Abstract

Background

Impairments in physical performance increase sharply with age. Low serum 25-hydroxyvitamin D (25-OHD) levels may be a modifiable risk factor for physical performance decline.

Methods

Five hundred thirty-two participants in the Women's Health Initiative Clinical Trial (WHI CT) were among a 25% randomly selected subsample of women who participated in performance-based measures of physical performance at baseline, year 1, year 3, and year 6. A physical performance summary score was derived from three tests: timed walk, chair-stand, and grip strength. Levels of 25-OHD were measured at baseline. We used the generalized estimating equations (GEE) method to examine repeated measures of physical performance as a function of follow-up time since baseline according to 25-OHD concentration.

Results

In 6 years of follow-up, participants with serum 25OHD ≥75 nmol/L had significantly higher scores for physical performance (β=2.64, 95% confidence interval [CI] 0.90-4.39) compared with the reference category (<35 nmol/L) after adjustment for age, chronic conditions, body mass index (BMI), race/ethnicity, time spent walking outside, trial arm, clinic latitude, and season of blood draw. However, the rate of decline in physical performance did not differ by level of 25OHD.

Conclusions

Higher baseline serum 25-OHD was associated with better physical performance but did not reduce decline in physical performance over the 6-year period.

Listeners rapidly adapt to many forms of degraded speech. What level of information drives this adaptation, however, remains unresolved. The current study exposed listeners to sinewave-vocoded speech in one of three languages, which manipulated the type of information shared between the training languages (German, Mandarin, or English) and the testing language (English) in an audio-visual (AV) or an audio plus still frames modality (A+Stills). Three control groups were included to assess procedural learning effects. After training, listeners’ perception of novel sinewave-vocoded English sentences was tested. Listeners exposed to German-AV materials performed equivalently to listeners exposed to English AV or A+Stills materials and significantly better than two control groups. The Mandarin groups and German-A+Stills group showed an intermediate level of performance. These results suggest that full lexical access is not absolutely necessary for adaptation to degraded speech, but providing AV-training in a language that is similar phonetically to the testing language can facilitate adaptation.

Although studies exploring relationships between obesity and cognitive impairment in the elderly are conflicting, literature suggests that overweight and obesity may be protective against cognitive impairment and dementia in older women. We examine the associations between changes in weight and waist circumference with global and domain-specific cognitive function in a large, well-defined cohort of 2283 older, post-menopausal women (age 65-79) prospectively followed through the Women's Health Initiative (WHI) Study of Cognitive Aging (WHISCA). We assessed the associations between changes in weight and waist circumference collected up to 5 years prior to WHISCA enrollment and mean levels of global and domain-specific cognitive performance across an average of 5.4 years of subsequent follow-up. There was a lack of associations between weight and cognition in women who remained stable or gained weight. The only significant relationships observed were in association with weight loss (p≤0.05), most likely signaling incipient disease. Moreover, cognition was not related to changes in waist circumference. Relationships were largely independent of initial BMI, self-reported caloric intake or dieting. The lack of associations between weight gain and cognition in women is consistent with the existent literature.

Abstract

Objective

To test the hypothesis of a significant association between resting heart rate (RHR) and coronary artery calcium (CAC).

Methods

This is a cross-sectional study of a subset of women enrolled in the estrogen-alone clinical trial of the Women's Health Initiative (WHI). We used a longitudinal study that enrolled 998 postmenopausal women with a history of hysterectomy between the ages of 50 and 59 at enrollment at 40 different clinical centers. RHR was measured at enrollment and throughout the study, and CAC was determined approximately 7 years after the baseline clinic visit.

Results

The mean (standard deviation [SD]) age was 55 (2.8) years. With adjustment for age and ethnicity, a 10-unit increment in RHR was significantly associated with CAC (SD 1.18, 95% confidence interval [CI] 1.01-1.38), but this was no longer significant after adjustment for body mass index (BMI), income, education, dyslipidemia, diabetes, smoking, and hypertension (SD 1.06, 95% CI 0.90-1.25). In a fully adjusted multivariable model, however, there was a significant interaction (p=0.03) between baseline RHR and systolic blood pressure (SBP) for the presence of any CAC. Compared to women with an RHR < 80 beats per minute (BPM) and an SBP < 140 mm Hg, those who had an RHR ≥ 80 BPM and an SBP ≥ 140 mm Hg had 2.66-fold higher odds (1.08-6.57) for the presence of any CAC.

Conclusions

Compared to those with normal BP and RHR, postmenopausal, hysterectomized women with an elevated SBP and RHR have a significantly higher odds for the presence of calcified coronary artery disease.

OBJECTIVE

To examine whether lower serum levels of serum 25-hydroxyvitamin (OH) D [25(OH)D] are associated with increased risk of developing type 2 diabetes.

RESEARCH DESIGN AND METHODS

A post hoc analysis of three nested case-control studies of fractures, colon cancer, and breast cancer that measured serum 25(OH)D levels in women participating in the Women’s Health Initiative (WHI) Clinical Trials and Observational Study who were free of prevalent diabetes at baseline. Diabetes was defined as self-report of physician diagnosis or receiving insulin or oral hypoglycemic medication. We used inverse probability weighting to make the study population representative of the WHI population as a whole. Weighted logistic regression models compared 25(OH)D levels (divided into quartiles, clinical cut points [<50, 50–<75, ≥75 nmol/L], or as a continuous variable) using the distribution of control subjects and adjusted for multiple confounding factors.

RESULTS

Of 5,140 women (mean age 66 years) followed for an average of 7.3 years, 317 (6.2%) developed diabetes. Regardless of the cut points used or as a continuous variable, 25(OH)D levels were not associated with diabetes incidence in either age or fully adjusted models. Nor was any relationship found between 25(OH)D and incident diabetes when evaluated by strata of BMI, race/ethnicity, or randomization status in the Calcium Vitamin D trial.

CONCLUSIONS

Lower serum 25(OH)D levels were not associated with increased risk of developing type 2 diabetes in this racially and ethnically diverse population of postmenopausal women.

Objective

We assessed whether vasomotor symptoms (VMS) were associated with coronary artery calcium (CAC) and how hormone therapy may influence this association.

Methods

Subjects were a subset of women aged 50 to 59 and a history of hysterectomy that enrolled in the Women’s Health Initiative (WHI) clinical trial of estrogen alone and underwent a computed tomography scan of the chest at the end of the trial to determine CAC. Participants provided information about VMS (hot flashes and/or night sweats), as well as HT use, on self-administered questionnaires at trial baseline.

Results

The sample consisted of 918 women with a mean (SD) age of 55.1 (2.8) years at WHI randomization and 64.8 (2.9) years at CAC ascertainment. The prevalence of a CAC score > 0 was 46%, while the prevalence of a CAC score ≥ 10 and > 100 was 39 and 19%, respectively. At randomization, 77% reported a history of any VMS at any time prior to or at enrollment in the WHI while 20% reported any VMS only present at enrollment. Compared to those without a history of any VMS and after adjustment for potential confounders, a history of any VMS at any time up to and including WHI enrollment was associated with a significantly reduced odds for CAC > 0 (Odds Ratio 0.66, 95% CI 0.45 – 0.98). Moreover, as duration of HT increased the inverse association between any VMS and CAC moved toward the null.

Conclusion

A history of any VMS was significantly associated with a reduced odds for CAC independent of traditional CVD risk factors and other relevant covariates. This association appears to be influenced by duration of hormone therapy.

OBJECTIVE

An International Expert Committee (IEC) and the American Diabetes Association (ADA) proposed diagnostic criteria for diabetes and pre-diabetes based on A1C levels. We hypothesized that screening for diabetes and pre-diabetes with A1C measurements would differ from using oral glucose tolerance tests (OGTT).

RESEARCH DESIGN AND METHODS

We compared pre-diabetes, dysglycemia (diabetes or pre-diabetes), and diabetes identified by the proposed criteria (A1C ≥6.5% for diabetes and 6.0–6.4% [IEC] or 5.7–6.4% [ADA] for high risk/pre-diabetes) with standard OGTT diagnoses in three datasets. Non-Hispanic white or black adults without known diabetes who had A1C and 75-g OGTT measurements were included from the prospective Screening for Impaired Glucose Tolerance study (n = 1,581), and from the National Health and Nutrition Examination Survey (NHANES) III (n = 2014), and NHANES 2005–2006 (n = 1,111).

RESULTS

OGTTs revealed pre-diabetes in 35.8% and diabetes in 5.2% of combined study subjects. A1C provided receiver operating characteristic (ROC) curve areas for diabetes of 0.79–0.83, but ROC curve areas were ≤0.70 for dysglycemia or pre-diabetes. The proposed criteria missed 70% of individuals with diabetes, 71–84% with dysglycemia, and 82–94% with pre-diabetes. Compared with the IEC criteria, the ADA criteria for pre-diabetes resulted in fewer false-negative and more false-positive result. There were also racial differences, with false-positive results being more common in black subjects and false-negative results being more common in white subjects. With use of NHANES 2005–2006 data, ∼5.9 million non-Hispanic U.S. adults with unrecognized diabetes and 43–52 million with pre-diabetes would be missed by screening with A1C.

CONCLUSIONS

The proposed A1C diagnostic criteria are insensitive and racially discrepant for screening, missing most Americans with undiagnosed diabetes and pre-diabetes.

Background

Recent studies have linked plasma markers of inflammation and endothelial dysfunction to type 2 diabetes mellitus (DM) development. However, the utility of these novel biomarkers for type 2 DM risk prediction remains uncertain.

Methods

The Women’s Health Initiative Observational Study (WHIOS), a prospective cohort, and a nested case-control study within the WHIOS of 1584 incident type 2 DM cases and 2198 matched controls were used to evaluate the utility of plasma markers of inflammation and endothelial dysfunction for type 2 DM risk prediction. Between September 1994 and December 1998, 93 676 women aged 50 to 79 years were enrolled in the WHIOS. Fasting plasma levels of glucose, insulin, white blood cells, tumor necrosis factor receptor 2, interleukin 6, high-sensitivity C-reactive protein, E-selectin, soluble intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 were measured using blood samples collected at baseline. A series of prediction models including traditional risk factors and novel plasma markers were evaluated on the basis of global model fit, model discrimination, net reclassification improvement, and positive and negative predictive values.

Results

Although white blood cell count and levels of interleukin 6, high-sensitivity C-reactive protein, and soluble intercellular adhesion molecule 1 significantly enhanced model fit, none of the inflammatory and endothelial dysfunction markers improved the ability of model discrimination (area under the receiver operating characteristic curve, 0.93 vs 0.93), net reclassification, or predictive values (positive, 0.22 vs 0.24; negative, 0.99 vs 0.99 [using 15% 6-year type 2 DM risk as the cutoff]) compared with traditional risk factors. Similar results were obtained in ethnic-specific analyses.

Conclusion

Beyond traditional risk factors, measurement of plasma markers of systemic inflammation and endothelial dysfunction contribute relatively little additional value in clinical type 2 DM risk prediction in a multiethnic cohort of postmenopausal women.

Background

In order to improve the delivery of health services for chronic medical conditions in our methadone clinic, we added an onsite health screening and brief health counseling to the treatment plans for patients receiving methadone maintenance treatment at the Atlanta Veterans Affairs Medical Center (VAMC). We then conducted a follow up retrospective chart review to assess whether this intervention improved health outcome for those patients.

Methods

We reviewed the charts of one hundred and two patients who received treatment at Atlanta VAMC methadone clinic between 2002 and 2008. We sought to determine whether our increased health education and screening intervention was associated with improved: 1) Improved drug addiction outcome (as measured by comparing percentage of opiate and cocaine positive drug screens from admission to most recent). 2) Basic health screening, (as measured by the patient's compliance with primary care physicians (PCP) appointments and current smoking status). 3) Management of co-occurring medical conditions (as measured by levels of LDL cholesterol, hemoglobin A1c, and systolic blood pressure (SBP). 4) Presence of QTc prolongation (difference in QTc between baseline and most recent EKG).

Results

Illicit drug use (opiate and cocaine) markedly decreased in patients overall. The effect was more robust for those successfully “retained” (n=55, p<0.0001) in treatment, compared to those who “dropped out” (n=40, p=0.05) of treatment. Compliance with PCP appointments was high (82% and 88% before and after the onsite intervention, respectively) for “retained” patients. LDL cholesterol level was within normal range for all patients. A1c improved by 40% after the onsite intervention as reflected by the decreased percentage of patients with A1c > 7 % from before to after the intervention (90% vs. 50%, p=0.05). However, the prevalence of uncontrolled hypertension did not significantly improve after the onsite intervention (38% vs. 28%, p=0.34). As might be expected with MMT, the prevalence of QTc prolongation actually increased from 399 m sec. (+/- 92) to 439 msec. (+/- 22) after the onsite intervention (p=0.003).

Conclusions

Our retrospective study supports the previous literature that methadone maintenance therapy is effective in reducing illicit drug use. Although patients with history of heroin dependence and in methadone maintenance treatment are at increased risk for chronic medical conditions like hepatitis C and diabetes, there are minimal federal guidelines for medical care, except than a physical exam upon admission, and basic screening for some infectious diseases e.g. HIV and Hepatitis C for those patients. Our study demonstrated the need for and potential benefit of enhancing the delivery of health promotion services for chronic medical conditions in methadone maintained patients. Improving management of hepatitis C, diabetes, hypertension, and other related conditions, in this high risk, difficult-to-treat, and underserved population may reduce their morbidity and premature mortality.

OBJECTIVE

The economic costs of hyperglycemia are substantial. Early detection would allow management to prevent or delay development of diabetes and diabetes-related complications. We investigated the economic justification for screening for pre-diabetes/diabetes.

RESEARCH DESIGN AND METHODS

We projected health system and societal costs over 3 years for 1,259 adults, comparing costs associated with five opportunistic screening tests. All subjects had measurements taken of random plasma and capillary glucose (RPG and RCG), A1C, and plasma and capillary glucose 1 h after a 50 g oral glucose challenge test without prior fasting (GCT-pl and GCT-cap), and a subsequent diagnostic 75 g oral glucose tolerance test (OGTT).

RESULTS

Assuming 70% specificity screening cutoffs, Medicare costs for testing, retail costs for generic metformin, and costs for false negatives as 10% of reported costs associated with pre-diabetes/diabetes, health system costs over 3 years for the different screening tests would be GCT-pl $180,635; GCT-cap $182,980; RPG $182,780; RCG $186,090; and A1C $192,261; all lower than costs for no screening, which would be $205,966. Under varying assumptions, projected health system costs for screening and treatment with metformin or lifestyle modification would be less than costs for no screening as long as disease prevalence is at least 70% of that of our population and false-negative costs are at least 10% of disease costs. Societal costs would equal or exceed costs of no screening depending on treatment type.

CONCLUSIONS

Screening appears to be cost-saving compared to no screening from a health system perspective, and potentially cost-neutral from a societal perspective. These data suggest that strong consideration should be given to screening—with preventive management—and that use of GCTs may be cost-effective.

Objectives. Determine outcome of the 2005 appropriateness use criteria (AUC) for SPECT in a diverse population of patients and physicians. Background. AUC for SPECT were the first cardiology document to identify 52 clinical indications for imaging, 49 of them for stress SPECT. AUC have been proposed as cornerstone of responsible use of perfusion imaging. Methods. 585 consecutive patients undergoing SPECT were evaluated prospectively. Appropriateness was examined for demographic variables, clinical variables, and for physician and patient subgroups. Combined end-point of total mortality, cardiac revascularization, and cardiac admissions at 1 year post SPECT was evaluated. Results. SPECT indications were: appropriate, 63%; uncertain, 20%; inappropriate, 14%; not assigned, 3%. Most appropriate SPECT were observed in patients with known coronary disease (72%), chest pain syndrome (89%), high pre-test likelihood of disease (100%), men (70%), inpatients (72%), and cardiovascular physicians' referrals (69%). End-point was reached in 53 patients (97.4% follow up). Unadjusted event rates were: appropriate (12%), uncertain (7.1%), inappropriate (2.4%) SPECT (P = .01). Conclusion. Appropriateness of SPECT differs in subgroups of patients and physicians. Clinically significant outcomes occur more frequently in the appropriate stress SPECT group. Focused efforts are need for outpatients, asymptomatic patients, women, and non-cardiovascular physicians.

Objective

Associations between dietary glycemic load (GL) and cardiovascular disease (CVD) risk factors, including plasma lipoprotein/lipid levels, blood pressure (BP), and glucose metabolism factors, in the Women's Health Initiative Observational Study were examined.

Methods

A random sample of 878 Observational Study participants (postmenopausal women age 50 to 79 years) with baseline blood measures (647 White, 104 Black, 127 Hispanic) was included. Dietary GL was estimated from baseline food frequency questionnaires, which assessed dietary intake over the previous three months. At the baseline visit, participants completed demographic and health habit questionnaires, fasting blood samples were collected, anthropometric measurements were completed, and BP was assessed.

Results

In all participants combined, GL was inversely associated with high-density lipoprotein (HDL) cholesterol (P for trend = 0.004) and positively associated with log10-transformed triglycerides (P = 0.008). While there were no statistically significant interactions of race/ethnicity with associations between GL and CVD risk factors, stratified results were suggestive, showing that GL was positively associated with total cholesterol (P = 0.018) and low-density lipoprotein (LDL) cholesterol (P = 0.038) in Hispanics. In Whites, there was a trend of reduced HDL cholesterol with higher GL (P = 0.003), while GL was positively associated with log10-transformed triglycerides (P = 0.015). Associations between GL and HDL cholesterol and GL and triglycerides also varied by BMI, although the interactions were not statistically significant.

Conclusions

Among these generally healthy postmenopausal women, GL was associated with HDL cholesterol and triglycerides. Suggestive effects of race/ethnicity and BMI on these associations need to be confirmed in larger studies.

OBJECTIVE

Eliminating health disparities is a national priority, but progress has been difficult because of racial/ethnic differences in insurance coverage and access to health care. We investigated whether there were differences in diabetes care in the Veterans Administration (VA), where health care access should be relatively uniform.

RESEARCH DESIGN AND METHODS

A1C and plasma glucose were compared before/after diagnosis of diabetes.

RESULTS

Data were available for 1,456 black and 2,624 white veterans who met criteria for consistent primary care. Over 4–5 years before and after diagnosis, blacks had similar glucose and ∼0.2% higher A1C levels than whites, and A1C differences could be attributed to glucose-independent associations between race and A1C. Blacks and whites also had comparable intervals between diagnostic-level hyperglycemia and diagnosis and between diagnosis and drug initiation. However, A1C was higher in blacks at the time of diagnosis (7.8 vs. 7.1%) and at initiation of pharmacotherapy (8.5 vs. 7.8%) (both P < 0.001). Differences in A1C at diagnosis and drug initiation were too large to be explained by differences in age, sex, BMI, and glucose-independent associations between race and A1C.

CONCLUSIONS

In the VA, glucose levels are generally comparable in blacks and whites except at the times of diagnosis and initiation of pharmacotherapy, when glucose levels are higher in blacks. While understanding the basis for such residual disparities may be important to improve the health of racial/ethnic minorities in the U.S., a health care system with structure and organization similar to that in the VA may also contribute importantly to relieving disparities in health.

Resolution of Type-2 diabetes mellitus (DM) after weight loss surgery is well documented, but the mechanism is elusive. We evaluated the glucose-insulin metabolism of patients undergoing a Roux-en-Y gastric bypass (RYGB) using the intravenous glucose tolerance test (IVGTT) and compared it with patients who underwent laparoscopic adjustable gastric band (AB) placement. Thirty-one female patients (age range, 20 to 50 years; body mass index, 47.2 kg/m2) underwent RYGB. Nine female patients underwent AB placement and served as control subjects. All patients underwent IVGTT at baseline and 1 month and 6 months after surgery. Thirteen patients undergoing RYGB and one patient undergoing AB exhibited impaired glucose tolerance defined by the American Diabetes Association. By 6 months post surgery, diabetes was resolved in all but one patient undergoing RYGB and none of the patients undergoing AB. Patients with diabetes undergoing demonstrated increased insulin secretion and β-cell responsiveness 1 month after surgery and continued this trend up to 6 months, whereas none of the patients undergoing AB had changes in β-cell function. Both patients undergoing RYGB and those undergoing AB demonstrated significant weight loss (34.6 and 35.0 kg/m2, respectively) and improved insulin sensitivity at 6 months. RYGB ameliorates DM resolution in two phases: 1) early augmentation of beta cell function at 1 month; and 2) attenuation of peripheral insulin resistance at 6 months. Patients undergoing AB only exhibited reduction in peripheral insulin resistance at 6 months but no changes in insulin secretion.

OBJECTIVE

To determine the proportion of the American population who would merit metformin treatment, according to recent American Diabetes Association (ADA) consensus panel recommendations to prevent or delay the development of diabetes.

RESEARCH DESIGN AND METHODS

Risk factors were evaluated in 1,581 Screening for Impaired Glucose Tolerance (SIGT), 2,014 Third National Health and Nutrition Examination Survey (NHANES III), and 1,111 National Health and Nutrition Examination Survey 2005–2006 (NHANES 2005–2006) subjects, who were non-Hispanic white and black, without known diabetes. Criteria for consideration of metformin included the presence of both impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), with ≥1 additional diabetes risk factor: age <60 years, BMI ≥35 kg/m2, family history of diabetes, elevated triglycerides, reduced HDL cholesterol, hypertension, or A1C >6.0%.

RESULTS

Isolated IFG, isolated IGT, and IFG and IGT were found in 18.0, 7.2, and 8.2% of SIGT; 22.3, 6.4, and 9.4% of NHANES III; and 21.8, 5.0, and 9.0% of NHANES 2005–2006 subjects, respectively. In SIGT, NHANES III, and NHANES 2005–2006, criteria for metformin consideration were met in 99, 96, and 96% of those with IFG and IGT; 31, 29, and 28% of all those with IFG; and 53, 57, and 62% of all those with IGT (8.1, 9.1, and 8.7% of all subjects), respectively.

CONCLUSIONS

More than 96% of individuals with both IFG and IGT are likely to meet ADA consensus criteria for consideration of metformin. Because >28% of all those with IFG met the criteria, providers should perform oral glucose tolerance tests to find concomitant IGT in all patients with IFG. To the extent that our findings are representative of the U.S. population, ∼1 in 12 adults has a combination of pre-diabetes and risk factors that may justify consideration of metformin treatment for diabetes prevention.

Objective

To estimate the frequency of depressive symptoms and selected psychiatric disorders in the Women’s Health Initiative Memory Study (WHIMS) cohort and related them to cognitive syndromes.

Design

WHIMS was a randomized, double-blinded, placebo-controlled prevention clinical trial examining whether opposed and unopposed hormone therapy reduced the risk of dementia in healthy postmenopausal women. Participants scoring below a designated cutpoint on a cognitive screener received a comprehensive neuropsychiatric workup and adjudicated outcome of no cognitive impairment, mild cognitive impairment, or probable dementia.

Participants

Seven thousand four hundred seventy-nine WHIMS participants between age 65 and 79 years and free of dementia at the time of enrollment in WHIMS. Five hundred twenty-one unique participants contributed complete data required for these analyses.

Measures

Depressive symptoms were measured with the 15-item Geriatric Depression Scale and the presence of selected psychiatric disorders (major depression, generalized anxiety, and panic and alcohol abuse) was made using the PRIME-MD.

Results

The 18% of women had at least one psychiatric disorder with depression being the most common (16%) followed by general anxiety or panic (6%) and alcohol abuse (1%). Depression and the presence of a psychiatric disorder were associated with impaired cognitive status. Participants having a psychiatric disorder were more than twice as likely to be diagnosed with cognitive impairment as those with no psychiatric disorder (odds ratio = 2.06, 95% confidence interval = 1.17–3.60). Older age, white race, and diabetes were also associated with cognitive impairment.

Conclusion

The frequency of a psychiatric disorder is associated with poorer cognitive functioning among older women enrolled in WHIMS. That approximately one in five women had a probable psychiatric disorder, most typically depression, highlights the need for greater detection and treatment efforts in this population.

Myotonic dystrophy (DM1), the most common muscular dystrophy in adults, is caused by an expanded (CTG)n tract in the 3′ UTR of the gene encoding myotonic dystrophy protein kinase (DMPK)1, which results in nuclear entrapment of the ‘toxic’ mutant RNA and interacting RNA-binding proteins (such as MBNL1) in ribonuclear inclusions2. It is unclear if therapy aimed at eliminating the toxin would be beneficial. To address this, we generated transgenic mice expressing the DMPK 3′ UTR as part of an inducible RNA transcript encoding green fluorescent protein (GFP). We were surprised to find that mice overexpressing a normal DMPK 3′ UTR mRNA reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, histopathology and RNA splicing defects in the absence of detectable nuclear inclusions. However, we observed increased levels of CUG-binding protein (CUG-BP1) in skeletal muscle, as seen in individuals with DM1. Notably, these effects were reversible in both mature skeletal and cardiac muscles by silencing transgene expression. These results represent the first in vivo proof of principle for a therapeutic strategy for treatment of myotonic dystrophy by ablating or silencing expression of the toxic RNA molecules.

Purpose

We conducted the first phase 0 clinical trial in oncology of a therapeutic agent under the Exploratory Investigational New Drug Guidance of the US Food and Drug Administration. It was a first-in-human study of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in patients with advanced malignancies.

Patients and Methods

ABT-888 was administered as a single oral dose of 10, 25, or 50 mg to determine the dose range and time course over which ABT-888 inhibits PARP activity in tumor samples and peripheral blood mononuclear cells, and to evaluate ABT-888 pharmacokinetics. Blood samples and tumor biopsies were obtained pre- and postdrug administration for evaluation of PARP activity and pharmacokinetics. A novel statistical approach was developed and utilized to study pharmacodynamic modulation as the primary end point for trials of limited sample size.

Results

Thirteen patients with advanced malignancies received the study drug; nine patients underwent paired tumor biopsies. ABT-888 demonstrated good oral bioavailability and was well tolerated. Statistically significant inhibition of poly (ADP-ribose) levels was observed in tumor biopsies and peripheral blood mononuclear cells at the 25-mg and 50-mg dose levels.

Conclusion

Within 5 months of study activation, we obtained pivotal biochemical and pharmacokinetic data that have guided the design of subsequent phase I trials of ABT-888 in combination with DNA-damaging agents. In addition to accelerating the development of ABT-888, the rapid conclusion of this trial demonstrates the feasibility of conducting proof-of-principle phase 0 trials as part of an alternative paradigm for early drug development in oncology.

Significant progress in research has been made in the areas of sex-specific aspects of cardiovascular disease. Despite these advances, coronary artery disease (CAD) is the leading cause of death of women in the Western world. Over the past decade, the focused research on women at risk for ischemic heart disease has helped to clarify our understanding of some of the sex-specific factors, which are important in detecting CAD. In women, the detection and evaluation of physiologically significant CAD is challenging, especially given that traditional tests designed to detect focal areas of coronary artery stenosis are less sensitive and specific in female patients who have a lower prevalence of obstructive coronary disease, greater burden of symptoms, and a high atherosclerotic burden. In this article, we review the available evidence on the role of contemporary cardiovascular imaging techniques in evaluating ischemic heart disease in women.

A gradient reversed-phase high performance liquid chromatographic method was developed for determining NSC 737664 (2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide; ABT-888) in human plasma and urine. Chromatographic separation used a mobile phase composed of 0.1% formic acid in water and 0.1% formic acid in acetonitrile, and a C18 column (150 mm × 4.6 mm, 5µ). Quantitation was performed using UV detection at 300 nm. Chromatographic peak identity was confirmed using positive-ion electrospray ionization mass spectrometry. The method was shown to be specific, accurate and reproducible, and thereby appropriate for monitoring plasma and urine levels of the agent in support of a phase 0 clinical study.

Objective

Although diabetes is conveniently assessed by self-report, few validation studies have been performed. Therefore, we studied whether self-report of prevalent and incident diabetes in Women's Health Initiative (WHI) participants was concordant with other diagnostic evidence of diabetes.

Study Design and Setting

A total of 161 808 postmenopausal women aged 50–79 were enrolled at 40 clinical centers in the U.S. in 1993–1998 and followed prospectively. At baseline, prevalent medication treated diabetes was defined as a self-report of physician diagnosis and treatment with insulin or oral antidiabetic drugs. During followup, incident treated diabetes was defined as a self-report of a new physician diagnosis of diabetes treated with insulin or oral drugs. Diabetes self-reports were compared with medication inventories and fasting glucose levels at baseline and during follow-up.

Results

At baseline, self-reported treated diabetes was concordant with the medication inventory in 79% of clinical trial, and 77% of observational study participants. Self-reported incident treated diabetes was concordant with the medication inventory in 78% between baseline and Year 1 in the clinical trials, in 62% between Year 1 and Year 3 in the clinical trials, and in 72% between baseline and Year 3 in the observational study. Over similar periods, 99.9% of those who did not report treated diabetes had no oral antidiabetic drugs or insulin in the medication inventory. At baseline, about 3% not reporting diabetes had fasting glucose >126 mg/dl, and 88% of these subjects subsequently reported treated diabetes during 6.9 years of follow-up.

Limitations

Incident self-reported diabetes treated by lifestyle alone was not determined in WHI. Medication inventories may have been incomplete and fasting glucose may have been lowered by treatment; therefore, concordance with self-reported treatment or fasting glucose ≥ 126 may have been underestimated.

Conclusion

In the WHI, self-reported prevalent and incident diabetes was consistent with medication inventories, and a high proportion of those with undiagnosed diabetes subsequently reported diabetes treatment. Self-reports of ‘treated diabetes’ are sufficiently accurate to allow use in epidemiologic studies.

Objective

Surgical menopause has been associated with an increased risk of coronary heart disease events. In this study, we aimed to determine the associations between coronary artery calcium (CAC) and hysterectomy, oophorectomy, and hormone therapy use with a focus on the duration of menopause for which there was no hormone therapy use.

Design

In a substudy of the Women’s Health Initiative placebo-controlled trial of conjugated equine estrogens (0.625 mg/d), we measured CAC by computed tomography 1.3 years after the trial was stopped. Participants included 1,064 women with previous hysterectomy, aged 50 to 59 years at baseline. The mean trial period was 7.4 years. Imaging was performed at a mean of 1.3 years after the trial was stopped.

Results

Mean age was 55.1 years at randomization and 64.8 years at CAC measurement. In the overall cohort, there were no significant associations between bilateral oophorectomy, years since hysterectomy, years since hysterectomy without taking hormone therapy (HT), years since bilateral oophorectomy, and years of HT use before Women’s Health Initiative enrollment and the presence of CAC. However, there was a significant interaction between bilateral oophorectomy and prerandomization HT use for the presence of any CAC (P = 0.05). When multivariable analyses were restricted to women who reported no previous HT use, those with bilateral oophorectomy had an odds ratio of 2.0 (95% CI: 1.2–3.4) for any CAC compared with women with no history of oophorectomy, whereas among women with unilateral or partial oophorectomy, the odds of any CAC was 1.7 (95% CI: 1.0–2.8). Among women with bilateral oophorectomy, HT use within 5 years of oophorectomy was associated with a lower prevalence of CAC.

Conclusions

Among women with previous hysterectomy, subclinical coronary artery disease was more prevalent among those with oophorectomy and no prerandomization HT use, independent of traditional cardiovascular disease risk factors. The results suggest that factors related to oophorectomy and the absence of estrogen treatment in oophorectomized women may be related to coronary heart disease.

Aims

To compare the utility of metabolic syndrome (MetS) to random plasma glucose (RPG) in identifying people with diabetes or prediabetes.

Methods

RPG was measured and an OGTT was performed in 1,155 adults. Test performance was measured by are under the receiver-operating-characteristic curve (AROC).

Results

Diabetes was found in 5.1% and prediabetes in 20.0%. AROC for MetS with FPG was 0.80 to detect diabetes, and 0.76 for diabetes or prediabetes – similar to RPG (0.82 and 0.72). However, the AROC for MetS excluding fasting plasma glucose (FPG) was lower: 0.69 for diabetes (p<0.01 vs. both RPG and MetS with FPG), and 0.69 for diabetes or prediabetes. AROCs for MetS with FPG and RPG were comparable and higher for recognizing diabetes in blacks vs. whites, and females vs. males. MetS with FPG was superior to RPG for identifying diabetes only in subjects with age <40 or BMI <25.

Conclusions

MetS features can be used to identify risk of diabetes, but predictive usefulness is driven largely by FPG. Overall, to identify diabetes or prediabetes in blacks and whites with varying age and BMI, MetS is no better than RPG – a more convenient and less expensive test.

Nonenzymatic glycation of peptides and proteins by d-glucose has important implications in the pathogenesis of diabetes mellitus, particularly in the development of diabetic complications. In this work, we report the first proteomics-based characterization of nonenzymatically glycated proteins in human plasma and erythrocyte membranes from individuals with normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes mellitus. Phenylboronate affinity chromatography was used to enrich glycated proteins and glycated tryptic peptides from both human plasma and erythrocyte membranes. The enriched peptides were subsequently analyzed by liquid chromatography coupled with electron transfer dissociation-tandem mass spectrometry, resulting in the confident identification of 76 and 31 proteins from human plasma and erythrocyte membranes, respectively. Although most of the glycated proteins could be identified in samples from individuals with normal glucose tolerance, slightly higher numbers of glycated proteins and more glycation sites were identified in samples from individuals with impaired glucose tolerance and type 2 diabetes mellitus.

Purpose

The purpose of this study is to compare glycemic control between blacks and whites in a setting where patient and provider behavior is assessed, and where a uniform treatment algorithm is used to guide care.

Methods

This observational cohort study was conducted in 3542 patients (3324 blacks, 218 whites) with type 2 diabetes with first and 1-year follow-up visits to a municipal diabetes clinic; a subset had 2-year follow-up. Patient adherence and provider management were determined. The primary endpoint was A1c.

Results

At presentation, A1c was higher in blacks than whites (8.9% vs 8.3%; P < .001), even after adjusting for demographic and clinical characteristics. During 1 year of follow-up, patient adherence to scheduled visits and medications was comparable in both groups, and providers intensified medications with comparable frequency and amount. After 1 year, A1c differences decreased but remained significant (7.7% vs 7.3%; P = .029), even in multivariable analysis (P = .003). However, after 2 years, A1c differences were no longer observed by univariate (7.6% vs 7.5%; P = .51) or multivariable analysis (P = .18).

Conclusions

Blacks have higher A1c than whites at presentation, but differences narrow after 1 year and disappear after 2 years of care in a setting where patient and provider behavior are comparable and that emphasizes uniform intensification of therapy. Presumably, racial disparities at presentation reflected prior inequalities in management. Use of uniform care algorithms nationwide should help to reduce disparities in diabetes outcomes.