Obesity-induced cognitive impairment in older adults: a microvascular perspective

Over two-thirds of individuals aged 65 and older are obese or overweight in the United States. Epidemiological data show an association between the degree of adiposity and cognitive dysfunction in the elderly. In this review, the pathophysiological roles of microvascular mechanisms, including impaired endothelial function and neurovascular coupling responses, microvascular rarefaction, and blood-brain barrier disruption in the genesis of cognitive impairment in geriatric obesity are considered. The potential contribution of adipose-derived factors and fundamental cellular and molecular mechanisms of senescence to exacerbated obesity-induced cerebromicrovascular impairment and cognitive decline in aging are discussed

The social cognition of medical knowledge, with special reference to childhood epilepsy

This paper arose out of an engagement in medical communication courses at a Gulf university. It deploys a theoretical framework derived from a (critical) sociocognitive approach to discourse analysis in order to investigate three aspects of medical discourse relating to childhood epilepsy: the cognitive processes that are entailed in relating different types of medical knowledge to their communicative context; the types of medical knowledge that are constituted in the three different text types analysed; and the relationship between these different types of medical knowledge and the discursive features of each text type. The paper argues that there is a cognitive dimension to the human experience of understanding and talking about one specialized from of medical knowledge. It recommends that texts be studied in medical communication courses not just in terms of their discrete formal features but also critically, in terms of the knowledge which they produce, transmit and reproduce

Diazoxide and dimethyl sulphoxide alleviate experimental cerebral hypoperfusion-induced white matter injury in the rat brain

Aging and dementia are accompanied by cerebral white matter (WM) injury. which is considered to be of ischemic origin. A causal link between cerebral ischemia and WM damage has been demonstrated in rats: however. few attempts appear to have, been made to test potential drugs for the alleviation of ischemia-related WM injury. We induced cerebral hypoperfusion via permanent, bilateral occlusion of the common carotid arteries of rats. A mitochondrial ATP-sensitive potassium channel opener diazoxide (5 or its solvent dimethyl sulphoxide (DMSO) was administered i.p. (0.25 ml) on 5 consecutive. days after surgery. Sham-operated animals served as control for surgery. and non-treated rats as controls for treatments. Thirteen weeks after surgery, the animals were sacrificed and astrocytes and microglia were labeled immunocytochemically in the internal capsule, the corpus callosum and the optic tract. The astrocytic proliferation was enhanced by cerebral hypoperfusion in the optic tract, and reduced by diazoxide in DMSO. but not by DMSO alone in the corpus callosum. After carotid artery occlusion, microglial activation was enhanced two-fold in the corpus callosum and four-fold in the optic tract. DMSO decreased microglial activation in the optic tract, while diazoxide in DMSO. but not DMSO alone.. restored microglial activation to the control level in the corpus callosum. In summary, the rat optic tract appeared to be particularly vulnerable to ischemia. while the effect of diazoxide was restricted to the corpus callosum. We conclude that diazoxide dissolved in DMSO can moderate ischemia-related neuroinflammation by suppressing glial reaction in selective cerebral WM areas. (C) 2004 Elsevier Ireland Ltd. All rights reserved

Mitochondrial dynamics associated with oxygen-glucose deprivation in rat primary neuronal cultures.

Our objective was to investigate the mitochondrial dynamics following oxygen-glucose deprivation (OGD) in cultured rat cortical neurons. We documented changes in morphology, protein expression, and DNA levels in mitochondria following OGD and examined the roles of mitochondrial fission [dynamin-related protein 1 (Drp1), fission protein-1 (Fis1)] and fusion [mitofusin-1 (Mfn1), mitofusin-2 (Mfn2), and optic atrophy-1 protein (OPA1)] proteins on mitochondrial biogenesis and morphogenesis. We tested the effects of two Drp1 blockers [15-deoxy-Δ12,14-Prostaglandin J2 (PGJ2) and Mitochondrial Division Inhibitor (Mdivi-1)] on mitochondrial dynamics and cell survival. One hour of OGD had minimal effects on neuronal viability but mitochondria appeared condensed. Three hours of OGD caused a 60% decrease in neuronal viability accompanied by a transition from primarily normal/tubular and lesser number of rounded mitochondria during normoxia to either poorly labeled or small and large rounded mitochondria. The percentage of rounded mitochondria remained the same. The mitochondrial voltage-dependent anion channel, Complex V, and mitoDNA levels increased after OGD associated with a dramatic reduction in Drp1 expression, less reduction in Mfn2 expression, an increase in Mfn1 expression, with no changes in either OPA1 or Fis1. Although PGJ2 increased polymerization of Drp1, it did not reduce cell death or alter mitochondrial morphology following OGD and Mdivi-1 did not protect neurons against OGD. In summary, mitochondrial biogenesis and maintained fusion occurred in neurons along with mitochondrial fission following OGD; thus Mfn1 but not Drp1 may be a major regulator of these processes

A study on immunotoxicological effects of subacute amitraz exposure in rats

The effects of amitraz, a formamidine pesticide, were investigated in four-week old outbred male Wistar rats on certain classic toxicological and haematological parameters as well as on specific immune functions. The animals were treated, per os by gavage for 28 days, in a five-day treatment two days break system, with 26.5, 21.1, 10.6 and 5.29 mg/kg/day amitraz. On the 29th day, organ weights of the thymus, heart, lung, spleen, liver, kidneys, adrenals, testicles and popliteal lymph node; WBC and RBC counts, Ht, MCV, haemoglobin; and cell content of the femoral bone marrow were determined. In two separate groups, the effects of amitraz on the PFC content of the spleen, and on the maximum level and time course of DTH reaction, were investigated. Amitraz in 26.5 mg/kg dose increased relative adrenal weight, and decreased relative liver weight, MCV value, PFC content of the spleen, and the maximum level of DTH reaction. The 21.1 mg/kg dose decreased only MCV value, while 10.6 mg/kg elevated the liver-to-brain weight ratio. Based of these findings, a NOEL dose of 5.29 mg/kg was determined for amitraz in this experimental system; while the LOEL doses were 10.6 mg/kg for the general toxicological, 21.1 mg/kg for the haematological and 26.5 mg/kg for the immune function parameters. The results show that the exposure sensitivity of these immune functions to amitraz is lower than that of some other toxicological and haematological parameters

Changes in Drp1 protein expression in neurons following OGD.

<p>Representative Drp1 blots are shown with the corresponding β-actin blot using standard western blot protocol and monoclonal Drp1 antibody in control and OGD samples (A) in non-treated and proteinase inhibitor (PI)-treated control and OGD samples (B). Drp1 is highly expressed in neurons under normoxic condition and decreases following 3 h OGD. Proteinase inhibitor treatment results in higher Drp1 expression in OGD cells but is still greatly reduced compared to control. (C) A representative immunoblot with its corresponding β-actin blot using non-denaturing conditions and monoclonal Drp1 antibody. Arrow indicates monomer sized Drp1. Note the two very faint bands of approximately 26 kDa and 32 kDa. Control neurons express high amount of dimer/trimer sized Drp1 that decrease following 3 h OGD. Relative immunoband intensity of Drp1 bands and Drp1 dimer/monomer band ratios are presented as means ± s.e.m. of <i>n</i> ≥3 independent experiments (D-E). *p<0.05 **p<0.005 ***p<0.001 vs. control. Drp1 = Dynamin-related protein 1, PI = proteinase inhibitor, OGD = oxygen-glucose deprivation, R/O = reoxygenation.</p

Changes in Ser616 phospho-Drp1 protein, and Drp1 gene expression in neurons following OGD.

<p>Representative P-Drp1 immunoblots with the corresponding β-actin blots using standard (A) and non-denaturing (C) western blot protocol in control and OGD samples. P-Drp1 expression is high in control cells but it decreases following 3 h of OGD. (C) The effect of phosphatase inhibitor (PhI) treatment on Ser616 phospho-Drp1 expression. Our PhI-treatment did not increase P-Drp1 expression significantly following 3 h OGD. (B and D) Show the relative immunoband intensity of Ser616 P-Drp1 and the Ser616 P-Drp1 monomer/oligomer ratio; (E) shows the relative Drp1 gene expression, which decreased significantly 24 h after 3 h OGD. *p<0.05 ***p<0.001 vs. control, Drp1 = Dynamin-related protein 1, Fis1 = Fission protein 1, P-Drp1 = Ser616 phospho-Drp1, PhI = phosphatase inhibitor, OGD = oxygen-glucose deprivation, R/O = reoxygenation.</p

Changes in VDAC, complex II and V proteins, and mtDNA expression following 3 h OGD.

<p>Representative western blots for VDAC, Complex II, and Complex V with their corresponding β-actin blots (A, B, C), together with relative intensity values for these proteins (D). VDAC and Complex V proteins showed increased expression, whereas Complex II protein expression did not change significantly following OGD. (E) Shows the changes in mtDNA expression following 3 h of OGD. MtDNA/nuclear DNA ratio significantly increased 12 h following 3 h OGD. *p<0.05 **p<0.005 ***p<0.001 vs. control, n≥3 independent experiments. mtDNA = mitochondrial DNA, OGD = oxygen-glucose deprivation, VDAC = voltage-dependent anion channel.</p