The Ca 2ϩ /calmodulin-activated kinases CaMKK2 and CaMKIV are highly expressed in the brain where they play important roles in activating intracellular responses to elevated Ca 2ϩ . To address the biological functions of Ca 2ϩ signaling via these kinases during brain development, we have examined cerebellar development in mice null for CaMKK2 or CaMKIV. Here, we demonstrate that CaMKK2/ CaMKIV-dependent phosphorylation of cAMP response element-binding protein (CREB) correlates with Bdnf transcription, which is required for normal development of cerebellar granule cell neurons. We show in vivo and in vitro that the absence of either CaMKK2 or CaMKIV disrupts the ability of developing cerebellar granule cells in the external granule cell layer to cease proliferation and begin migration to the internal granule cell layer. Furthermore, loss of CaMKK2 or CaMKIV results in decreased CREB phosphorylation (pCREB), Bdnf exon I and IV-containing mRNAs, and brain-derived neurotrophic factor (BDNF) protein in cerebellar granule cell neurons. Reexpression of CaMKK2 or CaMKIV in granule cells that lack CaMKK2 or CaMKIV, respectively, restores pCREB and BDNF to wild-type levels and addition of BDNF rescues granule cell migration in vitro. These results reveal a previously undefined role for a CaMKK2/CaMKIV cascade involved in cerebellar granule cell development and show specifically that Ca 2ϩ -dependent regulation of BDNF through CaMKK2/CaMKIV is required for this process.
Aim: Cerebral white matter lesions (WML) are known to increase with age, as is left ventricular (LV) diastolic dysfunction with normal contraction. Although aging is a common risk factor, the link between these diseases is not fully understood. The aim was to clarify this relationship, using the ratio between early diastolic mitral inflow and early diastolic mitral annular tissue velocity (E/E'). E/E' measured by tissue Doppler echocardiography offers an indicator of the severity of LV diastolic dysfunction, reflecting both diastolic LV stiffness and diastolic LV filling pressure.
Methods:Participants comprised 75 patients aged between 65 and 75 years with normal LV contraction and no signs or history of symptomatic heart failure, ischemic heart diseases, atrial fibrillation, stroke, or cognitive dysfunction. The volume of WML was quantified on brain magnetic resonance imaging.
Results:The participants were classified into three groups: Low E/E', E/E' ≤ 8; Middle E/E', 8 < E/E' < 15; and High E/E', E/E' ≥ 15. WML volume was 3.6 ± 3.0 mL in Low E/E', 5.4 ± 6.5 mL in Middle E/E' and 12.0 ± 11.0 mL in High E/E', increasing significantly with increased diastolic LV stiffness (Low vs High, P = 0.034; Middle vs High, P = 0.016). Linear regression analysis showed the positive association between the volume of WML and E/E' ratio (r = 0.377, P = 0.0009).
Conclusions:This investigation identified an association between LV diastolic dysfunction and WML. Further investigations are required to clarify whether there is a direct association between the two diseases. Geriatr Gerontol Int 2014; 14 (Suppl. 2): 71-76.Keywords: cerebral white matter lesions, left ventricular diastolic dysfunction, ratio of early diastolic mitral inflow to early diastolic mitral annular tissue velocity.
Type 2 diabetes mellitus accelerates loss of muscle mass and strength. Patients with Alzheimer’s disease (AD) also show these conditions, even in the early stages of AD. The mechanism linking glucose management with these muscle changes has not been elucidated but has implications for clarifying these associations and developing preventive strategies to maintain functional capacity. This study included 69 type 2 diabetes patients with a diagnosis of cognitive impairment (n = 32) and patients with normal cognition (n = 37). We investigated the prevalence of sarcopenia in diabetes patients with and without cognitive impairment and examined the association of glucose alterations with sarcopenia. Daily glucose levels were evaluated using self-monitoring of blood glucose, and we focused on the effects of glucose fluctuations, postprandial hyperglycemia, and the frequency of hypoglycemia on sarcopenia. Diabetes patients with cognitive impairment displayed a high prevalence of sarcopenia, and glucose fluctuations were independently associated with sarcopenia, even after adjusting for glycated hemoglobin A1c (HbA1c) levels and associated factors. In particular, glucose fluctuations were significantly associated with a low muscle mass, low grip strength, and slow walking speed. Our observation suggests the importance of glucose management by considering glucose fluctuations to prevent the development of disability.
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