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We prospectively examined the relationship between site-specific peak plantar pressure (PPP) and ulcer risk. Researchers have previously reported associations between diabetic foot ulcer and elevated plantar foot pressure, but the effect of location-specific pressures has not been studied. Diabetic subjects (n=591) were enrolled from a single VA hospital. Five measurements of in-shoe plantar pressure were collected using F-Scan. Pressures were measured at 8 areas: heel, lateral midfoot, medial midfoot, first metatarsal, second through fourth metatarsal, fifth metatarsal, hallux, and other toes. The relationship between incident plantar foot ulcer and PPP or pressure–time integral (PTI) was assessed using Cox regression. During follow-up (2.4years), 47 subjects developed plantar ulcers (10 heel, 12 metatarsal, 19 hallux, 6 other). Overall mean PPP was higher for ulcer subjects (219 vs. 194kPa), but the relationship differed by site (the metatarsals with ulcers had higher pressure, while the opposite was true for the hallux and heel). A statistical analysis was not performed on the means, but hazard ratios from a Cox survival analysis were nonsignificant for PPP across all sites and when adjusted for location. However, when the metatarsals were considered separately, higher baseline PPP was significantly associated with greater ulcer risk; at other sites, this relationship was nonsignificant. Hazard ratios for all PTI data were nonsignificant. Location must be considered when assessing the relationship between PPP and plantar ulceration.

Background The objective of this study was to explore the relationships between claw toe deformity, peripheral neuropathy, intrinsic muscle volume, and plantar aponeurosis thickness using computed tomography (CT) images of diabetic feet in a cross-sectional analysis. Methods Forty randomly-selected subjects with type 2 diabetes were selected for each of the following four groups ( n  = 10 per group): 1) peripheral neuropathy with claw toes, 2) peripheral neuropathy without claw toes, 3) non-neuropathic with claw toes, and 4) non-neuropathic without claw toes. The intrinsic muscles of the foot were segmented from processed CT images. Plantar aponeurosis thickness was measured in the reformatted sagittal plane at 20% of the distance from the most inferior point of the calcaneus to the most inferior point of the second metatarsal. Five measurement sites in the medial-lateral direction were utilized to fully characterize the plantar aponeurosis thickness. A linear mixed-effects analysis on the effects of peripheral neuropathy and claw toe deformity on plantar aponeurosis thickness and intrinsic muscle volume was performed. Results Subjects with concurrent neuropathy and claw toes had thicker mean plantar aponeurosis ( p  < 0.006) and may have had less mean intrinsic muscle volume ( p  = 0.083) than the other 3 groups. The effects of neuropathy and claw toes on aponeurosis thickness were synergistic rather than additive. A similar pattern may exist for intrinsic muscle volume, but results were not as conclusive. A negative correlation was observed between plantar aponeurosis thickness and intrinsic muscle volume (R 2  = 0.323, p  < 0.001). Conclusions Subjects with concurrent neuropathy and claw toe deformity were associated with the smallest intrinsic foot muscle volumes and the thickest plantar aponeuroses. Intrinsic muscle atrophy and plantar aponeurosis thickening may be related to the development of claw toes in the presence of neuropathy.

Intra-Abdominal Fat Is a Major Determinant of the National Cholesterol Education Program Adult Treatment Panel III Criteria for the Metabolic Syndrome Darcy B. Carr 1 , Kristina M. Utzschneider 2 , Rebecca L. Hull 2 , Keiichi Kodama 2 , Barbara M. Retzlaff 2 , John D. Brunzell 2 , Jane B. Shofer 3 , Brian E. Fish 2 , Robert H. Knopp 2 and Steven E. Kahn 2 1 Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington 2 Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, Veterans Affairs Puget Sound Health Care System and Harborview Medical Center, University of Washington, Seattle, Washington 3 Department of Rehabilitation Research and Development, University of Washington, Seattle, Washington Address correspondence and reprint requests to Darcy B. Carr, MD, Assistant Professor, Box 356460, Dept. OB/GYN, University of Washington, Seattle, WA 98195-6460. E-mail: darcarr{at}u.washington.edu Abstract The underlying pathophysiology of the metabolic syndrome is the subject of debate, with both insulin resistance and obesity considered as important factors. We evaluated the differential effects of insulin resistance and central body fat distribution in determining the metabolic syndrome as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III. In addition, we determined which NCEP criteria were associated with insulin resistance and central adiposity. The subjects, 218 healthy men ( n = 89) and women ( n = 129) with a broad range of age (26–75 years) and BMI (18.4–46.8 kg/m 2 ), underwent quantification of the insulin sensitivity index ( S i ) and intra-abdominal fat (IAF) and subcutaneous fat (SCF) areas. The metabolic syndrome was present in 34 (15.6%) of subjects who had a lower S i [median: 3.13 vs. 6.09 × 10 −5 min −1 /(pmol/l)] and higher IAF (166.3 vs. 79.1 cm 2 ) and SCF (285.1 vs. 179.8 cm 2 ) areas compared with subjects without the syndrome ( P < 0.001). Multivariate models including S i , IAF, and SCF demonstrated that each parameter was associated with the syndrome. However, IAF was independently associated with all five of the metabolic syndrome criteria. In multivariable models containing the criteria as covariates, waist circumference and triglyceride levels were independently associated with S i and IAF and SCF areas ( P < 0.001). Although insulin resistance and central body fat are both associated with the metabolic syndrome, IAF is independently associated with all of the criteria, suggesting that it may have a pathophysiological role. Of the NCEP criteria, waist circumference and triglycerides may best identify insulin resistance and visceral adiposity in individuals with a fasting plasma glucose <6.4 mmol/l. ATP III, Adult Treatment Panel III BP, blood pressure FPG, fasting plasma glucose GEE, generalized estimating equation IAF, intra-abdominal fat NCEP, National Cholesterol Education Program NHANES III, Third National Health and Nutrition Examination Survey PAI-1, plasminogen activator inhibitor type 1 SCF, subcutaneous fat TG, triglyceride TNF-α, tumor necrosis factor-α WC, waist circumference Footnotes Accepted May 17, 2004. Received February 28, 2004. DIABETES

Gestational Diabetes Mellitus Increases the Risk of Cardiovascular Disease in Women With a Family History of Type 2 Diabetes Darcy B. Carr , MD, MS 1 , Kristina M. Utzschneider , MD 2 , Rebecca L. Hull , PHD 2 , Jenny Tong , MD, MPH 2 , Tara M. Wallace , MD 2 , Keiichi Kodama , MD 2 , Jane B. Shofer , MS 3 , Susan R. Heckbert , MD, PHD 4 5 , Edward J. Boyko , MD, MPH 2 6 , Wilfred Y. Fujimoto , MD 2 , Steven E. Kahn , MB, CHB 2 and the American Diabetes Association GENNID Study Group * 1 Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington 2 Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, VA Puget Sound Health Care System and the University of Washington, Seattle, Washington 3 Department of Rehabilitation Research and Development, University of Washington, Seattle, Washington 4 Department of Epidemiology, University of Washington, Seattle, Washington 5 Cardiovascular Health Research Unit, VA Puget Sound Health Care System, Seattle, Washington 6 Epidemiologic Research and Information Center, VA Puget Sound Health Care System, Seattle, Washington Address correspondence and reprint requests to Darcy B. Carr, MD, MS, Box 356460, University of Washington, Seattle, WA 98195-6460. E-mail: darcarr{at}u.washington.edu Abstract OBJECTIVE — We sought to determine whether a history of gestational diabetes mellitus (GDM) further increases the risk of cardiovascular disease (CVD) in parous women with first-degree relatives with type 2 diabetes. RESEARCH DESIGN AND METHODS — Women with ( n = 332) and without ( n = 663) a history of GDM were compared regarding 1 ) the revised National Cholesterol Education Program Adult Treatment Panel III metabolic syndrome criteria, 2 ) the prevalence of type 2 diabetes, and 3 ) self-reported CVD. RESULTS — Women with prior GDM were younger (48.6 ± 0.7 vs. 52.4 ± 0.6 years [means ± SE]; P < 0.001) and less likely to be postmenopausal (48.3 vs. 57.9%; P < 0.005). Although both groups were obese (BMI 34.4 ± 1.2 vs. 33.7 ± 0.6 kg/m 2 ), women with prior GDM were more likely to have metabolic syndrome (86.6 vs. 73.5%; P < 0.001) and type 2 diabetes (93.4 vs. 63.3%; P < 0.001). Moreover, they had a higher prevalence of CVD (15.5 vs. 12.4%; adjusted odds ratio 1.85 [95% CI 1.21–2.82]; P = 0.005) that occurred at a younger age (45.5 ± 2.2 vs. 52.5 ± 1.9 years; P = 0.02) and was independent of metabolic syndrome (1.74 [1.10–2.76]; P = 0.02) and type 2 diabetes (1.56 [1.002–2.43]; P < 0.05). CONCLUSIONS — Among women with a family history of type 2 diabetes, those with prior GDM were even more likely to not only have CVD risk factors, including metabolic syndrome and type 2 diabetes, but also to have experienced CVD events, which occurred at a younger age. Thus, women with both a family history of type 2 diabetes and personal history of GDM may be especially suitable for early interventions aimed at preventing or reducing their risk of CVD and diabetes. CVD, cardiovascular disease GENNID, GENetics of Non-Insulin dependent Diabetes GDM, gestational diabetes mellitus Footnotes * ↵ * *The list of centers that comprise the American Diabetes Association GENNID Study Group can be found in ref. 24 . ↵ A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. ↵ The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted May 10, 2006. Received December 16, 2005. DIABETES CARE

Agitation/aggression in Alzheimer disease (AD) is a major cause of patient distress, caregiver burden, and institutionalization. Enhanced behavioral responsiveness to central nervous system norepinephrine (NE) release may contribute to the pathophysiology of agitation/aggression in AD. Prazosin, a nonsedating generic medication used for hypertension and benign prostatic hypertrophy, antagonizes NE effects at brain postsynaptic alpha-1 adrenoreceptors. This pilot study examined the efficacy and tolerability of prazosin for behavioral symptoms in patients with agitation/aggression in AD. Double-blind, placebo controlled, parallel group study. A university AD center and a nursing home in Seattle, WA. Twenty-two nursing home and community-dwelling participants with agitation/aggression and probable or possible AD (mean age: 80.6 ± 11.2). Randomization to placebo (N = 11) or prazosin (N = 11). Medication was initiated at 1 mg/day and increased up to 6 mg/day using a flexible dosing algorithm. The Brief Psychiatric Rating Scale (BPRS) and Neuropsychiatric Inventory (NPI) at Weeks 1, 2, 4, 6, and 8. The Clinical Global Impression of Change (CGIC) at Week 8. Participants taking prazosin (mean dose: 5.7 ± 0.9 mg/day) had greater improvements than those taking placebo (mean dose: 5.6 ± 1.2 mg/day) on the NPI (mean change: −19 ± 21 versus −2 ± 15, χ2 = 6.32, df = 1, p = 0.012) and BPRS (mean change: −9 ± 9 versus −3 ± 5, χ2 = 4.42, df = 1, p = 0.036) based on linear mixed effects models and the CGIC (mean: 2.6 ± 1.0 versus 4.5 ± 1.6, z = 2.57, p = 0.011 [Mann-Whitney test]). Adverse effects and blood pressure changes were similar between prazosin and placebo groups. Prazosin was well tolerated and improved behavioral symptoms in patients with agitation/aggression in AD.

OBJECTIVE: The study objective was to examine the associations among visceral fat (VF), all-cause mortality, and obesity-related mortality. RESEARCH DESIGN AND METHODS: A total of 733 Japanese Americans were followed for 16.9 years. Hazard ratios (HRs) per interquartile range increase in VF were calculated using time-dependent Cox proportional hazard models censored at age 82 years, with age as the time axis adjusted for sex and smoking. RESULTS: Higher VF was associated with all-cause mortality (HR 1.39 [95% CI 1.11–1.75] 107 deaths) and obesity-related mortality (1.39 [1.04–1.85], 68 deaths from cardiovascular disease, diabetes, or obesity-related cancer). After further adjustment for waist circumference, VF remained significantly associated with all-cause mortality (1.41 [1.04–1.92]) but not with obesity-related mortality. The associations between mortality and VF were not independent of BMI. CONCLUSIONS: VF was associated with all-cause mortality and obesity-related mortality in Japanese Americans. VF did not significantly improve mortality risk assessment beyond that of BMI.

Successful community and household ambulation require the ability to navigate corners and maneuver around obstacles, posing unique challenges compared to straight-line walking. The challenges associated with turning may contribute to an increased incidence of falling and the occurrence of fall-related injuries. A measure of stability applied to turning gait may be able to quantify a system's response to naturally occurring disturbances associated with turning and identify subjects at greater risk of falling. An index of stability has been used previously to assess the rate of kinematic separation (local dynamic stability) during straight-line gait. The purpose of this study was to determine if local dynamic stability during constant speed turning is reduced compared to straight-line treadmill walking. Maximum finite-time Lyapunov exponents ( λ) were used to estimate the local stability of able-bodied subjects’ ( n=19) sagittal plane hip, knee, and ankle trajectories for turning compared to straight-line walking at two different walking speeds. Turning λ was greater than straight λ for the hip, right knee, and ankle ( p<0.05). Turning λ for the left knee angle was similar to straight λ. There were no differences in λ between left and right limbs for the hip and ankle and also no differences between the inside and outside limbs during turning for all joints. These findings indicate able-bodied subjects’ hip, right knee, and ankle kinematics are less locally stable while turning than walking in a straight line and may be used as a comparative tool for determining the efficacy of therapeutic interventions for mobility-impaired populations.

Impact of Intra-Abdominal Fat and Age on Insulin Sensitivity and β-Cell Function Kristina M. Utzschneider 1 , Darcy B. Carr 2 , Rebecca L. Hull 1 , Keiichi Kodama 1 , Jane B. Shofer 3 , Barbara M. Retzlaff 1 , Robert H. Knopp 1 and Steven E. Kahn 1 1 Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, Veterans Affairs Puget Sound Health Care System, Harborview Medical Center and the University of Washington, Seattle, Washington 2 Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington 3 Department of Rehabilitation and Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, Washington Address correspondence and reprint requests to Kristina M. Utzschneider, MD, VA Puget Sound Health Care System (151), 1660 S. Columbian Way, Seattle, WA 98108. E-mail: kutzschn{at}u.washington.edu Abstract The prevalence of glucose intolerance and type 2 diabetes increases with age. To determine whether the hyperbolic relationship between insulin sensitivity and the insulin response is affected by age and whether the decline in β-cell function with age is related to increases in intra-abdominal fat or age per se, we studied 220 healthy subjects with fasting glucose <6.1 mmol/l (89 men and 131 women, aged 26–75 years, BMI 18.7–40.4 kg/m 2 ). The insulin sensitivity index ( S i ) and the acute insulin response to glucose (AIRg) were determined, and from these β-cell function was estimated as the disposition index ( S i × AIRg). Intra-abdominal fat and subcutaneous fat areas were quantified by computed tomography. S i (5.40 ± 0.5 vs. 7.86 ± 0.7 ×10 −5 min −1 /[pmol/l]), P < 0.01) was decreased and intra-abdominal fat (117 ± 10 vs. 81 ± 9 cm 2 , P < 0.05) was increased in the oldest (age 60–75 years) versus the youngest (age 26–44 years) quartile. The hyperbolic relationship between S i and AIRg was present independent of age; thus, β-cell function measured as the disposition index (1,412 ± 120 vs. 2,125 ± 150 ×10 −5 min −1 , P < 0.01) was lower in the oldest versus the youngest quartile. In multiple regression, intra-abdominal fat ( r = −0.470, P < 0.001) but not age was associated with S i , but both intra-abdominal fat ( r = −0.198, P = 0.003) and age ( r = −0.131, P = 0.05) were correlated with the disposition index. These data suggest that although intra-abdominal fat is a strong determinant of insulin sensitivity and β-cell function, age has an independent effect on β-cell function that may contribute to the increased prevalence of type 2 diabetes in older populations. AIRg, acute insulin response to glucose IGT, impaired glucose tolerance IRAS, Insulin Resistance Atherosclerosis Study Footnotes Accepted August 4, 2004. Received April 8, 2004. DIABETES

Abstract Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a dementia-related proteinopathy common in the elderly population. LATE-NC stages 2 or 3 are consistently associated with cognitive impairment. A condensed protocol (CP) for the assessment of Alzheimer disease neuropathologic change and other disorders associated with cognitive impairment, recommended sampling of small brain portions from specific neuroanatomic regions that were consolidated, resulting in significant cost reduction. Formal evaluation of the CP for LATE-NC staging was not previously performed. Here, we determined the ability of the CP to identify LATE-NC stages 2 or 3. Forty brains donated to the University of Washington BioRepository and Integrated Neuropathology laboratory with known LATE-NC status were resampled. Slides containing brain regions required for LATE-NC staging were immunostained for phospho-TDP-43 and reviewed by 6 neuropathologists blinded to original LATE-NC diagnosis. Overall group performance distinguishing between LATE-NC stages 0–1 and 2–3 was 85% (confidence interval [CI]: 75%–92%). We also used the CP to evaluate LATE-NC in a hospital autopsy cohort, in which LATE-NC was more common in individuals with a history of cognitive impairment, older age, and/or comorbid hippocampal sclerosis. This study shows that the CP can effectively discriminate higher stages of LATE-NC from low or no LATE-NC and that it can be successfully applied in clinical practice using a single tissue block and immunostain.

Impact of Differences in Fasting Glucose and Glucose Tolerance on the Hyperbolic Relationship Between Insulin Sensitivity and Insulin Responses Kristina M. Utzschneider , MD 1 , Ronald L. Prigeon , MD 2 , Darcy B. Carr , MD 3 , Rebecca L. Hull , PHD 1 , Jenny Tong , MD 1 , Jane B. Shofer , MS 4 , Barbara M. Retzlaff , RN 1 , Robert H. Knopp , MD 1 and Steven E. Kahn , MB, CHB 1 1 Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, VA Puget Sound Health Care System and Harborview Medical Center, University of Washington, Seattle, Washington 2 Geriatric Research, Education and Clinical Center, Baltimore VA Medical Center and Division of Gerontology, University of Maryland School of Medicine, Baltimore, Maryland 3 Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Washington, Seattle, Washington 4 Rehabilitation, Research and Development Center, VA Puget Sound Health Care System, Seattle, Washington Address correspondence and reprint requests to Kristina M. Utzschneider, MD, VA Puget Sound Health Care System (151), 1660 S. Columbian Way, Seattle, WA 98108. E-mail: kutzschn{at}u.washington.edu Abstract OBJECTIVE —To determine whether the hyperbolic relationship between insulin sensitivity and the acute insulin response to glucose (AIR g ) exists in subjects with impaired fasting glucose (IFG) or decreased glucose tolerance. RESEARCH DESIGN AND METHODS —We studied 219 healthy subjects (88 male and 131 female subjects, aged 26–75 years) with fasting plasma glucose (FPG) <6.11 mmol/l. Subjects underwent an intravenous glucose tolerance test to determine the insulin sensitivity index ( S i ), AIR g , and the glucose disappearance constant ( K g ), the latter a measure of intravenous glucose tolerance. RESULTS — S i and AIR g were inversely related for the entire cohort, and this relationship was not significantly different from hyperbolic. The inverse relationship between S i and AIR g was not significantly different when compared between groups based on fasting glucose (normal fasting glucose [NFG], FPG <5.56 mmol/l vs. IFG, FPG 5.56–6.11 mmol/l) or by the K g quartile. However, the curve relating S i and AIR g was left shifted in the IFG compared with NFG group ( P < 0.001) and was progressively more left shifted with decreasing K g ( P < 0.001), consistent with decreasing β-cell function. These changes were not observed for the curves relating S i and fasting insulin, suggesting that in the fasting state β-cell function is maintained even in patients with mild IFG. Finally, the disposition index (DI) ( S i × AIR g ) was calculated as a measure of β-cell function. The DI progressively decreased with increasing FPG, even in the group of subjects classified as NFG. CONCLUSIONS —The inverse relationship between insulin sensitivity and AIR g is consistent with a hyperbola not only in subjects with normal glucose tolerance but also with mild IFG or decreased K g . Based on a hyperbolic relationship, a decrease in β-cell function can be detected as FPG increases, even in patients who are normal glucose tolerant. AIRg, acute insulin response to glucose DI, disposition index FPG, fasting plasma glucose IFG, impaired fasting glucose NFG, normal fasting glucose Footnotes A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Accepted November 14, 2005. Received December 8, 2005. DIABETES CARE