Trans-cerebral HCO3- and PCO2 exchange during acute respiratory acidosis and exercise-induced metabolic acidosis in humans

This study investigated trans-cerebral internal jugular venous-arterial bicarbonate ([HCO(3)(−)]) and carbon dioxide tension (PCO(2)) exchange utilizing two separate interventions to induce acidosis: 1) acute respiratory acidosis via elevations in arterial PCO(2) (PaCO(2)) (n = 39); and 2) metabolic acidosis via incremental cycling exercise to exhaustion (n = 24). During respiratory acidosis, arterial [HCO(3)(−)] increased by 0.15 ± 0.05 mmol ⋅ l(−1) per mmHg elevation in PaCO(2) across a wide physiological range (35 to 60 mmHg PaCO(2); P < 0.001). The narrowing of the venous-arterial [HCO(3)(−)] and PCO(2) differences with respiratory acidosis were both related to the hypercapnia-induced elevations in cerebral blood flow (CBF) (both P < 0.001; subset n = 27); thus, trans-cerebral [HCO(3)(−)] exchange (CBF × venous-arterial [HCO(3)(−)] difference) was reduced indicating a shift from net release toward net uptake of [HCO(3)(−)] (P = 0.004). Arterial [HCO(3)(−)] was reduced by −0.48 ± 0.15 mmol ⋅ l(−1) per nmol ⋅ l(−1) increase in arterial [H(+)] with exercise-induced acidosis (P < 0.001). There was no relationship between the venous-arterial [HCO(3)(−)] difference and arterial [H(+)] with exercise-induced acidosis or CBF; therefore, trans-cerebral [HCO(3)(−)] exchange was unaltered throughout exercise when indexed against arterial [H(+)] or pH (P = 0.933 and P = 0.896, respectively). These results indicate that increases and decreases in systemic [HCO(3)(−)] – during acute respiratory/exercise-induced metabolic acidosis, respectively – differentially affect cerebrovascular acid-base balance (via trans-cerebral [HCO(3)(−)] exchange)

ER-Mitochondria Crosstalk during Cerebral Ischemia: Molecular Chaperones and ER-Mitochondrial Calcium Transfer

It is commonly believed that sustained elevations in the mitochondrial matrix Ca2+ concentration are a major feature of the intracellular cascade of lethal events during cerebral ischemia. The physical association between the endoplasmic reticulum (ER) and mitochondria, known as the mitochondria-associated ER membrane (MAM), enables highly efficient transmission of Ca2+ from the ER to mitochondria under both physiological and pathological conditions. Molecular chaperones are well known for their protective effects during cerebral ischemia. It has been demonstrated recently that many molecular chaperones coexist with MAM and regulate the MAM and thus Ca2+ concentration inside mitochondria. Here, we review recent research on cerebral ischemia and MAM, with a focus on molecular chaperones and ER-mitochondrial calcium transfer

Protective effects of carbonic anhydrase inhibition in brain ischaemia in vitro and in vivo models

Ischaemic stroke is a leading cause of death and disability. One of the major pathogenic mechanisms after ischaemia includes the switch to the glycolytic pathway, leading to tissue acidification. Carbonic anhydrase (CA) contributes to pH regulation. A new generation of CA inhibitors, AN11-740 and AN6-277 and the reference compound acetazolamide (ACTZ) were investigated in two models of brain ischaemia: in rat hippocampal acute slices exposed to severe oxygen, glucose deprivation (OGD) and in an in vivo model of focal cerebral ischaemia induced by permanent occlusion of the middle cerebral artery (pMCAo) in the rat. In vitro, the application of selective CAIs significantly delayed the appearance of anoxic depolarisation induced by OGD. In vivo, sub-chronic systemic treatment with AN11-740 and ACTZ significantly reduced the neurological deficit and decreased the infarct volume after pMCAo. CAIs counteracted neuronal loss, reduced microglia activation and partially counteracted astrocytes degeneration inducing protection from functional and tissue damage

Prevention of Hippocampus Neuronal Damage in lschemic Gerbils by a Novel Lipid Peroxidation Inhibitor (Quinazoline Derivative)

ABSTRACT ABBREVIATIONS: MAP2, microtuble-associated protein 2; PKC, protein kinase C; PDBu, phorbol 12,13-dibutyrate. 90

Lipofuscin Accumulation in Cultured Non-Dividing Cells as a Function of Time and Oxygen Tension

Cultivated human glial cells, kept in a state of density-dependent inhibition of growth, accumulate age-pigment (lipofucsin) within their lysosomal vacuomes with the same characteristics as the corresponding pigment observed in vivo. The rate of formation and accumulation of lipofuscin is greatly accelerated under the conditions of routine cell cultivation in comparison to the in vivo event. Lipofuscin is generally considered to be composed of polymerized products of lipid peroxidation and thus it would be reasonable to suggest that factors which influence lipid peroxidation would also alter the rate of lipofuscin formation. Human glial cells were grown in the presence of various oxygen concentrations in the gas-phase (5%, 10%, 20%, 40%). This was found to modulate (accelerate or decrease) the rate of lipofuscin formation. The present study thus provides: (1) important supportive evidence for the lipid peroxidation origin of lipofuscin, (2) a useful model system for studying the effect of lipofuscin accumulation on lysosomal function and cell growth kinetics, (3) evidence that our standard culture conditions are far from ideal since oxygen concentration may drastically alter rates of lipofuscin formation and accumulation. Cell culture technique, as we know it today, may benefit from more closely controlled oxygen tensions, i.e., by reducing oxygen to levels that more closely approximate conditions in vivo

On Nichols algebras associated to simple racks

This is a report on the present state of the problem of determining the dimension of the Nichols algebra associated to a rack and a cocycle. This is relevant for the classification of finite-dimensional complex pointed Hopf algebras whose group of group-likes is non-abelian. We deal mainly with simple racks. We recall the notion of rack of type D, collect the known lists of simple racks of type D and include preliminary results for the open cases. This notion is important because the Nichols algebra associated to a rack of type D and any cocycle has infinite dimension. For those racks not of type D, the computation of the cohomology groups is needed. We discuss some techniques for this problem and compute explicitly the cohomology groups corresponding to some conjugacy classes in symmetric or alternating groups of low order.Comment: 26 pages, minor change

Higher Blood Glucose within the Normal Range Is Associated with More Severe Strokes

Background. Higher fasting blood glucose (FBG) concentrations in the hyperglycemic range are associated with more severe strokes. Whether this association also extends into patients with FBG in the normoglycemic range is unclear. We studied the association of stroke severity and FBG in normoglycemic patients with ischemic stroke in a median of 7 days after stroke when the initial glycemic stress response has resolved. Method and Material. Included were 361 nondiabetic ischemic stroke patients with admission fasting blood glucose within 70–130 mg/dL admitted into an acute stroke rehabilitation unit in a median of 7 days after stroke. Data including neuroimaging, vital signs, cardiovascular risk factors, and admission functional independence measure (AFIM) were recorded prospectively. Results. FBG correlated with stroke severity in the normoglycemic 70–130 mg/dL range (FBG-AFIM correlation coefficient −0.17; P = 0.003). Odds ratio for more severe injury (below average AFIM score) was 2.02 for patients with FBG 110–130 mg/dL compared to FBG 70–90 mg/dL (95% confidence interval 1.10–3.73, P = 0.022). Each mg/dL increase in FBG was associated with an average decrease of 0.25 FIM points. In a multiple linear regression model, FBG was associated with more severe stroke (P = 0.002). Conclusion. One week after ischemic stroke, FBG within the normoglycemic range was associated with stroke severity

An Overview of Brain-Derived Neurotrophic Factor and Implications for Excitotoxic Vulnerability in the Hippocampus

The present paper examines the nature and function of brain-derived neurotrophic factor (BDNF) in the hippocampal formation and the consequences of changes in its expression. The paper focuses on literature describing the role of BDNF in hippocampal development and neuroplasticity. BDNF expression is highly sensitive to developmental and environmental factors, and increased BDNF signaling enhances neurogenesis, neurite sprouting, electrophysiological activity, and other processes reflective of a general enhancement of hippocampal function. Such increases in activity may mediate beneficial effects such as enhanced learning and memory. However, the increased activity also comes at a cost: BDNF plasticity renders the hippocampus more vulnerable to hyperexcitability and/or excitotoxic damage. Exercise dramatically increases hippocampal BDNF levels and produces behavioral effects consistent with this phenomenon. In analyzing the literature regarding exercise-induced regulation of BDNF, this paper provides a theoretical model for how the potentially deleterious consequences of BDNF plasticity may be modulated by other endogenous factors. The peptide galanin may play such a role by regulating hippocampal excitability

Pathomorphological effects of Alloxan induced acute hypoglycaemia in rabbits

Alloxan is one of the frequently used beta-cytotoxic agents for the induction of Type-1 diabetes mellitus in animal models and is the drug of choice in rabbits. Its beta-cytotoxic action results in a sudden release of insulin leading to severe hypoglycaemia and even mortality if glucose therapy is not given. In the present investigation the pathological effects of alloxan induced acute hypoglycaemia were studied in rabbits. New Zealand White rabbits, 1–1.5 kg body weight, were administered alloxan @100 mg/kg b.w., as a single intravenous dose. Blood glucose levels were monitored (0 h, 20 min, 1 h, and then hourly up to 5 h) and clinical signs noted. Rabbits dead due to hypoglycaemia were necropsied and histopathology performed. Severe histopathological changes were observed especially in the brain (neuronal degeneration and necrosis), kidneys (nephrosis, nephritis) and liver (hepatosis, hepatitis) and also, other organs. Histopathological observation of beta-cytolysis was suggestive that the drug induced hypoglycaemia is insulin mediated. It was concluded that acute hypoglycaemia causes severe pathological changes and the alloxan induced immediate hypoglycaemia if not managed in time, might exacerbate the pathological effects of hyperglycaemia in the induced diabetic models.Keywords: Alloxan hypoglycaemia; Pathology; Rabbit