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Biomedical subjects

Roland N Auer

Publications and source records attributed to Roland N Auer.

16 recordsLinked to original sources
PubMed2006

Primary intracerebral hemorrhage.

This article reviews the epidemiology, pathophysiology and management of primary intracerebral hemorrhage. In North American and European populations, 15% of strokes are due to intracerebral hemorrhage. Pathologically in hypertension, early arteriolar proliferation of smooth muscle is followed later by smooth muscle cell death and collagen deposition. This eventually leads to occlusion or ectasia of arterioles. The latter leads to Charcôt-Bouchard aneurysm formation and possible intracerebral hemorrhage. Amyloid deposition in the tunica media causes similar brittle arterioles. Fibrin globes in concentric spheres attempt to seal off the site of bleeding. But vasculopathy (either amyloid or hypertensive) inhibits the contractile capability of arterioles. The size of the final sphere of blood at cessation of bleeding determines the clinical spectrum, from asymptomatic to fatal. Since arteriolar bleeding is slower than arterial bleeding, several hours exist where intervention may be useful. While medical intervention is controversial, guidelines for blood pressure, intracranial pressure, glucose and seizure management exist. Surgical trials have tended to show no benefit. Recombinant factor VIIa is undergoing investigation as hemostatic therapy for intracerebral hemorrhage, to limit clot expansion and possibly also as a hemostatic adjunct to surgery.

Animals↗
PubMed2006

Rat neonatal immune challenge alters adult responses to cerebral ischaemia.

Infection, inflammation, and hyperthermia associated with cerebral ischaemia are known to contribute to enhanced neuronal cell loss and more severe behavioural deficits. Because neonatal exposure to an immune challenge has been shown to alter the severity of inflammatory and febrile responses to a further immune challenge experienced in adulthood, we hypothesised that this could also alter temperature responses and neuronal survival after ischaemia. Thus, male Sprague-Dawley rats were treated at postnatal day 14 with a single injection of the bacterial endotoxin lipopolysaccharide (LPS) and were examined as adults for temperature changes, behavioural deficits, and neuronal cell loss associated with global cerebral ischaemia after a two-vessel occlusion (2VO). Neonatally LPS-treated rats showed behavioural differences in a novel object exploration paradigm, as well as altered temperature responses to the 2VO compared with neonatally saline-treated controls. Interestingly, these neonatally LPS-treated rats also showed increased cell loss in the central nucleus of the amygdala, a region that is important in the processing of emotional responses, but that is not usually examined in animal models of cerebral ischaemia. No differences were seen in the CA1, CA3, or dentate gyrus regions of the hippocampus. This work shows the importance of examining brain regions other than the hippocampus in association with global ischaemia. We also highlight the importance of the early period of development in programming an animal's ability to deal with injury such as cerebral ischaemia in adulthood.

Age Factors↗
PubMed2005

Primary intracerebral hemorrhage: pathophysiology.

We here review the pathophysiology of primary intracerebral hemorrhage to compare and contrast bleeds due to hypertension and congophilic angiopathy. Hypertension is characterized by early proliferation of arteriolar smooth muscle, followed later by apoptotic smooth muscle cell death and collagen deposition. Eventually excess or deficient collagen deposition can lead respectively to arteriolar occlusion, ectasia or both. Collagen has no contractile capability and is brittle, unable to withstand breakage due to pulse pressure. Arterioles physiologically bring down both blood pressure and pulse pressure, but excessive dilatation results in Charcôt-Bouchard aneurysms, which are fusiform, not saccular structures. The distribution of hypertensive hemorrhage reflects the high pulse pressure of arterioles immediately downstream from major end arteries with minimal intervening branching. Cerebrovascular amyloidosis is a stagnant beta-fibrillosis of arterioles, arising from failure of brain egress of beta-amyloid, after amyloid precursor protein cleavage within brain parenchyma. The lobar distribution of changes reflect an impairment of amyloid removal from brain interstitial fluid and Virchow-Robin spaces. Both diseases cause similar brittle arterioles with poor contractile capability, likely accounting for early growth of hematomas when they rupture. Fibrin globes form in concentric spheres and attempt to seal off the site of bleeding. The size of the final sphere of blood at cessation of bleeding determines the clinical spectrum, from asymptomatic to fatal. Since arteriolar bleeding is slower than arterial bleeding, several hours exist where intervention may be useful with recombinant factor VIIa or other therapies. We speculate on the importance of pulse pressure in the etiology of hemorrhage and resolve the debate over the existence of Charcot-Bouchard aneurysms. The high pulse pressure and brisk interstitial fluid pumping in Virchow-Robin spaces deep within the brain selectively protects against amyloidosis, while leaving these basal arterioles vulnerable to hypertensive damage. Hypertensive hemorrhages occur deep within the centrencephalon, while amyloid hemorrhages occur in a lobar distribution, where pulse pressure and bulk flow are less, away from the major feeding vessels of the brain. The brain distributions of hypertensive and of amyloid hemorrhages are thus different and complementary.

Brain↗
PubMed2004

Hypoglycemic brain damage.

Hypoglycemia was long considered to kill neurons by depriving them of glucose. We now know that hypoglycemia kills neurons actively from without, rather than by starvation from within. Hypoglycemia only causes neuronal death when the EEG becomes flat. This usually occurs after glucose levels have fallen below 1 mM (18 mg/dl) for some period, depending on body glycogen reserves. At the time that abrupt brain energy failure occurs, the excitatory amino acid aspartate is massively released into the limited brain extracellular space and floods the excitatory amino acid receptors located on neuronal dendrites. Calcium fluxes occur and membrane breaks in the cell lead rapidly to neuronal necrosis. Significant neuronal necrosis occurs after 30 min of electrocerebral silence. Other neurochemical changes include energy depletion to roughly 25% of control, phospholipase and other enzyme activation, tissue alkalosis and a tendency for all cellular redox systems to shift towards oxidation. The neurochemistry of hypoglycemia thus differs markedly from ischemia. Hypoglycemia often differs from ischemia in its neuropathologic distribution, a phenomenon applicable in forensic practice. The border-zone distribution of global ischemia is not seen, necrosis of the dentate gyrus of the hippocampus can occur and a predilection for the superficial layers of the cortex is sometimes seen. Cerebellum and brainstem are universally spared in hypoglycemic brain damage. Hypoglycemia constitutes a unique metabolic brain insult.

Alkalosis↗
PubMed2004

Dietary restriction does not adversely affect bone geometry and mechanics in rapidly growing male wistar rats.

The present study assessed the effects of dietary restriction on tibial and vertebral mechanical and geometrical properties in 2-mo-old male Wistar rats. Two-month-old male Wistar rats were randomized to the ad libitum (n=8) or the 35% diet-restricted (DR) feeding group (n=9) for 5 mo. Tibiae and L6 vertebrae were dissected out for microcomputed tomography (microCT) scanning and subsequently fractured in biomechanical testing to determine geometrical and mechanical properties. The DR group had significantly lower mean tibial length, mass, area, and cross-sectional moment of inertia, as well as vertebral energy to maximal load. After adjustment for body mass, however, DR tibial mean maximal load and stiffness, and DR vertebral area, height, volume, and maximal load were significantly greater, relative to ad libitum means. No significant differences were found between the DR and ad libitum mineral ash fractions. Because the material properties of the tibiae between the two groups were not significantly different, presumably the material integrity of the bones was not adversely affected as a consequence of DR. The similar material characteristics were consistent with mineral ash fractions that were not different between the two groups. Vertebral maximal load and stiffness were not significant between the DR and ad libitum animals. Importantly, we show that a level of dietary restriction (35%) that is less severe than many studies (40%), and without micronutrient compensation does not adversely affect tibial and vertebral mechanical properties in young growing male rats when normalized for body mass.

Animal Feed↗
PubMed2004

Localization of nestin in amygdaloid kindled rat: an immunoelectron microscopic study.

BACKGROUND: Nestin is a class VI intermediate filament protein, expressed during early embryonic development in mammals. Postnatally, nestin and its mRNA are down-regulated and gradually disappear. Recently, nestin expression has been detected in the adult nervous system, and it has been suggested that this protein may be related to neurogenesis, although, its role in the mechanism of neurogenesis is not known. METHODS: The present study examined the localization of nestin in CNS tissue of the amygdaloid kindled rat by light and electron microscopy. RESULTS: Kindled animals showed nestin expression mainly in the piriform cortex and the perirhinal cortex. By light microscopy, nestin was shown to be expressed in astrocytes, neurons, and endothelial cells. Electron microscopy demonstrated nestin expression in endothelial cells, astrocytic perivascular end feet, the rare pericyte, neurons and oligodendrocytes. CONCLUSION: We conclude that epilepsy causes widespread nestin expression in many cell types in the CNS, including non-neural cells.

Amygdala↗
PubMed2004

Hypoglycemic brain damage.

Hypoglycemia was long considered to kill neurons by depriving them of glucose. We now know that hypoglycemia kills neurons actively rather than by starvation from within. Hypoglycemia only causes neuronal death when the EEG becomes flat. This usually occurs after glucose levels have fallen below 1 mM (18 mg/dL) for some period. At that time abrupt energy failure occurs, the excitatory amino acid aspartate is massively released into the limited brain extracellular space and floods the excitatory amino acid receptors located on neuronal dendrites. Calcium fluxes occur and membrane breaks in the cell lead rapidly to neuronal necrosis. Significant neuronal necrosis occurs after 30 min of electrocerebral silence. Other neurochemical changes include energy depletion to roughly 25% of control, phospholipase and other enzyme activation, tissue alkalosis, and a tendency for all cellular redox systems to shift towards oxidation. Hypoglycemia often differs from ischemia in its neuropathologic distribution, in that necrosis of the dentate gyrus of the hippocampus can occur and a predilection for the superficial layers of the cortex is sometimes seen. Cerebellum and brainstem are universally spared in hypoglycaemic brain damage. Hypoglycemia constitutes a unique metabolic brain insult.

Animals↗
PubMed2004

Delayed precursor cell markers expression in hippocampus following cold-induced cortical injury in mice.

The purpose of this study was to examine the possibility of neuronal remodeling and repair after cold-induced brain injury using immunoassay of nestin and 3CB2 (potential precursor cell markers). Male ddN strain mice were subjected to cold-induced cortical injury. Animals were divided into the following six groups: (1) 1 day after injury, (2) 1 week after injury, (3) 2 weeks after injury, (4) 1 month after injury, (5) sham controls, and (6) normal controls. Western blot analysis (n = 3 in each group) and histological examination (n = 5 in each group) were performed. At 1 day and 1 week after injury, TUNEL-positive cells were observed, while immunoreactivity of nestin and 3CB2 was absent. At 1 month after injury, expression of both nestin and 3CB2 was observed in the ipsilateral hippocampus. Nestin was expressed in GFAP- or 3CB2-positive astrocytes at 1 month after injury, and nestin expression with TUC-4 (immature neuron marker) was present in the hippocampal cell layer. The findings demonstrate delayed nestin expression in both glia and neuronlike cells after brain injury. The present study suggests that the delayed nestin expression in glia and neuron-like cells might be part of the adaptation to injury.

Animals↗
PubMed2004

Optimal blood glucose levels while using insulin to minimize the size of infarction in focal cerebral ischemia.

OBJECT: Insulin has been shown to ameliorate cerebral necrosis in global and, more recently, in focal cerebral ischemia. The goal of this study was to determine the relationship between this neuroprotective effect and blood sugar levels in a rat model of focal ischemia. METHODS: Thirty-four rats were subjected to 80 minutes of transient middle cerebral artery occlusion at a mean arterial blood pressure of 60 mm Hg and a temperature of 37 degrees C. Insulin (3.5 IU/kg) was administered 1 hour before (12 rats) and 20 minutes after (12 rats) ischemia; 10 animals served as controls. A quantitative histopathological study conducted after 1 week of survival showed that insulin was not beneficial in reducing the size of the infarction or selective neuronal necrosis in the penumbra when administered before or after ischemia. In addition to infarction, six animals from the insulin-treated groups had bilateral selective neuronal necrosis in the hippocampus or the neocortex. A nonlinear regression analysis in which glucose levels were compared with both cortical necrosis and total infarction yielded a U-shaped curve with a nadir for cerebral necrosis that lay in the 6- to 7-mM blood glucose range. The increased brain damage induced by insulin occurred in animals with very low blood sugar values in the range of 2 to 3 mM. CONCLUSIONS: These results in rats indicate that if insulin is used following ischemia, blood glucose levels should be maintained at approximately 6 to 7 mM. From these data one can infer that hypoglycemia of less than 3 mM should be avoided in situations of focal cerebral ischemia in which insulin is used. Additional animal studies and clinical trials in humans are needed to study the effects of insulin on ischemia.

Animals↗
PubMed2003

Mefenamate, an agent that fails to attenuate experimental cerebral infarction.

BACKGROUND: Blockade of nonselective cation channels is a potential therapeutic approach that has not been attempted in cerebral ischemia, in spite of the ability of these channels to allow cellular calcium influx into neurons. Fenamates are a class of molecules that block these channels, and many congeners are also anti-inflammatory and free radical scavenging. These three mechanisms may contribute to brain damage in ischemia. METHODS: Pretreatment or posttreatment with mefenamate (30 mg/kg) was evaluated in a temperature-controlled rat transient focal ischemia model. Quantitative histopathology on 26 coronal sections allowed determination of tissue necrosis and tissue atrophy at one week survival. RESULTS: Neither pre- nor postischemic administration of a dose previously shown effective in preventing epileptic neuronal necrosis was found to reduce necrosis in cortex, nor in any subcortical structures. CONCLUSIONS: We conclude that nonselective cation channel blockade with mefenamate affords no neuroprotection in this model. Publication bias against negative studies exists in the literature, but we here report negative findings due to the multiple potentially positive actions of the drug. Closer examination of the effects of the molecule, however, reveals several potentially negative effects as well. We conclude there may be inherent weakness in pharmacologic monotherapy, even with molecules having protean potentially beneficial effects. This conclusion seems to have been borne out by the results of recent clinical trials.

Animals↗
PubMed2003

Progress in clinical neurosciences: therapeutic hypothermia in severe traumatic brain injury.

Severe traumatic brain injury (sTBI) is a relatively common problem with few therapies proven effective. Despite its use for over 50 years, therapeutic hypothermia has not gained widespread acceptance in the treatment of sTBI due to conflicting results from clinical trials. This review will summarize the current evidence from animal, mechanistic and clinical studies supporting the use of therapeutic hypothermia. In addition, issues of rewarming and optimal temperature will be discussed. Finally, the future of hypothermia in sTBI will be addressed.

Animals↗
PubMed2002

Eubaric hyperoxemia and experimental cerebral infarction.

We explore three questions concerning arterial hyperoxygenation and focal ischemia. (1) Does greater benefit accrue with higher levels of arterial hyperoxemia? (2) Is the net effect of continuous (intraischemic plus postischemic) oxygen therapy toxic, or beneficial to middle cerebral artery infarction? (3) In view of free radical theories of reperfusion injury, does hyperoxia isolated to the reperfusion period damage tissue? Rats subjected to transient, focal, normothermic, normoglycemic ischemia were assessed at 2 weeks' survival. Arterial hyperoxygenation from 98.9 +/- 4.0 to 312.2 +/- 48.4mm Hg during ischemia improved (p < 0.05) neurological function, as did isolated reperfusion hyperoxemia, but treatment with continuous hyperoxemia both during and after ischemia yielded greatest benefit (p < 0.001). Cortical infarcts constituted 6.5 +/- 1.8% of the hemisphere at normoxia, but 2.3 +/- 0.9% at hyperoxic levels (p < 0.01). Hyperoxia isolated to the reperfusion period also reduced cortical necrosis, from 6.5% to 2.7 +/- 1.2%. However, continuous intraischemic and reperfusion hyperoxemia led to only 0.2 +/- 0.1% cortical necrosis (p = 0.0005). Increasing the degree of hyperoxemia did not augment the benefit. We conclude that (1) eubaric hyperoxemia improves neurological and neuropathological outcome, (2) continuous oxygen therapy offers the greatest benefit, and (3) reperfusion hyperoxemia is beneficial. The findings should allay clinical concerns regarding oxygen-induced reperfusion injury, and, by obviating hyperbaric chambers, encourage clinical trials studying arterial hyperoxemia in treating stroke.

Animals↗
PubMed2002

Peri-OVLT E-series prostaglandins and core temperature do not increase after intravenous IL-1beta in pregnant rats.

Rats have an attenuated febrile response to endogenous pyrogen near the term of pregnancy. Given the fundamental role of E-series prostaglandins (PGEs) in mediating the febrile response to blood-borne endogenous pyrogen, the present experiments were carried out to determine whether PGEs increase in the area surrounding the organum vasculosum laminae terminalis (peri-OVLT) of near-term pregnant (P) rats as in nonpregnant (NP) rats after intravenous (iv) administration of recombinant rat interleukin-1beta (rrIL-1beta). Core temperature was measured by telemetry and peri-OVLT interstitial fluid was sampled in 12 NP and 12 P chronically instrumented, Sprague-Dawley rats by microdialysis for determination of total PGEs by radioimmunoassay. Basal core temperatures were higher in NP compared with P rats (NP 37.9 degrees C +/- 0.5, P 36.9 degrees C +/- 0.4; P < 0.05), but basal peri-OVLT PGEs were similar in both groups (NP 260 +/- 153 pg/ml, P 278 +/- 177 pg/ml; P =not significant). Intravenous administration of rrIL-1beta to NP rats produced a significant increase in core temperature with a latency, magnitude, and duration of 10 min, 0.87 degrees C, and at least 170 min, respectively; peri-OVLT PGEs were increased significantly by 30 min and averaged 270% above basal levels throughout the experiment. In P rats, however, neither core temperature nor peri-OVLT PGEs increased significantly after iv administration of rrIL-1beta. Intravenous administration of vehicle did not significantly alter core temperature or peri-OVLT PGEs in either group of rats. Thus peri-OVLT PGEs do not increase in P rats as they do in NP rats after iv administration of rrIL-1beta. The mechanism of this interesting component of the maternal adaptation to pregnancy, which likely plays a major role in mediating the attenuated febrile response to endogenous pyrogen near the term of pregnancy, warrants further investigation.

Animals↗