhood controls based on gender and date of birth. Exposure to wood dust was associated with reduced risk of colon cancer that was partially masked before adjustment for confounders, and was limited to workers with frequent exposures that had begun at least 30 years before diagnosis [unadjusted and adjusted ORs, respectively, to exposures 5+ times a week beginning 30+ years before diagnosis = 0.63 (95% CI 0.36-1.13) and 0.39 (95% CI 0.20-0.77)]. This study provides additional evidence that heavy exposure to wood dusts may be associated with reduced risk of colon cancer in males after adjustment for other known causes of colon cancer.

Estrogen-progestin replacement therapy and endometrial cancer.

BACKGROUND: It has been known for more than 20 years that estrogen replacement therapy substantially increases a woman's risk of developing endometrial cancer. To reduce this increased risk, progestins have been added to estrogen replacement therapy for between 5 and 15 days (usually 7 or 10 days) per "month" in a sequential fashion (sequential estrogen-progestin replacement therapy) or with each dose of estrogen replacement therapy (continuous combined replacement therapy). At the present time, however, little is known about the effects of varying the number of days that progestin is used in sequential estrogen-progestin replacement therapy. PURPOSE: We sought to determine the effects of sequential estrogen-progestin replacement therapy and continuous combined replacement therapy on a woman's risk of developing endometrial cancer. METHODS: A population-based, case-control study of 833 case subjects and 791 control subjects was conducted. Women were postmenopausal, white, and aged 50-74 years when first diagnosed with invasive endometrial cancer or were aged 50-74 years at the matching date for control subjects. All subjects were interviewed in person with the aid of a month-by-month calendar. Relative risks were estimated by odds ratios (ORs); ORs were adjusted simultaneously for the different forms of hormone replacement therapy and for the known endometrial cancer risk factors. RESULTS: The adjusted OR was 2.17 (95% confidence interval [CI] = 1.91-2.47) per 5 years of estrogen replacement therapy use (based on 422 users among the case subjects and 262 users among the control subjects). For women who received sequential estrogen-progestin replacement therapy with the progestin given for less than 10 days (effectively 7 days) per month, the adjusted OR was only slightly reduced to 1.87 (95% CI = 1.32-2.65) per 5 years of use (74 case subjects and 47 control subjects). However, when progestin was given for 10 or more days (effectively 10 days), there was essentially no increased risk (adjusted OR = 1.07 per 5 years of use; 95% CI = 0.82-1.41) (79 case subjects and 88 control subjects). Continuous combined replacement therapy was also associated with essentially no increased risk (adjusted OR = 1.07 per 5 years of use; 95% CI = 0.80-1.43) (94 case subjects and 81 control subjects). CONCLUSIONS: The progestin in sequential estrogen-progestin replacement therapy needs to be given for at least 10 days to block effectively any increased risk of endometrial cancer. Continuous combined estrogen-progestin therapy is similarly effective. Neither regimen reduces a woman's underlying risk of endometrial cancer. The sharp distinction between the effects of less than 10 days (effectively 7 days) and 10 or more days (effectively 10 days) of progestin use in sequential estrogen-progestin replacement therapy suggests that the extent of endometrial sloughing may play a critical role in determining endometrial cancer risk.

The relationship between dietary fat intake and risk of colorectal cancer: evidence from the combined analysis of 13 case-control studies.

The objective of this study was to examine the effects of the intake of dietary fat upon colorectal cancer risk in a combined analysis of data from 13 case-control studies previously conducted in populations with differing colorectal cancer rates and dietary practices. Original data records for 5,287 cases of colorectal cancer and 10,470 controls were combined. Logistic regression analysis was used to estimate odds ratios (OR) for intakes of total energy, total fat and its components, and cholesterol. Positive associations with energy intake were observed for 11 of the 13 studies. However, there was little, if any, evidence of any energy-independent effect of either total fat with ORs of 1.00, 0.95, 1.01, 1.02, and 0.92 for quintiles of residuals of total fat intake (P trend = 0.67) or for saturated fat with ORs of 1.00, 1.08, 1.06, 1.21, and 1.06 (P trend = 0.39). The analysis suggests that, among these case-control studies, there is no energy-independent association between dietary fat intake and risk of colorectal cancer. It also suggests that simple substitution of fat by other sources of calories is unlikely to reduce meaningfully the risk of colorectal cancer.

Sexual, reproductive, and other risk factors for adenocarcinoma of the cervix: results from a population-based case-control study (California, United States)

The incidence of adenocarcinoma of the cervix increased steadily in young women in the United States between the early 1970s and the mid-1980s. Despite this increase, little is known about the etiology of this cancer, although a role for risk factors for both squamous cell carcinoma of the cervix and endometrial adenocarcinoma has been suggested. Incident cases of adenocarcinoma of the cervix diagnosed in women born after 1935 (ages 42 to 56 at diagnosis) were identified from the Los Angeles (California) County Cancer Surveillance Program (LACCSP). Data from personal interviews with 195 cases and 386 controls (matched on age, race, and neighborhood) were analyzed. Compared with women in the highest categories of education and income, women in the lowest categories had a 2.5 and 3.1-fold elevated risk of adenocarcinoma of the cervix. Number of sexual partners, especially before age 20, was strongly predictive of risk (odds ratio = 5.6, 95 percent confidence interval = 1.4-22.0 for 10 or more compared with no partners before age 20). Smoking was not associated significantly with risk. Weight gain and long-term use of oral contraceptives increased risk, while long-term diaphragm use was protective. This study suggests that both sexual and hormonal factors are important etiologic factors for adenocarcinoma of the cervix.

Psychosocial aspects of work and the risk of colon cancer.

Because experimental and epidemiologic evidence indicates that the colon is particularly sensitive to stress, and because work conditions contribute to an individual's stress experience, we examined the relation of both job stress (defined in terms of perceived job demand and job control) and job social support to the risk of colon cancer in a large population-based case-control study (744 pairs) in Los Angeles. Controls were individually matched to cases on age, sex, and neighborhood. For jobs held 5 years before, participants in the lowest tertile of job control had a slightly increased risk when compared with those in the highest tertile (multivariate adjusted odds ratio = 1.3; 95% confidence interval = 1.0-1.6), but there was no evidence of a trend. Lower levels of job social support were associated with a decreased risk of colon cancer (odds ratio = 0.6 for lowest vs highest tertile; 95% confidence interval = 0.4-1.0). We saw no effect for job demand. The effect of job control appeared to be independent of the level of job demand. We found no consistent pattern of effects associated with jobs held 30 years before. These findings indicate that if job stress, as reflected by perceived job demand or control, is a determinant of colon cancer, it is probably not a strong one.

Long-term diabetogenic effect of single pregnancy in women with previous gestational diabetes mellitus.

BACKGROUND: Pregnancy is associated with marked insulin resistance that seems to have little, if any, impact on the long-term risk of non-insulin-dependent diabetes mellitus (NIDDM) in the general population. The aim of this study was to test whether pregnancy would alter the risk of NIDDM among women with a high prevalence of pancreatic beta-cell dysfunction, as indicated by a history of gestational diabetes mellitus. METHODS: The cohort consisted of 666 Latino women with gestational diabetes attending a high-risk family planning clinic. They were followed up for up to 7.5 years, during which time they were weighed and underwent an oral glucose-tolerance test annually. The effect of an additional pregnancy, and of other risk factors for diabetes, was examined. FINDINGS: 87 (13%) of the women completed an additional pregnancy. 80 of those women did not have NIDDM immediately after the additional pregnancy and their subsequent annual incidence rate of NIDDM was 30.9% (95% CI 12.7-49.1), more than 2.5 times the annual incidence rate of NIDDM in the cohort overall (11.9%; 95% CI 10.0-13.8). Proportional hazards regression analysis using the presence or absence of an additional pregnancy as a time-dependent variable confirmed that an additional pregnancy increased the rate ratio of NIDDM to 3.34 (95% CI 1.80-6.19), compared with women without an additional pregnancy after adjustment for other potential diabetes risk factors during the index pregnancy (antepartum oral glucose tolerance, highest fasting glucose, gestational age at diagnosis of gestational diabetes) and during follow-up (postpartum body mass index [BMI], and glucose tolerance, weight change, breast feeding, and months of contraceptive use). Weight gain also was independently associated with an increased risk of NIDDM; the rate ratio was 1.95 (95% CI 1.63-2.33) for each 10 lb (4.5 kg) gained during follow-up after adjustment for the additional pregnancy and the other potential risk factors. INTERPRETATION: The study showed that a single pregnancy, independent of the well-known effect of weight gain, accelerated the development of NIDDM in a group of women with a high prevalence of pancreatic beta-cell dysfunction. This finding implies that episodes of insulin resistance may contribute to the decline in beta-cell function that leads to NIDDM in many high-risk individuals.

Computer-assisted rescreening of clinically important false negative cervical smears using the PAPNET Testing System.

OBJECTIVE: To investigate the efficacy of the PAPNET Testing System and its ability to detect significant areas on clinically important false negative gynecologic smears. STUDY DESIGN: Sixty-two gynecologic smears that had been obtained from women studied in a previous case-control investigation, completed in 1987, and had originally been interpreted as negative were rescreened by two independent, blind cytotechnologist-cytopathologist teams. Twenty-nine of these "negative" smears were from 19 women who had been subsequently diagnosed with invasive squamous cell carcinoma and had self-reported a history of only negative gynecologic smears. Thirty-three smears were from 33 control women who did not develop cervical cancer. One team, at the University of Southern California (USC), manually rescreened the smears as part of the original study. The other team, at the University of California at Los Angeles (UCLA), recently used the PAPNET Testing System to rescreen the same smears. This computer-assisted system utilizes neural network technology to recognize and select potentially abnormal cell scenes on a conventionally prepared gynecologic smear. The PAPNET-selected scenes are displayed for review by trained cytologists, who ultimately diagnose the smear. RESULTS: Manual reevaluation of the smears by the USC team in 1987 resulted in the reclassification of 9 of the 29 case smears (31%) and 2 of 33 control smears (6%) as class II to V (atypical squamous cells of undetermined significance to invasive carcinoma). Using the PAPNET System to scan and review the same smears, the cytotechnologist at UCLA referred 24 case smears to the cytopathologist, who ultimately reclassified 12 of the 29 case smears (41%) and 5 of the 33 control smears (15%) as abnormal. CONCLUSION: This study supports the use of the PAPNET System as an effective, routine rescreener for the detection of clinically significant false negative gynecologic smears.