Search

The article discusses a case of hypercalcemic older patient, later diagnosed with sarcoidosis via a diagnostic process entailing numerous tests and differential assessments. Topics include the atypical presentation of sarcoidosis in older patients, difficulties in diagnosing it without clear markers, and the necessity of considering broader differential diagnoses.

Objective: Type 2 diabetes is associated with increased risks of cognitive dysfunction and brain abnormalities. The extent to which risk factor modification can mitigate these risks is unclear. We investigated the associations between incident dementia, cognitive performance, and brain abnormalities among individuals with type 2 diabetes, according to the number of risk factors on target, compared with control subjects without diabetes.Research Design and Methods: Prospective data were from UK Biobank of 87,856 individuals (n = 10,663 diabetes, n = 77,193 control subjects; baseline 2006-2010), with dementia follow-up until February 2018. Individuals with diabetes were categorized according to the number of seven selected risk factors within the guideline-recommended target range (nonsmoking; guideline-recommended levels of glycated hemoglobin, blood pressure, BMI, albuminuria, physical activity, and diet). Outcomes were incident dementia, domain-specific cognitive performance, white matter hyperintensities, and total brain volume.Results: After a mean follow-up of 9.0 years, 147 individuals (1.4%) with diabetes and 412 control subjects (0.5%) had incident dementia. Among individuals with diabetes, excess dementia risk decreased stepwise for a higher number of risk factors on target. Compared with control subjects (incidence rate per 1,000 person-years 0.62 [95% CI 0.56; 0.68]), individuals with diabetes who had five to seven risk factors on target had no significant excess dementia risk (absolute rate difference per 1,000 person-years 0.20 [-0.11; 0.52]; hazard ratio 1.32 [0.89; 1.95]). Similarly, differences in processing speed, executive function, and brain volumes were progressively smaller for a higher number of risk factors on target. These results were replicated in the Maastricht Study.Conclusions: Among individuals with diabetes, excess dementia risk, lower cognitive performance, and brain abnormalities decreased stepwise for a higher number of risk factors on target. [ABSTRACT FROM AUTHOR]

Abstract: The atherothrombotic conditions, coronary artery disease, cerebrovascular disease and peripheral arterial disease (PAD), together account for almost one-half of all deaths in Europe each year; however, perception of the specific risks associated with PAD is generally poor compared with its related conditions. PAD is not just a localised disease — it has serious systemic effects, and affected individuals have a higher risk of serious cardiovascular sequelae or death within 1 year of diagnosis compared with those with coronary artery or cerebrovascular disease. PAD, which currently affects approximately 16% of the general population aged over 55 years, is increasing because of the population aging and the continuing rise in cardiovascular risk factors. The management of PAD is a multi-disciplinary approach, and while this can have its advantages, it can also mean that responsibility for patient care is unclear. Globally, almost one-third of all patients with PAD are under internist care. Internists are ideally placed to identify patients at risk of PAD and initiate prompt risk factor management because of their role in the continued care of elderly patients and those with diabetes, hypertension, dyslipidaemia, and chronic renal disease. Multi-disciplinary guidelines for the clinical management of PAD, based on consensus among international specialists in a number of fields, have been developed to create an informed, unified and proactive approach to the treatment of PAD. They stress the continuity of care, the use of office-based ankle–brachial index testing to aid early diagnosis, and prompt and aggressive risk factor management. [Copyright &y& Elsevier]

Objective: To determine the roles of nitric oxide, endothelin-1 and phosphatidylinositol 3-kinase (PI3-kinase) in acute responses of isolated rat skeletal muscle arterioles to insulin. Methods: Rat cremaster first order arterioles were separated from surrounding tissue, cannulated in a pressure myograph and responses to insulin (4 μU/ml–3.4 mU/ml) were studied without intraluminal blood or flow. Results: Insulin alone did not significantly affect arteriolar diameter. Non-selective antagonism of endothelin receptors, with PD-142893, uncovered insulin-induced vasodilatation (25±8% from baseline at 3.4 mU/ml), which was abolished by inhibition of NO synthesis with NG-nitro-l-arginine (l-NA). Inhibition of NO synthesis alone uncovered insulin-induced vasoconstriction at physiological concentrations (21±5% from baseline diameter at 34 μU/ml), which was abolished by PD-142893. The NO donor, S-nitroso-N-acetyl-penicillamine (SNAP) inhibited insulin-induced vasoconstriction during NOS inhibition, even at a concentration that did not elicit vasodilatation itself. Inhibition of PI3-kinase, an intracellular mediator of insulin-induced NO production, with wortmannin, also uncovered insulin-induced vasoconstriction (13±3% from baseline at 34 μU/ml) that was abolished by PD-142893. Conclusions: Insulin induces both nitric oxide and endothelin-1 activity in rat cremaster first-order arterioles. This study demonstrates for the first time that vasoconstrictive effects of physiological concentrations of insulin during inhibition of NOS activity are mediated by endothelin and that insulin induces endothelin-1-mediated vasoconstriction in isolated skeletal muscle arterioles during inhibition of PI3-kinase. These findings support the hypothesis of altered microvascular reactivity to insulin in conditions of diminished PI3-kinase activity, a prominent feature of insulin resistance. [Copyright &y& Elsevier]

Plasma homocysteine concentration predicts mortality in non-insulin-dependent diabetic patients with and without albuminuria. Background. A high plasma total homocysteine (tHcy) concentration is a risk factor for cardiovascular disease in the nondiabetic population and in nondiabetic patients with end-stage renal disease. Methods. We prospectively evaluated the impact of tHcy concentrations on mortality in 211 white non-insulin-dependent diabetic (NIDDM) patients of less than 70 years of age at entry (61 with microalbuminuria and 44 with macroalbuminuria). They were followed for a median of 6.4 (range 0.2 to 7.1) years. Results. At the end of the follow-up period, 49 of 211 (23%) patients had died, 30 (61%) from cardiovascular disease. Univariate Cox survival analysis revealed that baseline tHcy level (1 μmol/liter) was associated with an increased all-cause mortality risk of 1.11 [95% confidence interval (CI) 1.08 to 1.15, P < 0.0001], and a cardiovascular mortality risk of 1.09 (CI 1.03 to 1.16, P < 0.01). The six-year cumulative all-cause mortality hazard was 44%, 14%, and 15% in the high (tHcy ≥ 8.2 μmol/liter), the middle (tHcy 6.2–8.1 μmol/liter), and the low (tHcy ≤ 6.1 μmol/liter) tertile of tHcy levels, respectively (P < 0.001 high vs. middle; P < 0.001 high vs. low; and P = 0.88 middle vs. low). Cox proportional hazards regression analysis revealed significant predictors of all-cause mortality to be tHcy level (per 1 μmol/liter), relative risk 1.09 (1.03 to 1.14); pre-existing coronary heart disease (yes vs. no), relative risk 1.98 (1.09 to 3.61); log10 albumin excretion rate (AER; factor 10), relative risk 1.89 (1.31 to 2.74); and age (per 1 year), relative risk 1.08 (1.03 to 1.13). Predictors of cardiovascular mortality were pre-existing coronary heart disease, log10 AER, and age. tHcy level did not predict cardiovascular mortality independently of these risk factors. Conclusion.... [ABSTRACT FROM AUTHOR]

Over the past decade, there have been important breakthroughs in our understanding of the regulation and function of sex hormone–binding globulin (SHBG). A recent genome-wide association and Mendelian randomization study has provided new insights at the population level. Thorough study of genetic variants affecting serum SHBG has identified de novo lipogenesis as one of the mechanistic links between the metabolic syndrome and reduced serum SHBG levels in humans. Furthermore, careful deduction of the Mendelian randomization results suggests a direct, causal role for SHBG in the pathogenesis of type 2 diabetes, as a hepatokine, in women. These findings prompt the development of SHBG-raising therapies as a means to prevent or treat disorders such as type 2 diabetes and polycystic ovary syndrome. A recent genome-wide association study has identified a cluster of de novo lipogenesis genes that affect serum sex hormone–binding globulin (SHBG) levels. A recent Mendelian randomization study has shown that SHBG functions as a true hepatokine, at least in women, by reducing the risk of type 2 diabetes. SHBG-raising therapies, such as inhibitors of de novo lipogenesis or thyroid hormone receptor beta agonists, may provide promising future directions for the treatment and prevention of type 2 diabetes and polycystic ovary syndrome. [ABSTRACT FROM AUTHOR]

Hereditary fructose intolerance (HFI) is a rare inborn disease characterized by a deficiency in aldolase B, which catalyzes the cleavage of fructose 1,6-bisphosphate and fructose 1-phosphate (Fru 1P) to triose molecules. In patients with HFI, ingestion of fructose results in accumulation of Fru 1P and depletion of ATP, which are believed to cause symptoms, such as nausea, vomiting, hypoglycemia, and liver and kidney failure. These sequelae can be prevented by a fructose-restricted diet. Recent studies in aldolase B-deficient mice and HFI patients have provided more insight into the pathogenesis of HFI, in particular the liver phenotype. Both aldolase B-deficient mice (fed a very low fructose diet) and HFI patients (treated with a fructose-restricted diet) displayed greater intrahepatic fat content when compared to controls. The liver phenotype in aldolase B-deficient mice was prevented by reduction in intrahepatic Fru 1P concentrations by crossing these mice with mice deficient for ketohexokinase, the enzyme that catalyzes the synthesis of Fru 1P. These new findings not only provide a potential novel treatment for HFI, but lend insight into the pathogenesis of fructose-induced non-alcoholic fatty liver disease (NAFLD), which has raised to epidemic proportions in Western society. This narrative review summarizes the most recent advances in the pathogenesis of HFI and discusses the implications for the understanding and treatment of fructose-induced NAFLD. [ABSTRACT FROM AUTHOR]

Background: Altered white matter brain connectivity has been linked to depression. The aim of this study was to investigate the association of markers of white matter connectivity with prevalence, incidence and course of depressive symptoms. Methods: Markers of white matter connectivity (node degree, clustering coefficient, local efficiency, characteristic path length, and global efficiency) were assessed at baseline by 3 T MRI in the population-based Maastricht Study (n = 4866; mean ± standard deviation age 59.6 ± 8.5 years, 49.0% women; 17 406 person-years of follow-up). Depressive symptoms (9-item Patient Health Questionnaire; PHQ-9) were assessed at baseline and annually over seven years of follow-up. Major depressive disorder (MDD) was assessed with the Mini-International Neuropsychiatric Interview at baseline only. We used negative binominal, logistic and Cox regression analyses, and adjusted for demographic, cardiovascular, and lifestyle risk factors. Results: A lower global average node degree at baseline was associated with the prevalence and persistence of clinically relevant depressive symptoms [PHQ-9 ⩾ 10; OR (95% confidence interval) per standard deviation = 1.21 (1.05–1.39) and OR = 1.21 (1.02–1.44), respectively], after full adjustment. On the contrary, no associations were found of global average node degree with the MDD at baseline [OR 1.12 (0.94–1.32) nor incidence or remission of clinically relevant depressive symptoms [HR = 1.05 (0.95–1.17) and OR 1.08 (0.83–1.41), respectively]. Other connectivity measures of white matter organization were not associated with depression. Conclusions: Our findings suggest that fewer white matter connections may contribute to prevalent depressive symptoms and its persistence but not to incident depression. Future studies are needed to replicate our findings. [ABSTRACT FROM AUTHOR]

The complement system, particularly the alternative complement pathway, may contribute to vascular damage and development of cardiovascular disease (CVD). We investigated the association of factor D, the rate-limiting protease in alternative pathway activation, with adverse cardiovascular outcomes. In 2947 participants (50.6% men, 59.9 ± 8.2 years, 26.5% type 2 diabetes [T2D], oversampled) we measured markers of low-grade inflammation (LGI, composite score, in SD) and, endothelial dysfunction (ED, composite score, in SD), carotid intima-media thickness (cIMT, μm), ankle-brachial index (ABI), CVD (yes/no) and plasma concentrations of factor D (in SD). Associations were estimated using multiple linear and logistic regression, adjusting for demographic, lifestyle, and dietary factors. Factor D (per SD) significantly associated with LGI (0.171 SD [0.137; 0.205]), ED (0.158 SD [0.123; 0.194]) and CVD (OR 1.15 [1.04; 1.27]) but not significantly with cIMT (−6.62 μm [-13.51; 0.27]) or ABI (−0.003 [-0.007; 0.001]). Interaction analyses show that factor D more strongly associated with ED in non-diabetes (0.237 SD [0.189; 0.285] than in T2D (0.095 SD [0.034; 0.157]), p interaction <0.05. These results were largely corroborated by additional analyses with C3 and C3a. In contrast, factor D inversely associated with cIMT in non-diabetes (−13.37 μm [-21.84; −4.90]), but not in T2D (4.49 [-7.91; 16.89]), p interaction <0.05. Plasma factor D is independently associated with LGI, ED, and prevalent CVD but not with ABI or cIMT. Hence, greater plasma factor D concentration in CVD may potentially induce complement activation which, in turn, might contribute to further disease progression via a process that may involve inflammation and endothelial dysfunction but was not directly related to atherosclerosis or arterial injury. The observation that, in participants without diabetes, factor D associated with worse ED but smaller cIMT warrants further investigation. [Display omitted] • Greater plasma concentration of factor D significantly associates with multiple markers of low-grade inflammation and endothelial dysfunction. • Greater plasma concentration of factor D significantly associates with more cardiovascular disease. • These observations for factor D were largely corroborated in analyses with complement C3 and C3a. • The association of factor D with cardiovascular disease manifested particularly as cerebral cardiovascular disease in men. • Factor D was not positively associated with either a marker of subclinical atherosclerosis or a marker of arterial injury. [ABSTRACT FROM AUTHOR]

Background: If retinal indices of neurodegeneration are to be biomarkers for the monitoring of cerebral neurodegeneration, it is important to establish whether potentially modifiable risk factors for dementia are associated with retinal neurodegenerative changes. Objective: To study associations of dementia risk factors with retinal sensitivity, an index of retinal neural function, and retinal nerve fiber layer (RNFL) thickness, an index of retinal neural structure. Methods: We used cross-sectional data from The Maastricht Study (up to 5,666 participants, 50.5% men, mean age 59.7), and investigated associations with regression analyses (adjusted for potential confounders). Results: Most risk factors under study (i.e., hyperglycemia, unhealthy diet, lower cardiorespiratory fitness, smoking, alcohol consumption, and hypertension) were significantly associated with lower retinal sensitivity and lower RNFL thickness. Conclusion: Findings of this population-based study support the concept that retinal neural indices may be biomarkers for the monitoring of therapeutic strategies that aim to prevent early-stage cerebral neurodegeneration and, ultimately, dementia. [ABSTRACT FROM AUTHOR]

Background: Higher anxiety levels in older adults are associated with worse executive functioning and an increased risk for dementia. In this study individual anxiety disorders and clinically relevant generalized anxiety symptoms are studied in relation to multiple cognitive domains.Method: This cross-sectional study includes 7344 community-dwelling participants of The Maastricht Study aged 40-75 years and oversampling of type 2 diabetes. Panic disorder with and without agoraphobia, agoraphobia and lifetime panic disorder were measured with the Mini International Neuropsychiatric Interview. Generalized anxiety symptoms were measured with the Generalized Anxiety Disorder 7-item scale (GAD-7). Multiple cognitive domains (executive functioning, memory and processing speed) and cognitive impairment were assessed. Multivariable linear and logistic regression analyses were used with adjustment for potential confounders. Interaction analyses were performed to test the moderation of age, sex and type 2 diabetes (due to oversampling).Results: Agoraphobia was associated with worse scores on all cognitive domains (range B = -0.12 to -0.10; range 95%CI = -0.20 to -0.04) and with higher odds of cognitive impairment (OR = 1.51, 95%CI = 1.18-1.93). High scores on the GAD-7 were associated with worse scores on processing speed (B = -0.11, 95%CI = -0.20 to -0.03) and higher odds of cognitive impairment (OR = 1.42, 95%CI = 1.02-1.97). Panic disorder was significantly associated with worse scores on memory tasks (B = -0.25, 95%CI = -0.48 to -0.02). Associations were stronger in the younger participants and for agoraphobia and GAD-7 scores also in those with type 2 diabetes.Conclusion: Multiple anxiety disorders and generalized anxiety symptoms were associated with worse cognitive functioning on several cognitive domains. [ABSTRACT FROM AUTHOR]

Presents a correspondence on the interest of a contributor to a review article on diet, exercise and medication for glucose lowering, blood pressure lowering and aspirin therapy, published in an issue of the journal "Treatments in Endocrinology."

Microalbuminuria is associated with impaired brachial artery, flow-mediated vasodilation in elderly individuals without and with diabetes: Further evidence for a link between microalbuminuria and endothelial dysfunction—The Hoorn Study. Background Extensive endothelial dysfunction (i.e., affecting many aspects of endothelial function) has been hypothesized to explain why microalbuminuria (MA) is associated with cardiovascular disease risk. However, it is not clear whether MA is specifically associated with impaired endothelial nitric oxide (NO) synthesis in individuals without and with type 2 diabetes. Methods We did a population-based study in 645 individuals (mean age 68 years; 248 with normal glucose metabolism, 137 with impaired glucose metabolism, and 260 with type 2 diabetes) and investigated associations of MA [present (urinary albumin-creatinine ratio ≥2 mg/mmol) versus absent, and in four categories (<2, ≥2 to 5, ≥5 to 10, ≥10 mg/mmol)] with ultrasonically measured brachial artery endothelium-dependent, flow-mediated (FMD; an estimate of endothelial NO synthesis) and endothelium-independent, nitroglycerin-induced vasodilation (NID). Results FMD was 0.12 mm in the presence of MA ( N =93; 49 with diabetes), and 0.18 in its absence ( P =0.002). After adjustment for age, sex, baseline arterial diameter, and other potential confounders, FMD was 0.038 mm (95% CI, 0.001 to 0.075) lower in the presence of MA ( P =0.04), and decreased linearly across MA categories [by 0.027 mm (0.007 to 0.046) per category increase of MA; P =0.007]. NID was similar in individuals with and without MA. Results were similar in individuals without and with diabetes. Conclusion Microalbuminuria is linearly associated with impaired endothelium-dependent, flow-mediated vasodilation in elderly individuals without and with diabetes. These findings support the concept that impaired endothelial nitric oxide synthesis plays a role in the association of microalbuminuria with cardiovascular disease risk. [ABSTRACT FROM AUTHOR]

Microalbuminuria is associated with impaired brachial artery, flow-mediated vasodilation in elderly individuals without and with diabetes: Further evidence for a link between microalbuminuria and endothelial dysfunction—The Hoorn Study.Background.Extensive endothelial dysfunction (i.e., affecting many aspects of endothelial function) has been hypothesized to explain why microalbuminuria (MA) is associated with cardiovascular disease risk. However, it is not clear whether MA is specifically associated with impaired endothelial nitric oxide (NO) synthesis in individuals without and with type 2 diabetes.Methods.We did a population-based study in 645 individuals (mean age 68 years; 248 with normal glucose metabolism, 137 with impaired glucose metabolism, and 260 with type 2 diabetes) and investigated associations of MA[present (urinary albumin-creatinine ratio≥2 mg/mmol) versus absent, and in four categories (<2,≥2 to 5,≥5 to 10,≥10 mg/mmol)] with ultrasonically measured brachial artery endothelium-dependent, flow-mediated (FMD; an estimate of endothelial NO synthesis) and endothelium-independent, nitroglycerin-induced vasodilation (NID).Results.FMD was 0.12 mm in the presence of MA (N= 93; 49 with diabetes), and 0.18 in its absence (P= 0.002). After adjustment for age, sex, baseline arterial diameter, and other potential confounders, FMD was 0.038 mm (95% CI, 0.001 to 0.075) lower in the presence of MA (P= 0.04), and decreased linearly across MA categories[by 0.027 mm (0.007 to 0.046) per category increase of MA;P= 0.007]. NID was similar in individuals with and without MA. Results were similar in individuals without and with diabetes.Conclusion.Microalbuminuria is linearly associated with impaired endothelium-dependent, flow-mediated vasodilation in elderly individuals without and with diabetes. These findings support the concept that impaired endothelial nitric oxide synthesis plays a role in the association of microalbuminuria with cardiovascular disease risk. [ABSTRACT FROM AUTHOR]

Background: Individuals with depression often show an adverse cardiometabolic risk profile and might represent a distinct depression subtype. The aim of this study was to investigate whether a cardiometabolic depression subtype could be identified and to investigate its association with demographics and clinical characteristics (severity, symptomatology, anti-depressant use, persistence and cognitive functioning).Methods: We used data from The Maastricht Study, a population-based cohort in the southern part of The Netherlands. A total of 248 participants with major depressive disorder were included (mean [SD] age, 58.8 ± 8.5 years; 121 [48.8 %] were men). Major depressive disorder was assessed at baseline by the Mini-International Neuropsychiatric Interview. Cardiometabolic risk factors were defined as indicators of the metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. We measured severity and persistence of depressive symptoms by use of the 9-item Patient Health Questionnaire.Results: Latent class analysis resulted in two subtypes, one with cardiometabolic depression (n = 145) and another with non-cardiometabolic depression (n = 103). The cardiometabolic depression subtype was characterized by being male, low education, more severe depressive symptoms, less symptoms of depressed mood and more symptoms of loss of energy, more use of antidepressant medication and lower cognitive functioning.Limitations: No conclusions can be made about causality.Conclusions: Latent class analysis suggested a distinct cardiometabolic depression subtype. Participants with cardiometabolic depression differed from participants with non-cardiometabolic depression in terms of demographics and clinical characteristics. The existence of a cardiometabolic depression subtype may indicate the need for prevention and treatment targeting cardiometabolic risk management. [ABSTRACT FROM AUTHOR]

Objective: Epidemiological evidence regarding the relationship between fructose intake and intrahepatic lipid (IHL) content is inconclusive. We, therefore, assessed the relationship between different sources of fructose and IHL at the population level.Research Design and Methods: We used cross-sectional data from The Maastricht Study, a population-based cohort study (n = 3,981; mean ± SD age: 60 ± 9 years; 50% women). We assessed the relationship between fructose intake (assessed with a food-frequency questionnaire)-total and derived from fruit, fruit juice, and sugar-sweetened beverages (SSB)-and IHL (quantified with 3T Dixon MRI) with adjustment for age, sex, type 2 diabetes, education, smoking status, physical activity, and intakes of total energy, alcohol, saturated fat, protein, vitamin E, and dietary fiber.Results: Energy-adjusted total fructose intake and energy-adjusted fructose from fruit were not associated with IHL in the fully adjusted models (P = 0.647 and P = 0.767). In contrast, energy-adjusted intake of fructose from fruit juice and SSB was associated with higher IHL in the fully adjusted models (P = 0.019 and P = 0.009). Individuals in the highest tertile of energy-adjusted intake of fructose from fruit juice and SSB had a 1.04-fold (95% CI 0.99; 1.11) and 1.09-fold (95% CI 1.03; 1.16) higher IHL, respectively, in comparison with the lowest tertile in the fully adjusted models. Finally, the association for fructose from fruit juice was stronger in individuals with type 2 diabetes (P for interaction = 0.071).Conclusions: Fructose from fruit juice and SSB is independently associated with higher IHL. These cross-sectional findings contribute to current knowledge in support of measures to reduce the intake of fructose-containing beverages as a means to prevent nonalcoholic fatty liver disease at the population level. [ABSTRACT FROM AUTHOR]

Objective: Polycystic ovary syndrome (PCOS) has been associated with an increased risk of coronary artery disease (CAD). However, it remains uncertain whether this increased risk is the result of PCOS per se or, alternatively, is explained by obesity, a common feature of PCOS. The aim of this study was to assess the causal association between PCOS and CAD and the role of obesity herein. Design and Methods: We conducted two‐sample Mendelian randomisation analyses in large‐scale, female‐specific datasets to study the association between genetically predicted (1) risk of PCOS and risk of CAD, (2) body mass index (BMI) and risk of PCOS and (3) BMI and risk of CAD. Primary analyses were conducted with the inverse‐variance weighted (IVW) method. Simple median, penalized weighted median and contamination mixture analyses were performed to assess the robustness of the outcomes. Results: IVW analyses did not show a statistically significant association between PCOS and CAD (odds ratio [OR]: 0.99, 95% confidence interval [CI]: 0.89, 1.11). In contrast, genetically predicted BMI was statistically significantly associated with an increased odds of PCOS (OR: 3.21, 95% CI: 2.26, 4.56) and CAD (OR: 1.38, 95% CI: 1.14, 1.67). Similar results were obtained when secondary analyses were performed. Conclusion: These sex‐specific analyses show that the genetically predicted risk of PCOS is not associated with the risk of CAD. Instead, the genetically predicted risk of obesity (and its downstream metabolic effects) is the common denominator of both PCOS and CAD risk. [ABSTRACT FROM AUTHOR]

• A systematic review and meta-analysis of 16 studies involving 5,060,687 participants. • High waist circumference (WC) was associated with a greater risk of cognitive impairment and dementia. • The risk is higher for individuals older than 65 years old. Central obesity, measured by the waist circumference (WC) or waist-to-hip ratio, has been linked with metabolic dysfunction and structural abnormalities in the brain, two risk factors for cognitive impairment and dementia. The current analysis was performed to understand the influence of central obesity on the incidence of cognitive impairment and dementia. It included 21 studies involving 5,060,687 participants and showed that a high WC was associated with a greater risk of cognitive impairment and dementia (HR = 1.10, 95 % CI: 1.05–1.15), compared with a low WC. Sub-group analysis showed that a high WC increased the likelihood of developing cognitive impairment and dementia in individuals older than 65 years of age (HR = 1.13, 95 % CI: 1.08–1.19), whereas no association was observed in individuals younger than 65 years of age (HR = 1.04, 95 % CI: 0.93–1.16). Furthermore, dose-response meta-analysis confirmed that a high WC was a risk factor for cognitive impairment and dementia. In conclusion, central obesity, as measured by WC, was associated with a risk of cognitive impairment and dementia. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Given the transient nature of exercise-induced improvements in insulin sensitivity, it has been speculated that daily exercise is preferred to maximize the benefits of exercise for glycemic control. The current study investigates the impact of daily exercise versus exercise performed every other day on glycemic control in type 2 diabetic patients. RESEARCH DESIGN AND METHODS--Thirty type 2 diabetic patients (age 60 ± 1 years, BMI 30.4 ± 0.7 kg/m², and HbA1c 7.2 ± 0.2%) participated in a randomized crossover experiment. Subjects were studied on three occasions for 3 days under strict dietary standardization but otherwise free-living conditions. Blood glucose homeostasis was assessed by continuous glucose monitoring over 48 h during which subjects performed no exercise (control) or 60 min of cycling exercise (50% maximal workload capacity) distributed either as a single session performed every other day or as 30 min of exercise performed daily. RESULTS--The prevalence of hyperglycemia (blood glucose.10 mmol/L) was reduced from 7:40±1:00 h:min per day (32±4% of the time) to 5:46±0:58 and 5:51±0:47 h:min per day, representing 24±4 and 24±3% of the time, when exercise was performed either daily or every other day, respectively (P < 0.001 for both treatments). No differences were observed between the impact of daily exercise and exercise performed every other day. CONCLUSIONS--A short 30-min session of moderate-intensity endurance-type exercise substantially reduces the prevalence of hyperglycemia throughout the subsequent day in type 2 diabetic patients. When total work is being matched, daily exercise does not further improve daily glycemia compared with exercise performed every other day. [ABSTRACT FROM AUTHOR]

Abstract: Background: To identify frail elderly individuals, several index or scoring systems have been developed for research purposes. The practical value of these scores for screening and diagnostic use is uncertain. Aim: The available scoring systems were reviewed to determine whether they can be used in daily practice. Methods: Literature study on relevant test instruments developed for the detection of frailty on the basis of theoretical views on the frailty concept. Data on sensitivity and specificity and predictive values were extracted. Results: Several (n=6) frailty scores were described with respect to their value as a screening or diagnostic test. Outcome of the selected test instruments is presented as a risk of negative health outcome when a test is positive. The reported AUCs of ROCs varied from 0.55 for functional decline in people admitted to an accident and emergency department to 0.87 for prediction of mortality on the basis of a co-morbidity score. As the prevalence of frailty and resulting negative health outcomes in published reports was low (5–41%), presented sensitivity and specificity values lead to low positive predictive values (6–49%) but reasonable negative predictive values (73–96%). Conclusions: As the number of false positive values of most available tests is substantial, these frailty scores are of limited value for both screening and diagnostic purposes in daily practice. As diagnostic instruments they can best be used to exclude frailty. The false-positive rate of currently available tests is too high to allow major decisions on medical care to be made on the basis of a positive test. [Copyright &y& Elsevier]

Abstract: A rapid and sensitive single-column high-performance liquid chromatography method and application for the detection of protein bound pentosidine is described. Pentosidine, a cross-link between arginine and lysine, is a well-characterized advanced glycation endproduct. In order to detect protein-bound pentosidine, plasma proteins were hydrolysed in 6N HCl. Detection of pentosidine is done based on its own fluorescence characteristics using fluorimetric detection (E x =325nm, E m =385nm). Separation is done, with a run-to-run time of 30min, on a C18 Allspehere ODS-II column with a citric acid acetonitrile buffer. This detection enables sensitive and specific determination of protein bound pentosidine in plasma with a detection limit of 2.2nmol/l or 0.02pmol/mg protein (signal-to-noise: 6). The intra-assay coefficient variation is 6.5% at a plasma pentosidine concentration of 0.47pmol/mg protein and 2.0% at a concentration of 1.27pmol/mg protein. The inter-assay coefficient variation is 3.1% at a plasma pentosidine concentration of 0.43pmol/mg protein and 1.6% at a concentration of 1.40pmol/mg protein. Linearity is tested in 4 different plasma samples and showed linearity (0–200nmol/l, r 2 >0.99). Recovery of pentosidine in 4 different plasma samples at different concentration levels is 102±10% (mean±SD). Using this method protein bound pentosidine concentration is investigated in healthy controls (n =24, age 67±9 years) and patients with end stage renal disease (n =24, age 65±10 years). Higher plasma concentrations of protein bound pentosidine are measured in the patient group as compared with the control group 3.05 (2.03–3.92)pmol/mg protein and 0.21 (0.19–0.33)pmol/mg protein, respectively (median (interquartile range), p <0.00001). These results are consistent with previously reported results. [Copyright &y& Elsevier]

Statins can protect endothelial activation independent from their lipid-lowering effects. To gain more insight in mechanisms via which HMG-CoA inhibition may attenuate endothelial activation, we assessed the effects of mevastatin on eNOS expression of non- and modified-LDL treated endothelial cells and on basal and hydrogen peroxide-induced lipid peroxidation. Oxidized-LDL (Ox-LDL), but not glycated or acylated LDL decreased eNOS expression in human endothelial cells. The extent to which Ox-LDL decreases eNOS expression depends on the extent of modification of Ox-LDL. Mevastatin increased eNOS-expression, both in the presence and absence of Ox-LDL. In addition, mevastatin decreased the H2O2-induced (100 μM) lipid peroxidation in endothelial cells. This study shows that mevastatin has protective effects on endothelial cells by inducing eNOS and by inhibiting lipid peroxidation. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- To study the relationship of nonproliferative and proliferative retinopathy with all-cause mortality and cardiovascular disease (CVD) incidence in type 1 diabetic patients and, additionally, the role of cardiovascular risk factors in these associations. RESEARCH DESIGN AND METHODS -- This prospective study included 2,237 type 1 diabetic patients from 31 centers in 16 European countries at baseline, aged 15-60 years, who were examined for retinopathy by taking two-field 45° fundus photographs, which were centrally graded. Mortality and cardiovascular morbidity follow-up was assessed 6-8 years after baseline examination according to a standardized protocol. RESULTS -- After 7.9 years of follow-up, 64 patients had died and 128 patients had incident CVD. The age- and sex-adjusted hazard ratios (HIEs) of all-cause mortality were 1.45 (95% CI 0.71-2.96) and 4.16 (1.96- 8.84) in patients with nonproliferative and proliferative retinopathy at baseline, respectively. Adjustments for cardiovascular risk factors completely obliterated the association with nonproliferative retinopathy, whereas the association with proliferative retinopathy remained twofold increased, although nonsignificant. The age- and sex-adjusted HRs of incident CVD were 1.73 (1.15-2.60) and 2.05 (1.22-3.45) in patients with nonproliferative and proliferative retinopathy, respectively. After adjustments for cardiovascular risk factors, both associations were attenuated and lost statistical significance. CONCLUSIONS -- This study shows that type 1 diabetic patients with nonproliferative or proliferative retinopathy have an increased risk for all-cause mortality and incident CVD. The presence of cardiovascular risk factors explained the associations to a large extent, except for the associations with proliferative retinopathy, which suggests that other shared mechanisms may be involved. [ABSTRACT FROM AUTHOR]

• LGI and ED were both associated with incident depressive symptoms. • The association of ED was substantially mediated by LGI. • ED was associated with a persistent course of depressive symptoms. • LGI was not associated with a persistent course of depressive symptoms. • This suggests a temporal, vascular contribution of LGI and ED to the etiology and chronicity of depressive symptoms. Low-grade inflammation (LGI) and endothelial dysfunction (ED) might play a key role in the development of depression. We investigated the associations and mediation of LGI and ED with four-year incidence and course of depressive symptoms (remitted, recurrent or persistent). In this prospective cohort study (mean age 59.6 ± 8.2 years, 48.9% women, 26.6% diabetes by design), Cox and multinomial regression analyses, adjusted for age, sex, educational level and diabetes status were used to investigate the associations of LGI and ED with onset and course of depressive symptoms as assessed by the PHQ-9 questionnaire. During 10,847 person-years of follow-up, 264 participants developed incident depression. Higher levels of LGI (OR [95%CI] per SD 1.32[1.16–1.49], p < 0.001) and ED (1.26[1.11–1.43], p < 0.001) were associated with incident depressive symptoms. In mediation analysis, 60% of the total effect of ED with incident depressive symptoms could be attributed to LGI. 76 out of 2637 participants had a persistent course of depressive symptoms. Higher levels of LGI (1.75[1.40–2.19], p < 0.001) and ED (1.33[1.04–1.71], p = 0.021) were associated with a persistent course of depressive symptoms. Higher ED was more strongly associated with persistent depressive symptoms (1.33[1.04–1.71], p = 0.021), while LGI was associated with remission of depression symptoms. LGI and ED were both associated with incident depressive symptoms, where the latter association was substantially mediated by LGI. ED was further associated with a persistent course of depressive symptoms, while LGI was not. These results suggest a temporal, vascular contribution of both LGI and ED to the etiology and chronicity of depressive symptoms. [ABSTRACT FROM AUTHOR]

Objective: To examine the association between adiponectin, a known predictor of diabetes in Pima Indians, and markers of inflammation and endothelial function in nondiabetic subjects and to assess whether these markers predict later diabetes in a case-control study within a longitudinal health study in Pima Indians.Research Design and Methods: Participants with normal glucose tolerance at baseline were selected. Case subjects (who later developed type 2 diabetes), and control subjects (n = 71 pairs) were matched for BMI, age, and sex. Adiponectin, C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor-alpha, phospholipase A2 (sPLA2), soluble E-selectin (SE-selectin), soluble intracellular adhesion molecule-1, soluble vascular adhesion molecule-1, and von Willebrand factor (vWF) were measured in baseline samples.Results: Adiponectin was negatively correlated with CRP (r = -0.25, P < 0.05), IL-6 (r = -0.20, P < 0.05), sPLA2 (r = -0.22, P < 0.05), and SE-selectin (r = -0.20, P < 0.05). CRP and IL-6 did not predict diabetes. Only vWF predicted the development of diabetes (incidence rate ratio 0.67 for a 1-SD difference, 95% CI 0.41-1.00, P = 0.05), but this was not significant after adjustment for age, glucose, HbA(1c), waist circumference, and fasting insulin (hazard rate ratio 0.73, 95% CI 0.46-1.16, P = 0.18).Conclusions: Adiponectin is negatively correlated with markers of inflammation in vivo. In case and control subjects matched for BMI, with the exception of vWF, none of the inflammatory markers predicted diabetes. Adiponectin may be the link between adiposity, inflammation, and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: In a combination of in vivo and in vitro studies, we investigated mechanisms via which α-tocopherol, a lipid soluble form of vitamin E, can directly affect endothelial activation as induced by H2O2 and TNFα. Methods: We measured effects of α-tocopherol on H2O2-induced lipid peroxidation as determined with a fluorescent C-11 BODIPY581/591 probe and on adhesion molecule expression in cultured endothelial cells. In 20 healthy volunteers treated with increasing doses of α-tocopherol up to 800 IU/ml for 12 weeks, plasma levels of soluble cell adhesion molecules (sCAMs) and C-reactive protein were measured. Results: We showed that α-tocopherol protects cultured endothelial cells against H2O2-induced lipid peroxidation, while TNFα did not induce lipid peroxidation. Moreover, α-tocopherol attenuated H2O2-, but not TNFα-induced increases in adhesion molecule expression. In healthy persons, α-tocopherol decreased plasma levels of sE-selectin from 65±6 to 60±6 ng/ml (P=0.002), sVCAM from 893±31 to 853±23 ng/ml (P=0.022), and sICAM from 483±21 to 463±16 ng/ml (P=0.048). C-Reactive protein, as a sensitive marker of low grade inflammation, was not significantly affected. Conclusion: α-Tocopherol specifically inhibits lipid peroxidation-induced endothelial activation in vitro. The observed vitamin E-induced decrease in sCAMs in control subjects suggests that lipid peroxidation can take place in healthy individuals. Although vitamin E supplementation may be especially effective in specific groups of patients exposed to increased oxidative stress, our study suggests that vitamin E supplementation can be of benefit in healthy individuals as well. [Copyright &y& Elsevier]

Objective: In 196 type 1 diabetic subjects and 195 nondiabetic subjects aged 30-55 years, we examined whether C-reactive protein (CRP) is elevated in diabetes and whether CRP is associated with coronary artery calcification (CAC).Research Design and Methods: CRP was measured with a highly sensitive immunoassay. CAC was measured using electron beam computed tomography.Results: CRP was elevated in diabetic women compared with nondiabetic women (median 1.62 vs. 0.85 mg/l, P < 0.001) independently of other factors, but was similar in diabetic and nondiabetic men (median 0.82 vs. 0.81 mg/l). Insulin dose per day was positively correlated with CRP in diabetic women (Spearman's rho = 0.36, P = 0.0003) but much less so in men (rho = 0.16, P = 0.09). Being in the top tertile for CRP was associated with CAC in diabetic and nondiabetic men even after adjustment for other risk factors (adjusted odds ratio [OR] = 4.6 and 4.3, respectively, P = 0.02 for both). In nondiabetic women, being in the top tertile for CRP was associated with CAC (OR 3.1, P = 0.04), but not independently of BMI (OR = 1 after adjustment). Among diabetic women the association was not significant even before adjustment for BMI (OR = 2.6, P = 0.07).Conclusions: Elevated CRP in diabetic women might reflect a particular sensitivity to insulin levels or might reflect insulin resistance. In general, CRP is an important marker of subclinical atherosclerosis, but the clinical significance of elevated CRP in diabetic women needs to be addressed in prospective studies, since CRP was not clearly associated with CAC in this group. [ABSTRACT FROM AUTHOR]

Several studies have shown that humoral markers of inflammation and endothelial dysfunction are predictive of macrovascular events, and correlated with indirect measures of adiposity and insulin action, thus providing a possible link between obesity, insulin resistance and atherosclerosis. We examined the relationship between humoral markers of inflammation and endothelial dysfunction and direct measures of adiposity and insulin action in Pima Indians, a population with a very high prevalence of obesity and insulin resistance, but a relatively low propensity for atherosclerotic disease. Fasting plasma concentrations of the inflammatory markers C-reactive protein (CRP), secretory phospholipase A2 (sPLA2) and soluble intercellular adhesion molecule-1 (sICAM-1) and of the endothelial markers E-selectin and von Willebrand factor (vWF) were measured in 32 non-diabetic Pima Indians (18 M/14 F, age 27±1 years) in whom percent body fat and insulin-stimulated glucose disposal (M) were assessed by DEXA and a hyperinsulinemic clamp, respectively. CRP, sPLA2, and sICAM-1 were all positively correlated with percent body fat (r=0.71, 0.57, and 0.51, all P<0.01). E-selectin and vWF were not correlated with percent body fat, but were negatively correlated with M (r=−0.65 and −0.46, both P<0.001) and positively correlated with CRP (r=0.46, and 0.33, both P<0.05). These findings indicate that humoral markers of inflammation increase with increasing adiposity in Pima Indians whereas humoral markers of endothelial dysfunction increase primarily in proportion to the degree of insulin resistance and inflammation. Thus, obesity and insulin resistance appear to be associated with low-grade inflammation and endothelial dysfunction, respectively, even in an obesity- and diabetes-prone population with relatively low propensity for atherosclerosis. [Copyright &y& Elsevier]

Investigates the metabolism of homocysteine in chronic renal failure. Role of hyperhomocysteinemia in the progression of atherothrombotic disease; Relationship between glomerular filtration rate and plasma homocysteine level; Impairment of homocysteine remethylation in dialysis patients.

The article compares' risks of all-cause and cardiovascular disease (CVD) mortality in the American Diabetes Association and the United Nations World Health Organization glucose tolerance categories after 9 years of follow-up in the Hoorn Study and to study the test-retest reproducibility of those categories. Subjects with known diabetes had a four to five times higher risk of all-cause and CVD mortality compared with normal subjects. Both sets of diagnostic criteria identify criteria-specific diabetic subjects with an increased mortality risk compared with normal subjects, and the reproducibility of both criteria is similar.

Background: Moderate to vigorous physical activity (MVPA) can help to prevent depression, but identification of the most important psycho-biological pathways involved is unclear. The improvement of cardio-respiratory fitness (CRF) in response to MVPA can vary markedly, we therefore examined the association between CRF and the incidence of depressive symptoms.Methods: We used data from The Maastricht Study, a large population-based prospective-cohort study. CRF was estimated at baseline from a graded submaximal exercise protocol and MVPA was measured with accelerometry. Depressive symptoms were assessed using the validated Dutch version of the 9-item Patient Health Questionnaire, both at baseline and during annual follow-up over five years. Cox proportional hazards models were used.Results: A total of 1,730 individuals without depressive symptoms at baseline were included in the analysis. During the 5-year follow-up, n = 166 (9.6%) of individuals developed depressive symptoms. Compared to individuals with a low CRF, those with a moderate-to-high CRF had a significantly lower risk of developing depressive symptoms, independent of MVPA (medium CRF: HR = 0.49 (95%CI = 0.33-0.72); high CRF: HR = 0.48 (95% CI = 0.30-0.75). These associations were adjusted for age, sex, level of education, diabetes status, smoking status, alcohol use, energy intake, waist circumferences and antidepressant medications.Limitations: PHQ-9 is a validated screening instrument, but it is not a diagnostic tool of depression.Conclusions: Higher CRF was strongly associated with a lower risk of incident depressive symptoms over 5-year follow-up, independent of the level of MVPA at baseline, suggesting that interventions aimed at improving CRF could reduce the risk of depression. [ABSTRACT FROM AUTHOR]

Objective: Diabetes is a risk factor for severe limb ischemia (SLI), a condition associated with high mortality, morbidity, and limb loss. The reactive glucose-derived dicarbonyl methylglyoxal (MGO) is a major precursor for advanced glycation end products (AGEs) and a potential driver of cardiovascular disease. We investigated whether plasma MGO levels are associated with poor outcomes in SLI.Research Design and Methods: We measured plasma levels of MGO, free AGEs, and d-lactate, the detoxification end product of MGO, with ultraperformance liquid chromatography-tandem mass spectrometry at baseline in 160 patients (64.8 ± 13.3 years, 67.5% male, 37.5% with diabetes) with no-option SLI and recorded major adverse outcomes (n = 86, comprising n = 53 deaths and n = 49 amputations [first event counted]) over the 5-year follow-up. Data were analyzed with linear or Cox regression, after Ln-transformation of the independent variables, adjusted for sex, age, trial arm, diabetes, estimated glomerular filtration rate, systolic blood pressure, cholesterol levels, and BMI. Associations are reported per 1 SD plasma marker.Results: Higher plasma MGO levels were associated with more adverse outcomes (relative risk 1.44; 95% CI 1.11-1.86) and amputations separately (1.55; 1.13-2.21). We observed a similar but weaker trend for mortality (1.28; 0.93-1.77). The MGO-derived AGE Nε-(carboxyethyl)lysine was also associated with more adverse outcomes (1.46; 1.00-2.15) and amputations (1.71; 1.04-2.79). d-Lactate was not associated with adverse incident outcomes. Higher plasma MGO levels were also associated with more inflammation and white blood cells and fewer progenitor cells.Conclusions: Plasma MGO levels are associated with adverse outcomes in SLI. Future studies should investigate whether MGO-targeting therapies improve outcomes in SLI. [ABSTRACT FROM AUTHOR]

The risk of pulmonary embolism (PE) in patients with Coronavirus Disease 2019 (COVID-19) is recognized. The prevalence of PE in patients with respiratory deterioration at the Emergency Department (ED), the regular ward, and the Intensive Care Unit (ICU) are not well-established. We aimed to investigate how often PE was present in individuals with COVID-19 and respiratory deterioration in different settings, and whether or not disease severity as measured by CT-severity score (CTSS) was related to the occurrence of PE. Between April 6th and May 3rd, we enrolled 60 consecutive adult patients with confirmed COVID-19 from the ED, regular ward and ICU who met the pre-specified criteria for respiratory deterioration. A total of 24 (24/60: 40% (95% CI: 28–54%)) patients were diagnosed with PE, of whom 6 were in the ED (6/23: 26% (95% CI: 10–46%)), 8 in the regular ward (8/24: 33% (95% CI: 16–55%)), and 10 in the ICU (10/13: 77% (95% CI: 46–95%)). CTSS (per unit) was not associated with the occurrence of PE (age and sex-adjusted OR 1.06 (95%CI 0.98–1.15)). The number of PE diagnosis among patients with COVID-19 and respiratory deterioration was high; 26% in the ED, 33% in the regular ward and 77% in the ICU respectively. In our cohort CTSS was not associated with the occurrence of PE. Based on the high number of patients diagnosed with PE among those scanned we recommend a low threshold for performing computed tomography angiography in patients with COVID-19 and respiratory deterioration. • The high prevalence of pulmonary embolism in COVID-19 is not limited to the ICU • Respiratory deterioration in COVID-19 patients should prompt a low threshold CTPA • Regular thromboprophylaxis may be insufficient to prevent PE in COVID-19 patients [ABSTRACT FROM AUTHOR]

• A validated UPLC-MS/MS method for the determination of fructose in serum and urine. • Rapid in use, simple sample pretreatment, and high throughput analysis. • Accurate and precise measurement of fructose in the micromolar range. • Clinical application is demonstrated in a number of exploratory experiments. The study of the involvement of fructose in the pathogenesis of cardiometabolic disease requires accurate and precise measurements of serum and urinary fructose. The aim of the present study was to develop and validate such a method by Ultra Performance Liquid Chromatography–tandem Mass Spectrometry (UPLC-MS/MS). Fructose was quantified using hydrophilic interaction UPLC-MS/MS with a labelled internal standard. Serum fructose levels were determined in healthy individuals (n = 3) after a 15-gram oral fructose load. Twenty-four hours urinary fructose levels were determined in individuals consuming low (median: 1.4 g/day, interquartile range [IQR]: 0.9–2.0; n = 10), normal (31 g/day, 23–49; n = 15) and high (70 g/day, 55–84; n = 16) amounts of fructose. The calibration curves showed perfect linearity in water, artificial, serum, and urine matrices (r2 > 0.99). Intra- and inter-day assay variation of serum and urinary fructose ranged from 0.3 to 5.1% with an accuracy of ~98%. Fasting serum fructose levels (5.7 ± 0.6 µmol/L) increased 60 min after a 15-gram oral fructose load (to 150.3 ± 41.7 µmol/L) and returned to normal after 180 min (8.4 ± 0.6 µmol/L). Twenty-four hours urinary fructose levels were significantly lower in low fructose consumers when compared to normal and high fructose consumers (median: 36.1 µmol/24 h, IQR: 26.4–64.2; 142.3 µmol/24 h, 98.8–203.0; and 238.9 µmol/24 h, 127.1–366.1; p = 0.004 and p < 0.001, respectively). Fructose concentrations can be measured accurately and precisely with this newly-developed UPLC-MS/MS method. Its robustness makes it suitable for assessing the value of fructose in clinical studies. [ABSTRACT FROM AUTHOR]

Objective: Type 2 diabetes has been associated with depression. However, the underlying pathophysiological mechanisms remain unknown. Cerebral small vessel disease, a consequence of diabetes, may lead to depression. Therefore, we evaluated whether cerebral small vessel disease mediates the association between type 2 diabetes and higher depressive symptoms.Research Design and Methods: We used longitudinal data from the population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, with examinations from 2002 to 2006 and 5 years later. Type 2 diabetes was defined as self-reported history of type 2 diabetes, use of blood glucose-lowering drugs, or fasting blood glucose level ≥7.0 mmol/L. Cerebral small vessel disease load was quantified in a composite score based on MRI-defined presence of high white matter hyperintensity volume, low total brain parenchyma volume, and subcortical infarcts, cerebral microbleeds, and large perivascular spaces. The 5-year change in the 15-item Geriatric Depression Scale score (GDS-15) was measured between baseline and follow-up.Results: Included were 2,135 individuals without dementia and baseline depression (baseline age 74.5 [SD 4.6] years, 1,245 women [58.3%], and 197 [9.2%] with diabetes). The GDS-15 score increased 0.4 (SD 1.6) points over time. Baseline diabetes was associated with a greater increase in the GDS-15 score (β = 0.337; 95% CI 0.094; 0.579), adjusted for age, sex, education, and cardiovascular risk factors. Baseline cerebral small vessel disease and change of cerebral small vessel disease statistically significantly mediated a part of this association.Conclusions: Type 2 diabetes is associated with a greater increase in depressive symptoms score over 5 years, and cerebral small vessel disease partly explains this association. [ABSTRACT FROM AUTHOR]

Purpose: In individuals with diabetes, injury to the corneal nerve fibres predisposes to delayed corneal epithelial healing, reduced corneal sensitivity and corneal erosion. We investigated to what extent a reduction in corneal nerve fibre length (CNFL) is present in individuals with prediabetes or type 2 diabetes (DM2) compared with individuals with normal glucose metabolism (NGM). Methods: Using composite images acquired by corneal confocal microscopy, we assessed total CNFL per mm2 in the subbasal nerve plexus of the cornea in 134 participants (mean age 59 ± 8 years, 49% men, 87 NGM, 20 prediabetes, 27 DM2). Multivariable linear regression was used to assess the association between CNFL and glucose metabolism status, adjusted for age and sex. Results: In individuals with type 2 diabetes, the mean CNFL was significantly reduced [β = −1.86 mm/mm2 (95% CI −3.64 to −0.08), p = 0.04], as compared with individuals with normal glucose metabolism after adjustment for age and sex. Part of the reduction was present in individuals with prediabetes [β = −0.96 mm/mm2 (95% CI −2.91 to 0.99), p = 0.34], with a linear trend of corneal nerve fibre reduction with severity of glucose metabolism status (p trend = 0.04). Conclusions: A significant reduction in CNFL was found in individuals with DM2 compared with individuals with NGM. A trend of reduction in CNFL was observed between individuals with NGM and prediabetes. The reduction in corneal nerve fibre length could contribute to a delayed corneal healing and an increased risk for corneal complications after surgery. [ABSTRACT FROM AUTHOR]

Objective: Physical activity may provide a means for the prevention of cardiovascular disease via improving microvascular function. Therefore, this study investigated whether physical activity is associated with skin and retinal microvascular function. Methods: In The Maastricht Study, a population‐based cohort study enriched with type 2 diabetes (n = 1298, 47.3% women, aged 60.2 ± 8.1 years, 29.5% type 2 diabetes), we studied whether accelerometer‐assessed physical activity and sedentary time associate with skin and retinal microvascular function. Associations were studied by linear regression and adjusted for major cardiovascular risk factors. In addition, we investigated whether associations were stronger in type 2 diabetes. Results: In individuals with type 2 diabetes, total physical activity and higher‐intensity physical activity were independently associated with greater heat‐induced skin hyperemia (regression coefficients per hour), respectively, 10 (95% CI: 1; 18) and 36 perfusion units (14; 58). In individuals without type 2 diabetes, total physical activity and higher‐intensity physical activity were not associated with heat‐induced skin hyperemia. No associations with retinal arteriolar %‐dilation were identified. Conclusion: Higher levels of total and higher‐intensity physical activity were associated with greater skin microvascular vasodilation in individuals with, but not in those without, type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Glucose variability (GV) measured by continuous glucose monitoring (CGM) has become an accepted marker of glycemic control. Nevertheless, several methodological aspects of GV assessment require further study. We, therefore, investigated the minimum number of days needed to reliably measure GV, assessed GV reference values, and studied the correlation of GV with established glycemic indices (i.e., HbA1c, seven-point oral glucose tolerance test [OGTT]-derived indices). Methods: We used cross-sectional data from The Maastricht Study, an observational population-based cohort enriched with type 2 diabetes. Participants with more than 48 h of CGM (iPro2; Medtronic) were included for analysis (n = 851; age: 60 ± 9years; 49% women; 23% type 2 diabetes). We used mean sensor glucose (MSG), standard deviation (SD), and coefficient of variation (CV) as CGM-derived indices (the latter two for GV quantification). We calculated reliability using the Spearman-Brown prophecy formula, established reference values by calculating 2.5th-97.5th percentiles, and studied correlations using Spearman's rho. Results: Sufficient reliability (R > 0.80) was achieved with two (MSG and SD), or three monitoring days (CV). The reference ranges, assessed in individuals with normal glucose metabolism (n = 470), were 90.5-120.6 mg/dL (MSG), 7.9-24.8 mg/dL (SD), and 7.74%-22.45% (CV). For MSG, the strongest correlation was found with fasting plasma glucose (rho = 0.65 [0.61; 0.69]); for SD, with the 1-h OGTT value (rho = 0.61 [0.56; 0.65]); and for CV, with both the incremental glucose peak (IGP) during the OGTT (rho = 0.50 [0.45; 0.55]) and the 1-h OGTT value (rho = 0.50 [0.45; 0.55]). Conclusions: The reliability findings and reference values are relevant for studies that aim to investigate CGM-measured GV. One-hour OGTT and IGP values can be used as GV indices when CGM is unavailable. [ABSTRACT FROM AUTHOR]

Objective: Low heart rate variability (HRV), a marker for cardiac autonomic dysfunction, is a known feature of type 2 diabetes, but it remains incompletely understood whether this also applies to prediabetes or across the whole glycemic spectrum. Therefore, we investigated the association among prediabetes, type 2 diabetes, and measures of glycemia and HRV.Research Design and Methods: In the population-based Maastricht Study (n = 2,107; mean ± SD age 59 ± 8 years; 52% men; normal glucose metabolism [n = 1,226], prediabetes [n = 331], and type 2 diabetes [n = 550, oversampled]), we determined 24-h electrocardiogram-derived HRV in time and frequency domains (individual z-scores, based upon seven and six variables, respectively). We used linear regression with adjustments for age, sex, and major cardiovascular risk factors.Results: After adjustments, both time and frequency domain HRV were lower in prediabetes and type 2 diabetes as compared with normal glucose metabolism (standardized β [95% CI] for time domain: -0.15 [-0.27; -0.03] and -0.34 [-0.46; -0.22], respectively, P for trend <0.001; for frequency domain: -0.14 [-0.26; -0.02] and -0.31 [-0.43; -0.19], respectively, P for trend <0.001). In addition, 1-SD higher glycated hemoglobin, fasting plasma glucose, and 2-h postload glucose were associated with lower HRV in both domains (time domain: -0.16 [-0.21; -0.12], -0.16 [-0.21; -0.12], and -0.15 [-0.20; -0.10], respectively; frequency domain: -0.14 [-0.19; -0.10], -0.14 [-0.18; -0.09], and -0.13 [-0.18; -0.08], respectively).Conclusions: Both prediabetes and type 2 diabetes were independently associated with lower HRV. This is further substantiated by independent continuous associations between measures of hyperglycemia and lower HRV. These data strongly suggest that cardiac autonomic dysfunction is already present in prediabetes. [ABSTRACT FROM AUTHOR]

Dynamic sitting, such as fidgeting and desk work, might be associated with health, but remains difficult to identify out of accelerometry data. We examined, in a laboratory study, whether dynamic sitting can be identified out of triaxial activity counts. Among 18 participants (56% men, 27.3 ± 6.5 years), up to 236 counts per minute were recorded in the anteroposterior and mediolateral axes during dynamic sitting using a hip-worn accelerometer. Subsequently, we examined in 621 participants (38% men, 80.0 ± 4.7 years) from the AGES-Reykjavik Study whether dynamic sitting was associated with cardio-metabolic health. Compared to participants who recorded the fewest dynamic sitting minutes (Q1), those with more dynamic sitting minutes had a lower BMI (Q2 = −1.39 (95%CI = −2.33;–0.46); Q3 = −1.87 (−2.82;–0.92); Q4 = −3.38 (−4.32;–2.45)), a smaller waist circumference (Q2 = −2.95 (−5.44;–0.46); Q3 = −3.47 (−6.01;–0.93); Q4 = −8.21 (−10.72;–5.71)), and a lower odds for the metabolic syndrome (Q2 = 0.74 [0.45;1.20] Q3 = 0.58 [0.36;0.95]; Q4 = 0.36 [0.22;0.59]). Our findings suggest that dynamic sitting might be identified using accelerometry and that this behaviour was associated with health. This might be important given the large amounts of time people spend sitting. Future studies with a focus on validation, causation and physiological pathways are needed to further examine the possible relevance of dynamic sitting. [ABSTRACT FROM AUTHOR]

Physical activity (PA) constitutes an established protective factor while sedentary behavior (SB) an emerging independent risk factor for cardiovascular diseases. This study evaluated the association of PA and SB with endothelial dysfunction (ED) depending on kidney function status. Cross-sectional data from the prospective, population-based Maastricht Study were used. PA and SB were measured using the ActivPAL3 accelerometer 24h/day for eight consecutive days. ED was evaluated by plasma levels of soluble vascular cell adhesion protein-1, intercellular adhesion molecule-1, E-selectin and von Willebrand factor, which were combined into an ED score with higher values depicting higher ED. Overall, 2,668 participants, 323 with chronic kidney disease, were included. In normal kidney function individuals, the ED score presented a significant negative association with total, lower-intensity and moderate-to-vigorous PA duration and a positive association with total sedentary time, sedentary breaks and sedentary bout duration. In participants with chronic kidney disease, a significant negative association of ED score with total [ β : -4.42, 95% confidence intervals (95% CI): -7.98; −0.87] and lower-intensity (β : -7.08, 95% CI: -13.41; −0.74) PA duration, as well as a positive association of ED score with sedentary bout duration (β : 43.72, 95% CI: 9.85; 77.59) were noted. The strength of associations did not significantly differ across kidney function subgroups (p > 0.05). This analysis showed that PA duration is inversely associated with ED both among patients with normal kidney function and chronic kidney disease. In chronic kidney disease, longer sedentary bouts were associated with greater endothelial dysfunction. [Display omitted] • Endothelial dysfunction is inversely associated with physical activity duration. • Sedentary behavior is associated with higher endothelial dysfunction score. • These associations are not modified by the presence of chronic kidney disease. • Endothelial dysfunction in chronic kidney disease is linked to lower physical activity. • In chronic kidney disease, endothelial dysfunction is associated with sedentary bouts duration. [ABSTRACT FROM AUTHOR]

The article presents the discussion on showing the substitution of low- and no-calorie sweetened beverages for sugarsweetened beverages. Topics include KHK catalyzing the phosphorylation of fructose, the main caloric constituent of sugarsweetened beverages; and minor A allele, a common missense variant in KHK being associated with greater urinary fructose excretion and protection from colorectal cancer.

Abstract Background and aims Familial combined hyperlipidemia (FCHL) is a complex dyslipidemia associated with premature cardiovascular disease (CVD). The present study was conducted to 1) determine the incidence of CVD in FCHL in this era of protocolled, primary prevention; and 2) examine whether cardiovascular risk estimation based on the Systemic Coronary Risk Estimation (SCORE) chart, as proposed in the 2016 ESC/EAS guidelines for the management of dyslipidemia, is justified in FCHL. Methods FCHL patients, their normolipidemic (NL) relatives and spouses originally included in our baseline cohort in 1998–2005 (n = 596) were invited for a follow-up visit to determine the incidence of CVD, defined as (non-)fatal coronary artery disease, ischemic stroke and peripheral artery disease requiring invasive treatment. Results Follow-up data (median: 15 years) was acquired for 85% of the original cohort. The cumulative incidence of CVD was significantly higher in FCHL patients than in spouses (23.6% versus 4.7%; hazard ratio (HR): 5.4, 95%CI: 2.0–14.6; HR after adjustment for risk factors included in SCORE: 4.7, 95%CI: 1.6–13.8), but not in NL relatives compared to spouses (5.8% versus 4.7%). The SCORE chart tended to overestimate CVD risk in the spouses (observed [O]/expected [E] ratio:0.2, p = 0.01), but not in FCHL patients (O/E:1.3, p = 0.50). Conclusions Risk of primary CVD is still substantially increased in FCHL patients, despite preventive measures. The overestimation of CVD risk by the SCORE chart – a nowadays frequently observed phenomenon thanks to improved primary prevention – was not seen in FCHL. These results suggest that more aggressive treatment is justified to avoid excessive CVD in FCHL. Graphical abstract Image 1 Highlights • Three quarters of familial combined hyperlipidemia (FCHL) patients receive lipid lowering treatment. • The 15-year incidence of cardiovascular disease is still very high in FCHL. • The SCORE risk factors do not fully account for the increased risk in FCHL. [ABSTRACT FROM AUTHOR]

Purpose: To calculate the prevalence of all vitreomacular interface (VMI) disorders and stratify according to age, sex and (pre)diabetes status. Methods: The presence of VMI disorders was assessed in 2660 participants aged between 40 and 75 years from The Maastricht Study who had a gradable macular spectral‐domain optical coherence tomography (SD‐OCT) volume scan in at least one eye [mean 59.7 ± 8.2 years, 50.2% men, 1531 normal glucose metabolism (NGM), 401 prediabetes, 728 type 2 diabetes (DM2, oversampled)]. A stratified and multivariable logistic regression analysis was used. Results: The prevalence of the different VMI disorders for individuals with NGM, prediabetes and DM2 was, respectively, 5.7%, 6% and 6.7% for epiretinal membranes; 6%, 9.6% and 6.8% for vitreomacular traction; 1.1%, 0.7% and 0.3% for lamellar macular holes; 0.1%, 0% and 0% for pseudoholes; 1.1%, 1.9% and 5.5% for macular cysts. None of the participants was diagnosed with a macular hole. The prevalence of epiretinal membranes, vitreomacular traction and macular cysts was higher with age (p < 0.001). Vitreomacular traction and lamellar macular holes were more frequent in women (p < 0.01). DM2 is positively associated [OR = 3.9 (95% CI 2.11–7.22, p < 0.001)] with macular cysts and negatively associated with lamellar macular holes [OR = 0.2 (95% CI 0.04–0.9, p = 0.036)] after adjustment for age and sex. The calculated prevalence of VMI disorders was 15.9%. Conclusions: The calculated prevalence of VMI disorders in individuals aged between 40 and 75 years is 15.9%. The prevalence depends on age, sex and glucose metabolism status for several types of VMI disorders. [ABSTRACT FROM AUTHOR]

MRI features of cerebral small vessel disease (CSVD), i.e. white matter hyperintensities, lacunes, microbleeds, perivascular spaces, and cerebral atrophy, may be associated with clinical events, but the strength of these associations remains unclear. We conducted a systematic review and meta-analysis on the association between these features and incident ischaemic and haemorrhagic stroke, all-cause dementia and depression, and all-cause mortality. For the association with stroke, 36 studies were identified (number of individuals/events [n] = 38,432/4,136), for dementia 28 (n = 16,458/1,709), for depression nine (n = 9,538/1,746), and for mortality 28 (n = 23,031/2,558). Only two studies evaluated perivascular spaces; these results were not pooled. Pooled analyses showed that all other features were associated with all outcomes (hazard ratios ranged 1.22–2.72). Combinations of two features were more strongly associated with stroke than any individual feature. Individual features and combinations of CSVD features are strongly associated with incident ischaemic and haemorrhagic stroke, all-cause dementia and depression, and all-cause mortality. If these associations are causal, the strength of these associations suggests that a substantial burden of disease is attributable to CSVD. [ABSTRACT FROM AUTHOR]

Background: Arterial stiffening may underlie the association between depression and cardiovascular disease (CVD), but reported data are inconsistent. We investigated the associations between aortic stiffness and major depressive disorder (MDD) and depressive symptoms, and whether these differed by sex and age. Methods: We measured carotid to femoral pulse wave velocity (cfPWV) using applanation tonometry, and we assessed depression using the Mini-International Neuropsychiatric Interview (MINI) and the Patient Health Questionnaire-9 (PHQ-9) in a cohort of participants from The Maastricht Study. Logistic and negative binominal models were adjusted for age, type 2 diabetes mellitus (T2DM), mean arterial pressure (MAP) and CVD risk factors. Results: We included 2757 participants in our analyses (48.8% men, mean age 59.8 ± 8.1 yr, 27% T2DM). We found that cfPWV was associated with MDD in men (fully adjusted odds ratio [OR] 2.36, 95% confidence interval [CI] 1.45-3.84), but not in women (OR 1.57, 95% CI 0.93-2.66), aged 60 years or younger. The ORs were not significant in individuals older than 60 years (men: OR 1.03, 95% CI 0.63-1.68; women: OR 0.64, 95% CI 0.32-1.31). Similarly, cfPWV was associated with a higher PHQ-9 score in men (rate ratio 1.28, 95% CI 1.09-1.52), but not in women (rate ratio 1.11, 95% CI 0.99-1.23), aged 60 years or younger. Associations were not significant in individuals older than 60 years (men: rate ratio 0.96, 95% CI 0.84-1.08; women: rate ratio 1.00, 95% CI 0.90-1.12). Limitations: We cannot rule out reversed causation in this cross-sectional study. Conclusion: Greater aortic stiffness is associated with MDD and depressive symptoms among middle-aged men and to a lesser extent in women, whereas this association was not observed in old age. [ABSTRACT FROM AUTHOR]

Aims: To evaluate whether participant characteristics and way of expressing circulating fatty acids (FA) influence the strengths of associations between self-reported intake and circulating levels of linoleic acid (LA), alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Methods: Cross-sectional analyses were performed in pooled data from the CODAM (n = 469) and Hoorn (n = 702) studies. Circulating FA were measured by gas liquid chromatography and expressed as proportions (% of total FA) and concentrations (µg/mL). Dietary intakes were calculated from a validated food frequency questionnaire. Effects of participant characteristics on associations between dietary and circulating FA were calculated using interaction analyses. Results: Standardized regression coefficients between dietary FA and proportions of circulating FA (% of total FA) were LA β = 0.28, ALA β = 0.13, EPA β = 0.34, and DHA β = 0.45. Body mass index (BMI), waist circumference, and presence of CVD influenced associations for LA; gender influenced LA, EPA, and DHA; alcohol intake influenced LA and DHA; and glucose tolerance status influenced ALA (p values interaction <0.05). Coefficients for circulating FA as concentrations were LA β = 0.19, ALA β = 0.10, EPA β = 0.31, and DHA β = 0.41. Conclusions: This study suggests that characteristics such as BMI, alcohol intake, and expressing circulating FA as proportions or concentrations, influence associations between dietary and circulating FA. [ABSTRACT FROM AUTHOR]