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.

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.

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.

Prevalence and nature of orofacial and dental problems in family medicine.

OBJECTIVE: To determine the prevalence and nature of orofacial and dental problems in 2 family medicine practices. DESIGN: Prospective, cross-sectional analysis of consecutive patient visits. SETTING: Urban and rural family medicine practices. PATIENTS AND PARTICIPANTS: Four hundred seventy-two patients between age 10 and 86 years. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Prevalence and nature of patient visits to family medicine practices that were either initiated by problems in the region of the oral cavity or that involved questions raised by the patient concerning oral or perioral sites. RESULTS: Twenty-one patients (4.5%) of 472 met the inclusion criteria, 16 (76%) of whom had an oral problem as the primary or secondary reason for their visit. Perioral pain and mucosal ulcerations were the most common problems, and gingival tissue was the most common location. Almost two thirds of these patients had bacterial, fungal, or viral infections. Regarding treatment, 13 (62%) of these patients received advice, 10 (48%) received prescriptions, and 3 (15%) were referred to a dentist or another medical specialist. CONCLUSIONS: Oral and perioral problems are common in the practice of family medicine, which suggests the desirability for specific oral medicine topics in the training and continuing education of primary care physicians. Arch Fam Med. 2000;9:1009-1012

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.

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.

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.

Racial differences in symptoms and complications in adults with type 2 diabetes mellitus.

OBJECTIVE: To compare the frequency of common symptoms and complications between African- and white American adults with type 2 diabetes mellitus in a primary care setting, and to examine associations of these conditions with glycemic control. DESIGN: Three hundred and four adults with type 2 diabetes participated in this cross-sectional analysis; 142 of whom were African-Americans. Patients were recruited from a family practice ambulatory care unit and a community health center. RESULTS: Both male and female African-Americans had higher mean diastolic blood pressure and poorer metabolic control than their white counterparts. After adjustment for diabetes duration, glycosylated hemoglobin and diastolic blood pressure, African-American females were significantly more likely to experience constipation and hypertension but less likely to experience chest pain, claudication, peripheral neuropathy or have peripheral vascular disease. Among male subjects, African-Americans were significantly more likely to experience blurred vision and hypertension but less likely to have peripheral atherosclerotic disease. Poor glycemic control was more strongly associated with the occurrence of common diabetic symptoms in African-American subjects. CONCLUSIONS: Both African- and white Americans with type 2 diabetes are likely to experience a wide variety of symptoms and vascular complications. African-American subjects appear more likely than whites to experience symptoms related to glycemic control but less likely to have, or experience symptoms and complications of, cardiovascular disease. That nearly half of these subjects seen in a primary care setting had microalbuminuria suggests that vascular complications are likely to be present in the majority of adults with type 2 diabetes, even in these currently asymptomatic. These findings may have implications for screening and preventive strategies for the treatment of this disease.

Body fat, fat distribution, and psychosocial factors among patients with Type 2 diabetes mellitus.

Diabetes, a risk factor for cardiovascular disease, requires lifestyle modifications (diet, exercise, weight loss). The relations between body mass index, waist-hip ratio (WHR), and psychosocial indicators, such as affect and stress, among 302 diabetic patients from a clinic and a neighborhood health center were analyzed. Data included stress and mood scale responses, body size (height, weight, and WHR) and potential confounders (physical activity, energy intake, and diabetes duration). In univariate analyses, body mass index was positively associated with stress and inversely associated with positive affect only in women. Multiple regression analyses indicated that stress was associated with body mass index and negative mood was associated with the WHR. The findings suggested that stress and affect may be important correlates of body fat among women with Type 2 diabetes, leading to more complications. Healthcare providers can help women with Type 2 diabetes lose weight and lower the risk of cardiovascular disease by recognizing and helping them deal with these psychosocial issues.

Hyperinsulinemia in hypertension: associations with race, abdominal obesity, and hyperlipidemia.

OBJECTIVE: To determine the relative contributions of race, sex, abdominal obesity, and hyperlipidemia to the development of hyperinsulinemia among patients with hypertension. DESIGN: Cross-sectional survey. SETTING: A large family practice ambulatory care unit in Winston-Salem, NC. PATIENTS: One hundred and forty adult patients with essential hypertension (systolic blood pressure > or = 160 mm Hg or diastolic blood pressure at or above 90 mm Hg on 2 or more occasions) or who were receiving antihypertensive treatment. MAIN OUTCOME MEASURES: Fasting insulin, lipid, and glucose levels; glycosylated hemoglobin; waist-hip ratio; and resting blood pressure. METHODS: Among 4 patient subgroups (hypertension alone; hypertension and abdominal obesity; hypertension and hyperlipidemia; and hypertension, abdominal obesity, and hyperlipidemia) logistic regression analysis was used to determine correlates of elevated fasting insulin levels. RESULTS: Controlling for age and blood pressure, black males had the highest fasting insulin levels (135 +/- 70 pmol/L [18.8 +/- 9.6 microU/mL] and 265 pmol/L [37.0 +/- 0.0 microU/mL] [mean +/- SD] for obese and nonobese black males, respectively); nonobese white males had the lowest fasting insulin levels (23 +/- 22 pmol/L [3.2 +/- 3.0 microU/mL]). Multivariate logistic regression indicated that the addition of abdominal obesity or hyperlipidemia to pure hypertension more than doubled the risk of hyperinsulinemia (adjusted odds ratio, 2.69; 95% confidence interval, 1.04-6.89; and adjusted odds ratio, 2.62; 95% confidence interval, 0.37-8.6, respectively). The combination of abdominal obesity and hyperlipidemia exerted additive effects among patients with hypertension for elevated insulin levels (adjusted odds ratio, 5.1; 95% CI, 1.59-16.4). CONCLUSIONS: Race, sex, abdominal obesity, and hyperlipidemia interact to produce increases in fasting insulin levels. This knowledge may help physicians prevent sequelae from hyperinsulinemia syndrome among their patients with hypertension.

Health education to increase screening for cervical cancer among Lumbee Indian women in North Carolina.

Although age-adjusted mortality rates from cancer among Native-Americans are generally lower than for the US population as a whole, cervical cancer mortality rates are higher. This report presents results from a National Cancer Institute-funded health education program conducted among the Lumbee tribe in North Carolina that was designed to increase the proportion of women, age 18 and older, who receive Pap smears to screen for cervical cancer. The Solomon Four Group research design was used for this project. Participants were selected at random from the enrollment records of the Lumbee tribe and data collection was carried out during face-to-face interviews. The health education program was provided one-on-one in women's homes by a trained lay health educator and included verbal, print and videotape information. A total of 979 women were enrolled in the study, and 125 were lost to follow-up between the pre-test and post-test. Women who received the education program were found to be more likely to have knowledge of the Pap smear and to report a Pap smear in the past year at the post-test than those in the control group, regardless of whether they received the pre-test interview, P < 0.05. Women most likely to respond to the education program were also likely to have reported that they receive an annual physical examination. Women with better knowledge of the Pap smear tended to have more education, higher income and greater identification with Native-American culture than those with less knowledge. We conclude that the health education program was associated with greater knowledge about cervical cancer prevention and higher proportions of Lumbee women obtaining Pap smears in the past year.

Correlates of abnormal urinary albumin excretion rates among primary care patients with essential hypertension.

BACKGROUND: The excretion of small amounts of urinary protein, known as microalbuminuria, among patients with essential hypertension is associated with increased mortality from cardiovascular disease and, possibly, future renal decline. Correlates of microalbuminuria among primary care patients with essential hypertension, however, have not been well described. METHODS: One hundred forty patients enrolled in a large family practice ambulatory care center who had essential hypertension but not diabetes participated in a screening project to document cardiovascular and renal diseases in this population. Patients underwent a brief physical examination and submitted blood and urine samples for analysis. RESULTS: Twenty-five percent of patients had elevated urinary albumin excretion (UAE) rates, defined as greater than 30 micrograms/min. Patients with elevated UAE rates did not differ from patients without elevated UAE rates by age, race, sex, duration of hypertension, or type of antihypertensive medications used (if any). Although no patients had abnormally elevated glycosylated hemoglobin, after controlling for age and duration of hypertension, elevated UAE rates were significantly related to higher mean glycosylated hemoglobin levels (odds ratio [OR] = 3.06, 95 percent confidence interval [CI] = 1.11 to 8.41) and to current smoking (OR = 3.14, 95 percent CI = 1.09 to 9.04). CONCLUSIONS: These data are the first in a primary care population to show a threefold increase in risk for elevated UAE rates among patients with essential hypertension who currently smoke or who have above-average glycosylated hemoglobin levels. Although cross-sectional in nature, these data can also point toward subgroups of hypertensive patients who have a worse cardiovascular prognosis.

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.

Sleep history is neglected diagnostic information. Challenges for primary care physicians.

Sleep problems are treatable causes of morbidity and mortality, but little is known about how often the history fundamental to diagnosis is obtained. We recorded the frequency of sleep histories during encounters with simulated patients by 20 experienced primary care practitioners, 23 uninstructed medical interns, and 22 interns who had previous instruction about sleep disorders. Sleep histories were uncommonly obtained by uninstructed physicians (0% of practitioners, 13% of interns), but trained interns more often (81.8%) asked about sleep. If sleep problems are to be prioritized, major changes in physician education and behaviors are essential. Focused instruction about sleep influences physician behavior.

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.

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.