Clinical and Subclinical Macrovascular Disease as Predictors of Cognitive Decline in Older Patients With Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study

OBJECTIVE

Macrovascular disease may contribute to increased risk of accelerated cognitive decline in patients with type 2 diabetes. We aimed to determine associations of measures of macrovascular disease with cognitive change in a cognitively healthy older population with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Eight hundred thirty-one men and women (aged 60–75 years) attended two waves of the prospective Edinburgh Type 2 Diabetes Study (ET2DS). At baseline, clinical and subclinical macrovascular disease was measured, including cardiovascular event history, carotid intima-media thickness (cIMT), ankle brachial index (ABI), and serum N-terminal probrain natriuretic peptide (NT-proBNP). Seven neuropsychological tests were administered at baseline and after 4 years; scores were combined to a standardized general ability factor (g). Adjustment of follow-up g for baseline g assessed 4-year cognitive change. Adjustment for vocabulary (estimated premorbid ability) was used to estimate lifetime cognitive change.

RESULTS

Measures of cognitive decline were significantly associated with stroke, NT-proBNP, ABI, and cIMT, but not with nonstroke vascular events. The association of stroke with increased estimated lifetime cognitive decline (standardized β, −0.12) and of subclinical markers with actual 4-year decline (standardized β, −0.12, 0.12, and −0.15 for NT-proBNP, ABI, and cIMT, respectively) reached the Bonferroni-adjusted level of statistical significance (P < 0.006). Results altered only slightly on adjustment for vascular risk factors.

CONCLUSIONS

Stroke and subclinical markers of cardiac stress and generalized atherosclerosis are associated with cognitive decline in older patients with type 2 diabetes. Further investigation into the potential use of subclinical vascular disease markers in predicting cognitive decline is warranted.Cognitive abilities are essential for independent living in later life, and some domains of cognitive functioning decline in mean level from relatively early adulthood (1). Age-related cognitive decline is accompanied by pathological changes in the brain, including cerebral microvascular changes, and although individual differences exist in the severity of age-related microvascular damage in the brain, this is difficult to investigate noninvasively. Systemic atherosclerotic changes in the body may serve as a marker of vascular-related changes in the brain (2) that, in turn, lead to cognitive deficits (3,4). However, the potential of large vessel changes distant from the brain itself to function as markers of cognitive decline remains unclear. We aimed to study a range of measures of clinical and subclinical macrovascular disease that focus on different areas of the vasculature or different underlying pathophysiological mechanisms to assess which of these might function as proxies of cognitive decline.Understanding the role of macrovascular disease in age-related cognitive impairment is particularly important in diabetes, given the higher prevalence of atherosclerotic large vessel disease as well as the accelerated cognitive decline and increased risk of cognitive impairment (5,6) associated with this condition, and the potentially modifiable nature of macrovascular disease (7). The prevalence of stroke, of transient ischemic attack (TIA) (8), and of coronary heart disease (9) are higher in diabetic populations than in nondiabetic populations, and average natriuretic peptide levels, a marker of cardiac stress, are increased (10). Markers of subclinical atherosclerosis also are altered, with increased average carotid intima-media thickness (cIMT) (11) and reduced mean ankle brachial index (ABI) (12). Despite this, investigation into the role of macrovascular disease in age-related cognitive impairment in people with diabetes is limited compared with investigation into this issue in the general (predominantly nondiabetic) population. We set out to determine the association of a variety of measures of subclinical macrovascular disease and cardiovascular event categories with cognitive decline in a sample of older people, all of whom had diabetes (the Edinburgh Type 2 Diabetes Study [ET2DS]). We did so using two cognitive outcomes, actual late-life cognitive change over a 4-year period and estimated lifetime cognitive change. These analyses are timely given the increasing prevalence of diabetes at younger ages (13) that, together with greater survival (14) and greater lifetime exposure to diabetes in current generations, is likely to contribute to increasing prevalence of cognitive impairment.     

Activin A-Induced Differentiation of Embryonic Stem Cells into Endoderm and Pancreatic Progenitors—The Influence of Differentiation Factors and Culture Conditions

The differentiation of murine and human embryonic stem (ES) cells into pancreatic cell types has been shown by several methods including spontaneous differentiation, formation of multi-lineage progenitors, lineage selection or transgene expression. However, these strategies led to a mixture of cells of all three primary germ layers and only a low percentage of definitive endoderm cells giving rise to pancreas, liver, lung and intestine. To reproducibly generate functional insulin-producing cells, ES cells have to be differentiated via definitive endoderm and pancreatic endocrine progenitors recapitulating the in vivo development. Activin A, a member of the transforming growth factor beta superfamily, has been shown to induce definitive endoderm cells dependent on concentration, culture conditions and time of application. Moreover, serum components or contamination by feeder cells as well as differentiation and proliferation factors are critical for successful generation of activin A-induced ES cells into endoderm and pancreatic cells. The review presents an overview on those factors that influence activin A activity on endoderm and endocrine progenitor cells and determines the role of signaling factors in the differentiation process into the pancreatic lineage. Sabine Sulzbacher and Insa S. Schroeder contributed equally to this work.     

Short-term prognosis of patients admitted for probable acute coronary syndrome without ST-segment elevation. Role of new myocardial damage markers and acute-phase reactants

OBJECTIVES: The relative value of classic markers, myocardial damage variables, and levels of acute-phase reactants in establishing the pre-discharge prognosis of acute coronary syndrome without ST-segment elevation was analyzed. METHOD: We prospectively studied 385 consecutive patients admitted from our chest pain unit with a high-probability diagnosis of acute coronary syndrome without ST-segment elevation. The clinical and electrocardiographic data, myocardial damage markers (troponin I, CK-Mb mass, myoglobin), and acute-phase reactants (high-sensitivity C-reactive protein, fibrinogen) were recorded. RESULTS: During admission, 15 deaths (3.9%) and 16 complicative infarctions (4.2%) occurred, for a total of 31 major events (death and/or infarction: 8.1%). Age (p = 0.03), insulin-dependent diabetes (p = 0.009), and C-reactive protein (p = 0.05) were independently related to death. Fibrinogen was related to infarction (p = 0.01); by fibrinogen quartiles: 1.4%; 1.4%; 2.9%, and 11.7% (p = 0.02). Age (p = 0.01), insulin-dependent diabetes (p = 0.02), and C-reactive protein (p = 0.04) were independent predictors of major events; by C-reactive protein quartiles: 1.4%; 5.5%; 5.4%, and 16.7% (p = 0.004). Troponin I was related to major events (p = 0.03), but it was not an independent predictor. CONCLUSIONS: Acute-phase reactants add independent information to clinical variables in the short-term risk stratification of patients with an acute coronary syndrome. The predictive power of troponins is lower than that of other variables.     

In vitro differentiation of rat liver derived stem cells results in sensitization to TNFalpha-mediated apoptosis

Hepatic stem cells are activated after liver damage and have a critical role in tissue homeostasis and repair. Characterization of molecular and cellular events accompanying the expansion and differentiation of liver stem cells is essential for understanding the basic biology of stem cells and for facilitating clinical application of the stem cells. We assessed whether in vitro differentiation of putative hepatic progenitor (rat liver epithelial [RLE]) cells toward hepatocytic lineage affects the response to TNFalpha-mediated cytotoxicity, a common determinant of liver injury. The data show that 50% of differentiated cells underwent apoptosis after 6 hours of TNFalpha treatment whereas control RLE cells were resistant. Both cell types displayed mitochondrial depolarization and release of cytochrome c but the TNFalpha treatment resulted in activation of caspases 9 and 3 and the execution of apoptosis only in differentiated RLE cells. Apoptotic death was associated with increased ROS production and depletion of glutathione. Antioxidants completely prevented both glutathione depletion and apoptosis induced by TNFalpha in differentiated RLE cells. Conversely, glutathione-depleting agents sensitized control RLE cells to TNFalpha induced apoptosis. In conclusion, efficient antioxidant defense system involving glutathione renders hepatic progenitor cells resistant to TNFalpha-mediated apoptosis and acquisition of sensitivity to death stimuli is an implicit feature of the differentiation process. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).     

Phlegmasia cerulea dolens in patients with testicular carcinoma

We describe a case of phlegmasia cerulea dolens secondary to venous thrombosis due to compression of inferior vena cava, in a 31-year-old man with a germ cell tumour. He was treated with systemic thrombolytic agents, intravenous heparin and urgent chemotherapy He presented a complete tumoral response and complete revascularization of the vena cava and right femoral vein.     

Spinal Lesions as Clinical Manifestations of Plasma Cell Neoplasia

(1) Background: Plasma cell neoplasia can be separated into independent subtypes including multiple myeloma (MM) and solitary plasmacytoma of the bone (SBP). The first clinical signs patients present with are skeletal pain, most commonly involving ribs and vertebrae. (2) Methods: Retrospective analysis of 114 patients (38 female, 76 male) receiving spinal surgery from March 2006 until April 2020. Neurological impairments and surgical instability were the criteria for intervention in this cohort. Analysis was based on demographic data, Spinal Instability Neoplastic Score (SINS), location of the lesion, spinal levels of tumor involvement, surgical treatment, histopathological workup, adjuvant therapy, functional outcome, and overall survival (OS). (3) Results: The following surgical procedures were performed: posterior stabilization only in 9 patients, posterior stabilization and decompression without vertebral body replacement in 56 patients, tumor debulking and decompression only in 8 patients, anterior approach in combined approach without vertebral body replacement and without biopsy and/or without kyphoplasty in 33 patients, 3 patients received biopsies only, and 5 patients received kyphoplasty only. The histopathology diagnoses were MM in 94 cases and SBP in 20 cases. Median OS was 72 months (53.4–90.6 months). Preoperative KPSS was 80% (range 40–100%), the postoperative KPSS was 80% (range 50–100%). (4) Conclusions: Surgery for patients with plasma cell neoplasia is beneficial in case of neurological impairment and spinal instability. Moreover, we were able to show that patients with MM and a low number of spinal levels to be supplied have a better prognosis as well as a younger age at the time of the surgical intervention.     

Does a rise in plasma erythropoietin after high-altitude exposure affect FGF23 in healthy volunteers on a normal or low-phosphorus diet?

Background and aimsData of experimental rodent models suggest that hypoxia with subsequent increase in erythropoietin stimulates the expression of the phosphaturic hormone fibroblast growth factor 23 (FGF23).Methods and resultsTo translate the findings of animal studies into human physiology, herein we exposed eight healthy volunteers to high altitude (2656 m above sea level) for four days. The volunteers were randomized on a low-phosphorous diet (n = 4) or a normal phosphorus diet (n = 4). Although high-altitude exposure caused a significant increase in plasma erythropoietin (EPO) (before high-altitude exposure: low phosphorus: median EPO 6.6 mIU/ml [interquartile range (IQR) 6.0; 8.2], normal phosphorus: median EPO 9.0 mIU/ml [IQR 7.9; 11.5]; at day 2: low phosphorus: median EPO 21.3 mIU/ml [IQR 19.5; 23.8], normal phosphorus: median EPO 19.4 mIU/ml [IQR 18.0; 20.8]), there was no consistent increase in plasma c-terminal FGF23 or plasma intact FGF23. We observed only a single, intermittent peak in c-terminal FGF23 levels after 5 h of maximal aerobic exercise.ConclusionThese data do not support a substantial effect of moderate hypoxia alone on the expression of FGF23, but they suggest that combined exercise and high-altitude exposure may temporarily induce FGF23 expression.