Subpopulation targeting of pyruvate dehydrogenase and GLUT1 decouples metabolic heterogeneity during collective cancer cell invasion.

Phenotypic heterogeneity exists within collectively invading packs of tumor cells, suggesting that cellular subtypes cooperate to drive invasion and metastasis. Here, we take a chemical biology approach to probe cell:cell cooperation within the collective invasion pack. These data reveal metabolic heterogeneity within invasive chains, in which leader cells preferentially utilize mitochondrial respiration and trailing follower cells rely on elevated glucose uptake. We define a pyruvate dehydrogenase (PDH) dependency in leader cells that can be therapeutically exploited with the mitochondria-targeting compound alexidine dihydrochloride. In contrast, follower cells highly express glucose transporter 1 (GLUT1), which sustains an elevated level of glucose uptake required to maintain proliferation. Co-targeting of both leader and follower cells with PDH and GLUT1 inhibitors, respectively, inhibits cell growth and collective invasion. Taken together, our work reveals metabolic heterogeneity within the lung cancer collective invasion pack and provides rationale for co-targeting PDH and GLUT1 to inhibit collective invasion.

Image-guided genomics of phenotypically heterogeneous populations reveals vascular signalling during symbiotic collective cancer invasion.

Phenotypic heterogeneity is widely observed in cancer cell populations. Here, to probe this heterogeneity, we developed an image-guided genomics technique termed spatiotemporal genomic and cellular analysis (SaGA) that allows for precise selection and amplification of living and rare cells. SaGA was used on collectively invading 3D cancer cell packs to create purified leader and follower cell lines. The leader cell cultures are phenotypically stable and highly invasive in contrast to follower cultures, which show phenotypic plasticity over time and minimally invade in a sheet-like pattern. Genomic and molecular interrogation reveals an atypical VEGF-based vasculogenesis signalling that facilitates recruitment of follower cells but not for leader cell motility itself, which instead utilizes focal adhesion kinase-fibronectin signalling. While leader cells provide an escape mechanism for followers, follower cells in turn provide leaders with increased growth and survival. These data support a symbiotic model of collective invasion where phenotypically distinct cell types cooperate to promote their escape.

Effectiveness of health education to increase screening for cervical cancer among eastern-band Cherokee Indian women in North Carolina.

BACKGROUND: The North Carolina Native American Cervical Cancer Prevention Project was a 5-year, National Cancer Institute-funded trial of health education designed to increase screening for cervical cancer among Native-American women in North Carolina. PURPOSE: This study was conducted to evaluate the effectiveness of this education program in the Eastern-Band Cherokee target population. METHODS: Cherokee tribal lands were mapped and all households (N = 2223) were listed to ensure maximum coverage of the eligible population (women, aged 18 years and older, who were enrolled tribal members). Eligible women were identified by the use of a brief questionnaire administered to an adult member of the household. Of the 1279 households with eligible women, 1020 (79.8%) agreed to participate. The intervention was an individualized health education program delivered by female Cherokee lay health educators. The participants were randomly assigned to receive or not to receive the intervention (i.e., to program and control groups, respectively) by use of the Solomon Four-Group design. Data were collected in face-to-face interviews conducted in the participant's home. Of the 996 women who were ultimately enrolled, 540 were randomly assigned to receive a pretest (preintervention) interview that involved administration of a 96-item questionnaire designed to collect data on knowledge, intentions, and behaviors related to cervical cancer; of these 540 women, 263 were randomly assigned to receive the education program. The remaining 456 women did not receive the pretest, but 218 were randomly assigned to receive the education program. Six months after receiving the education program, the women in all four groups were administered a post-test that was identical to the pretest. Logistic regression was used to assess the effects of the pretest and the educational program. All P values resulted from two-sided statistical tests. RESULTS: Eight hundred and fifteen (81.8%) of the 996 participants completed the post-test interview. The remaining 181 women who were lost to follow-up were evenly distributed among the four study groups. At the post-test, 282 (73.2%) of the 385 women who received the education program reported having had a Pap smear following the intervention, compared with 275 (64%) of the 430 control subjects. Women who received the education program were more likely to answer all knowledge items correctly on the post-test (odds ratio [OR] = 2.18, 95% confidence interval [CI] = 1.08-4.39) and to report having obtained a Pap smear in the past year (OR = 2.06, 95% CI = 1.14-3.72) than women in the control groups. CONCLUSION: Women who received the education program exhibited a greater knowledge about cervical cancer prevention and were more likely to have reported having had a Pap smear within the past year than women who did not receive the program.

Racial differences in lipid and lipoprotein levels in diabetes.

Racial differences in plasma lipid and lipoprotein levels were investigated in 145 patients with non-insulin-dependent diabetes mellitus (NIDDM). Black men had higher high-density lipoprotein (HDL) cholesterol levels, lower triglyceride levels, and an improved atherogenic index compared with white men. Premenopausal black women were also found to have higher HDL cholesterol levels, lower triglyceride levels, and a lower atherogenic index than their white counterparts. Adjustment for age, waist to hip ratio (WHR), hemoglobin A1c (HbA1c), and physical activity did not eliminate the significant differences found. There were no racial differences found regarding total and low-density lipoprotein (LDL) cholesterol. Metabolic control as measured by HbA1c was significantly correlated with the triglyceride level in black women. These data confirm that racial differences exist in plasma lipid levels among patients with NIDDM.

Quality of diabetes care among low-income patients in North Carolina.

BACKGROUND: Diabetes is a leading cause of death and disability, disproportionately affecting most ethnic minority groups, people of low socioeconomic status, the elderly, and people in rural areas. Despite the availability of evidence-based clinical recommendations, barriers exist in the delivery of appropriate diabetes care. The purpose of this study is to examine the level of diabetes care among low-income populations in North Carolina. METHODS: Baseline medical record abstractions were performed (N=429) on diabetic patients at 11 agencies serving low-income populations (community health centers, free clinics, primary care clinics, and public health clinics) across the state participating in a quality-of-diabetes-care initiative. Data were collected for four process (measurement of glycosylated hemoglobin and lipids, dilated eye examination, nephropathy assessment) and two outcome (glycemic and lipid control) measures based on the Diabetes Quality Improvement Project (DQIP) and the Health Plan Employer Data and Information Set (HEDIS), and three additional indicators (blood pressure measurement and control, and lower limb assessment). Compliance rates to individual measures were calculated overall and by demographic and health characteristics. RESULTS: Diabetes care compliance rates ranged from 77.9% for blood pressure testing to 3.3% for complete foot examinations. Differences in care were observed by age, insulin use, and prevalent disease. CONCLUSIONS: This study indicates low compliance with diabetes care guidelines in underserved North Carolinians, and inconsistency of care according to some demographic and health characteristics. These results stress the need for quality improvement initiatives that enhance the level of care received by patients with diabetes, particularly those most vulnerable to diabetes and its complications.

Four factors of clinical decision making: a teaching model.

For more than 25 years, Bowman Gray has been placing fourth-year students in community-based primary care settings. Upon their return to campus, the students participate in a seminar in which they discuss issues raised by their primary care experiences. In these seminars, the students have consistently identified four key factors of clinical decision making that reflect current trends in medicine: quality, cost, ethics, and legal concerns. These factors influence the practice of medicine and affect the health care of individuals and communities. The authors discuss the nature of these factors and the physician's role and obligation in clinical decision making. Physicians have two responsibilities in this decision-making model: to be the primary advocates for quality health care and to ensure that there be a balance among the weights given the four factors. While physicians must take the lead in ensuring quality care, they must work in partnership with patients, payers, lawyers, ethicists, and the government. It is up to those responsible for the education of future physicians to see that students understand all the factors of clinical decision making and how best to balance them to fulfill their future obligations to patients.

The Association of Teachers of Preventive Medicine's recommendations for postgraduate education in prevention.

The Guide to Clinical Preventive Services, prepared in 1989 by the U.S. Preventive Services Task Force, assesses the effectiveness of 169 types of preventive interventions. In 1990, the Association of Teachers of Preventive Medicine formed a panel to review the guide and recommend ways it could be used to enhance both undergraduate and postgraduate medical education. This paper outlines the panel's recommendations of the types of knowledge and attitudes on which postgraduate medical education in prevention should be built. Detailed recommendations are presented, based on the summary findings of the guide, for residency education in prevention. Implementation of these recommendations will integrate preventive services into the continuum of medical care. These recommendations are presented to achieve the goal of educating physicians to approach the total patient, putting the patient's health rather than the disease process in the forefront of primary medical care.

Evaluations by three graduating classes of a required community health project.

The authors analyzed seniors' evaluations of the first three years of an intensive community health project at the Bowman Gray School of Medicine of Wake Forest University in 1988-89, 1989-90, and 1990-91. The project was designed to provide a public health perspective by having the students select, study, and propose solutions to a community health problem. Of 285 seniors, 240 (84%) completed evaluation questionnaires, using a five-point scale. The students' perceptions of the value of the project became steadily more favorable with each subsequent class; the classes of 1990 and 1991 rated the value of the project as being greater than that of most other experiences in their medical education. The project was more positively evaluated by the 106 responding students (44%) who planned to enter primary care specialties. The students who invested more time in the project also perceived its value to be greater.

Effects of Terazosin on Glycemic Control, Cholesterol, and Microalbuminuria in Patients with Non--Insulin-Dependent Diabetes Mellitus and Hypertension.

The use of antihypertensive agents that have positive or neutral effects on blood sugar, lipid profiles, and microalbuminuria can be important clinical treatment for patients with diabetes. We evaluated the effects of both terazosin, a selective alpha-one-adrenergic blocker, and hydrochlorothiazide (HCTZ), a standard mild antihypertensive agent, on glycemic control, urinary albumin excretion rate overnight total cholesterol, and other parameters in non--insulin-dependent diabetes mellitus (NIDDM) patients. A randomized, placebo-controlled, cross-over design was implemented in 25 patients. Over an 8-week treatment period fasting plasma glucose (FPG) and glycosylated hemoglobin (GHgb) improved in the terazosin group. Post-treatment FPG was 200 plus minus 85 and 187 plus minus 71 for patients who received HCTZ and terazosin, respectively. Although the GHgb improved significantly for terazosin patients (12.2 plus minus 5.8 for HCTZ versus 10.7 plus minus 4.6 for terazosin, p = 0.03), microalbuminuria did not improve in terazosin patients in this pilot study. A larger randomized study with tighter blood pressure end points are needed to assess fully the impact of terazosin on micoroalbuminuria and overall glycemic control in the NIDDM patient.

Changes in diabetic urinary transferrin excretion after moderate exercise.

Microalbuminuria following submaximal exercise testing has been proposed for detecting renal abnormalities in diabetic patients. We compared urinary transferrin and albumin excretion between eight adults with insulin dependent diabetes mellitus and eight nondiabetic controls without microalbuminuria before and after a standardized exercise challenge of only moderate intensity for 20 min. Both groups were similar for age, sex, and METs expended during treadmill walking. Urinary excretion ratios of transferrin (UTER) and albumin (UAER) did not significantly increase for nondiabetic subjects. After exercise, UTER increased on average 207% in diabetic subjects (P = 0.009) and UAER increased 209% (P = 0.046). The percent increase in UTER appears to be a function of workload intensity, while the percent increase in UAER appears less dependent on the duration of exercise. A standardized treadmill challenge of moderate intensity easily differentiated changes in urinary transferrin excretion ratios between diabetic and nondiabetic subjects. Measuring transferrin excretion may be a more sensitive parameter than albumin in studies using urinary protein excretion as a response to a provocative exercise challenge.

Association of gender with symptoms and complications in type II diabetes mellitus.

Females with Type II diabetes appear more likely than males to experience symptoms and vascular complications related to their disease.

Association between exercise and other preventive health behaviors among diabetics.

Two hundred and seventy patients were studied to investigate the cross sectional association between exercise and other preventive health behaviors in a diabetic population. Patients included both insulin and noninsulin dependent diabetics and were recruited from the Family Practice and Pediatrics Clinics at Bowman Gray School of Medicine. During screening, patients underwent a physical examination as well as completing a survey to assess exercise and health behavior habits. Three exercise groups were compared: (a) patients who expended more than 600 kilocalories per week during exercise, (b) patients who expended 600 kilocalories or less, and (c) patients who did not exercise. The mean body weights of both exercise groups were found to be less than the nonexercise group, and the heavy exercise group also had a lower mean body mass index. Heavy exercisers reported greater caloric intakes than both moderate and nonexercisers. There were no differences found concerning the composition of their diets among groups. The heavy exercise group reported wearing their seatbelts a greater percentage of the time and visited the dentist more often compared with the sedentary group. There were no significant differences found among exercise groups concerning blood sugar monitoring, alcohol consumption, smoking, or in obtaining periodic health examinations. It was concluded that exercise was associated with several, but not a majority, of other healthful behaviors in a population of diabetics.

Microtransferrinuria and microalbuminuria: enhanced immunoassay.

An enhanced-sensitivity immunoassay for urinary microtransferrin and microalbumin was devised based on protein precipitation with cold trichloroacetic acid followed by dissolution of the precipitate in a small volume of phosphate buffer. Samples can be concentrated 10-fold by this method while at the same time removing many of the chromogens present in urine. Concentrated samples were assayed by immunoturbidity and radial immunodiffusion. The average recovery for urinary microtransferrin was 82 percent and for microalbumin 91 percent. The reference range for 80 normal adults for microtransferrinuria and microalbuminuria is 0 to 0.9 and 5 to 32 mg per g creatinine, respectively. The same method can be used for the assay of other proteins such as B2-microglobulin in the urine or the cerebrospinal fluid.

Measurement feasability of advanced glycated end-products from skin samples after antioxidant vitamin supplementation in patients with type 2 diabetes.

PURPOSE: To determine the feasibility of measuring advanced glycated end-products (AGEs)from skin samples and to evaluate the effects of a combination of vitamins E and C on measures of glycemic control and AGEs in patients with type 2 diabetes mellitus. METHODS: Twenty-two patients with type 2 diabetes from a Family Medicine clinic were randomly assigned to receive a daily dietary supplement containing either a combination of 400 mg of vitamin E and 500 mg of vitamin C or matching placebo for a period of one year. AGEs were measured from skin samples taken from the buttock. RESULTS: Nineteen subjects completed this one-year pilot study. There were no major problems found in measuring AGEs from skin samples taken from the butttock. Neither the treatment or placebo group had significant changes in glycemic control, protein glycosylation or AGEs. DISCUSSION: Skin samples taken from the buttock area may be an appropriate site for the determination of AGE levels as this procedure appeared to be well-tolerated. Daily vitamin E and C supplementation did not improve measures of glycemic control or AGE levels in this small sample of patients with type 2 diabetes. Because antioxidant vitamins are inexpensive and free of side effects, additional research using a variety of antioxidant vitamin combinations and dosing regimens is needed.

Smoking status and psychosocial variables in type 1 diabetes mellitus.

While depression, anxiety, and negative affect are associated with smoking and smoking cessation outcomes in healthy individuals, these associations have not been established in smokers with chronic diseases such as diabetes mellitus, a condition which greatly increases cardiovascular disease risk. Other psychosocial variables such as stress and locus of control may also be associated with smoking but are seldom reported. We examined stress, affect, and locus of control by smoking status in patients with type 1 diabetes mellitus. Results indicated that current smokers reported significantly higher levels of perceived stress, a more negative affect, and higher powerful others locus of control compared with nonsmokers. These findings indicate that those patients who have diabetes and who smoke are at greater risk for depressive symptoms. This knowledge may aid clinicians in their attempts to help these patients quit smoking.

Abnormal urinary protein excretion in African Americans with type 2 diabetes mellitus.

The purpose of this investigation was to determine the prevalence and correlates of abnormal urinary albumin excretion and to examine the possible additive effects of cardiovascular risk factors on urinary albumin excretion in African Americans with type 2 diabetes mellitus. One hundred fifty-one African-American subjects who met WHO criteria for type 2 diabetes were included in this cross-sectional analysis. Subjects were identified through computerized medical records from a family medicine clinic and a community health center. Urinary albumin excretion ratios (UAER) were determined from overnight samples. The prevalence of abnormal urinary protein excretion was 51%. Of those with abnormal protein excretion, 36% had microalbuminuria and 15% had macroalbuminuria. Diabetes duration, waist to hip ratio, blood pressure, and total- and LDL cholesterol were significantly higher in subjects with macroalbuminuria. Regression analysis indicated that mean arterial blood pressure, diabetes duration and total cholesterol were independently associated with UAER. Mean UAER significantly increased with the addition of one or more syndrome X risk factors to pure diabetes. Our results indicate that African Americans with type 2 diabetes mellitus have a high prevalence of abnormal urinary protein excretion, which is associated with a clustering of additional cardiovascular risk factors. The fact that this increased risk was associated with hypertension indicates that screening for albuminuria in this population is essential and that a majority of African Americans with diabetes may be at risk for developing cardiovascular complications.

Using a family practice preceptorship to teach clinical epidemiology.

Because physicians in training can benefit from an epidemiological approach to primary care practice, research, and education, educators are turning their attention to better methods and settings to teach preventive and epidemiological principles while cultivating an attitude for clinical research. This report describes the development of a clinical epidemiological problem studied in the context of a one-week family practice preceptorship. The project was designed to study the possible association between obesity and hypertension and to familiarize students with a common study design. Data from 393 case control pairs produced results of the same magnitude as that documented by formal, carefully controlled research studies. Students participated with dedication and excitement in the clinical application of relevant and practical epidemiologic and biostatistical tools in a clinical setting. Often difficult to comprehend concepts of interaction and confounding were clearly demonstrated using data derived from actual patients encountered during the preceptorship experience.

A family practice residency curriculum in critical appraisal of the medical literature.

This paper reports a five-year experience with a comprehensive curriculum for teaching critical appraisal and practical research skills to family practice residents. The curriculum includes a seminar series in research and medical practice and simulated research projects. Rationale, methods, format, and evaluations of the curriculum are presented. The curriculum prepared graduates to critically review research studies in the professional literature and translate valid conclusions into medical practice. Residents were able to identify potential areas of research interest and acquired additional skills that encouraged continuing education and professional growth.

Using standardized patient instructors to teach health promotion interviewing skills.

BACKGROUND: Medical students report knowledge, but inadequate skills, in health promotion and disease prevention (HPDP) technology. An established methodology using standardized patient instructors (SPIs) was adapted and tested for effectiveness in teaching HPDP. METHODS: Thirteen lay persons were trained and given profiles showing high cardiovascular risks. During their family medicine clerkship, 104 students engaged in one-to-one exercises with the SPIs. Half of these sessions were spent in the doctor-patient interview; in the other half, the SPI gave specific feedback using a validated scale. Encounters were videotaped. RESULTS: The students rated the SPI feedback as the program's most valuable aspect and the videotaping as the least valuable. The SPI feedback was rated valuable by 90%-96% of the students. The students also reported that the skills acquired were likely to be used, and they had learned "much" or "very much." As a group, students' self-assessments did not differ from the SPIs' assessments of the students. CONCLUSION: Lay SPIs are a powerful educational tool.

Women's cardiovascular health.

Significant coronary artery disease is uncommon in premenopausal women, but it is the leading cause of death among postmenopausal women. This article briefly discusses atherosclerotic disease in women, including the effects of menopause and estrogen, the role of cholesterol, hypertension, exercise and weight control, smoking cessation, and diabetes mellitus. The role of screening and testing for coronary artery disease and carotid artery stenosis is discussed. Recommendations for prevention and patient education are included in each section.