Peter Eriksson

Enriched Environment Increases Neural Stem/Progenitor Cell Proliferation and Neurogenesis in the Subventricular Zone of Stroke-Lesioned Adult Rats

Background and Purpose— The subventricular zone in the adult brain is identified as an endogenous resource of neuronal precursors that can be recruited to adjacent lesioned areas. The hypothesis was tested that postischemic environmental enrichment might enhance subventricular zone cell genesis. Methods— A cortical infarct was induced in adult spontaneously hypertensive rats by ligating the middle cerebral artery distal to the striatal branches, after which animals were housed in either standard or enriched environment and allowed to survive for 5 weeks. The thymidine analogue bromodeoxyuridine was administered during the first postischemic week. The generation of neural stem/progenitor cells and neuronal precursors in the subventricular zone were studied with cell specific markers such as Ki67 and phosphorylated histone H3 (cell proliferation), Sox-2 (neural stem/progenitor cells), bromodeoxyuridine (slowly cycling, nonmigratory putative neural stem cells), and doublecortin (newborn immature neurons). Results— Proliferating cells in the subventricular zone were identified as chiefly neural progenitors but also putative neural stem cells and neuronal precursors. Five weeks after stroke, proliferation in the subventricular zone was lower in stroke-lesioned rats housed in standard environment compared with nonlesioned rats. Postischemic environmental enrichment normalized cell proliferation levels, increased the numbers of putative neural stem cells as assessed with bromodeoxyuridine, and increased doublecortin-positive neuroblasts, which extended in migratory chains toward the infarct. Conclusions— Enriched environment increased the neural stem/progenitor cell pool and neurogenesis in the adult subventricular zone 5 weeks after a cortical stroke. This might be of potential importance for tissue regeneration.

Sleep-disordered breathing: a novel predictor of atrial fibrillation after coronary artery bypass surgery

BACKGROUND Sleep-disordered breathing is a common condition associated with nocturnal hypoxaemia, sympathetic activation and haemodynamic stress that can trigger arrhythmias. We examined whether preoperatively diagnosed disordered breathing was associated with an increased incidence of atrial fibrillation after coronary artery bypass surgery. METHODS A sleep study was performed in 121 consecutive patients, who were monitored prospectively until discharge from hospital after surgery. Disordered breathing was defined as an apnoea-hypopnoea index (AHI) > or = 5 or an oxygen desaturation index (ODI) > or = 5. All episodes of atrial fibrillation requiring pharmacological intervention or cardioversion were included in the analysis. RESULTS Atrial fibrillation was diagnosed in 32% of patient with AHI > or = 5 (25 of 78) and in 18% patients with AHI < 5 (7 of 39, P = 0.11). Similarly, atrial fibrillation was diagnosed in 39% of patients with ODI > or = 5 (19 of 49) and in 18% of patients with ODI < 5 (13 of 72, P = 0.02). In a multiple-logistic regression model including age, left ventricular function, aortic cross clamp time, maximum postoperative level of lactate dehydrogenase and disordered breathing (ODI > or = 5), greater age and disordered breathing were independent predictors of postoperative atrial fibrillation. The relative risk of atrial fibrillation was 2.0 (95% confidence interval 1.1-3.8) for a 10-year increase in age and 2.8 (95% confidence interval 1.2-6.8) for disordered breathing (ODI > or = 5). CONCLUSIONS Pre-operatively diagnosed sleep-disordered breathing with nocturnal hypoxaemia is an independent predictor of atrial fibrillation after coronary bypass surgery.

Sleep-disordered breathing in women: occurrence and association with coronary artery disease.

PURPOSE To examine the occurrence of sleep apnea and nocturnal hypoxemia in women with and without coronary artery disease (CAD) and to investigate the relationship between sleep-disordered breathing and coronary artery disease. PATIENTS AND METHODS In a case-control study, 102 cases were randomly selected among women with angina pectoris and angiographically verified coronary disease. Fifty age-matched controls without known heart disease were selected from the population registry. Pulse oximetry, oronasal thermistors, body position indicator, and recording of body and respiratory movements were used to quantify oxygen desaturations (the number of desaturations > or = 4% per hour of sleep, oxygen desaturation index [ODI]) and apneas (the number of apneas or hypopneas per hour of sleep, apnea-hypopnea index [AHI]). RESULTS Women with CAD had a high occurrence of disordered breathing measured as AHI > or = 5, 54% (n = 54), AHI > or = 10, 30% (n = 30) or ODI > or = 5, 34% (n = 35) while the same proportions in controls were 20% (n = 10, P < 0.0001), 10% (n = 5, P < 0.01) and 18% (n = 9, P < 0.05), respectively. In a multiple logistic regression model, sleep apnea (AHI > or = 5), hypertension, and smoking habits were independent predictors of CAD with odds ratios of 4.1 (95% confidence interval [CI] 1.7 to 9.7, P < 0.01), 3.4 (CI 1.3 to 8.9, P < 0.05) and 2.4 (CI 1.0 to 5.7, P < 0.05), respectively. CONCLUSION Sleep apnea is common in women with CAD and remains as a significant predictor of coronary disease after adjustment for age, body mass index, hypertension, smoking habits, and diabetes.

GABA induces Ca2+ transients in astrocytes

By using the Ca(2+)-sensitive indictor Fura-2/AM, the cytosolic Ca2+ levels [Ca2+]i were measured in type 1 astrocytes in rat cortical astroglial primary cultures, after stimulation with GABA, muscimol (GABAA agonist), or baclofen (GABAB agonist). We report the first evidence that stimulation of both GABAA and GABAB receptors evokes Ca2+ transients in type I astrocytes. Two types of Ca2+ responses were seen: the single-phase curve, which was the most common, and the biphasic, which consisted of an initial rise that persisted at the maximal or submaximal level. Both types of Ca2+ responses appeared with some latency. The responses were obtained in astrocytes grown for 12-16 days in culture and the response frequencies for all three agonists were 18% of the total number of examined cells. However, when the astrocytes were grown in a mixed astroglial/neuronal culture the response frequencies for all three agonists increased to 35% of the total number of examined cells. In some cells, the responses after GABA stimulation were blocked to baseline levels after exposure to bicuculline (GABAA antagonist). In other cells, bicuculline only slightly reduced the GABA-evoked responses, and the addition of phaclofen (GABAB antagonist) did not potentiate this partial inhibition. However, the muscimol-evoked rises in [Ca2+]i were completely inhibited after exposure to bicuculline, while the responses after baclofen could only be partly blocked by phaclofen. GABA evoked rises in [Ca2+]i which alternatively were inhibited (mostly) or persisted in Ca(2+)-free buffer. The rises in [Ca2+]i persisted, but were reduced, in Ca(2+)-free buffer after stimulation with muscimol, but were inhibited after baclofen stimulation. The GABA uptake blockers guvacine, 4,5,6,7-tetrahydroisoxazolo(4,5-c)pyridin-3-ol and nipecotic acid were also able to reduce the GABA-evoked rises in [Ca2+]i. However, the L-type Ca2+ channel antagonist nifedipine failed to influence on the GABA-evoked Ca2+ transients. The results suggest that type 1 astrocytes in primary culture express GABA receptors which can elevate [Ca2+]i directly or indirectly via Ca2+ channels and/or via release from internal Ca2+ stores. The results also suggest that GABA can have intracellular Ca(2+)-mobilizing sites since the GABA-evoked responses were reduced after incubation with GABA uptake blockers.

Ischemic Stroke After Acute Myocardial Infarction: A Population-Based Study

BACKGROUND AND PURPOSE Modern treatment may have influenced the risk of stroke after myocardial infarction (MI). The purpose of this study was to examine the incidence of ischemic stroke during the first month after an acute MI in an unselected population, to identify predictors of MI-related stroke, and to investigate the secular trend in MI-related stroke incidence. METHODS In this case-control study, from a population of approximately 310000 25- to 74-year-old inhabitants, case subjects with a stroke within 1 month after an MI were prospectively recorded in the population-based Northern Sweden MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) study from 1985 to 1994. The same number of control subjects with an MI but without a stroke were matched for age, sex, and year when MI occurred. RESULTS One hundred twenty-four case subjects were recorded. Fifty-one percent (63/124) of the strokes occurred within 5 days after onset of MI. The odds ratios (ORs) of an MI-related stroke were for a history of hypertension 1.7 (95% confidence interval [CI], 1.0 to 3.2), previous stroke 2.4 (CI, 1.0 to 6.1), chronic atrial fibrillation 3.0 (CI, 1.1 to 9.2), onset of atrial fibrillation during the hospital stay 3.5 (CI, 1.4 to 10.1), ST-segment elevation 2.4 (CI, 1.4 to 4.6), and anterior infarction 1.5 (CI, 0.9 to 2.6). In a conditional multiple logistic regression model, previous stroke (OR, 2.8; CI, 1.1 to 7.6), chronic atrial fibrillation (OR, 3.8; CI, 1.3 to 11.0), new-onset atrial fibrillation (OR, 4.6; CI, 1.6 to 12.8), and ST-segment elevation (OR, 3.4; CI, 1.6 to 7.4) were independent predictors of stroke. MIs preceding stroke were larger and in 51% were located anteriorly. There was a decrease in the incidence and event rate of MI-related stroke during the study period (P < .01 and P < .05, respectively). CONCLUSIONS The risk of stroke is highest the first 5 days after MI. Only approximately half of the strokes occurring the first month after an MI are preceded by an anterior MI. The most important predictors of MI-related stroke are atrial fibrillation (chronic or new onset), ST elevation, and a history of a previous stroke. There is a long-term trend toward a lower incidence of MI-related stroke. These findings have important implications concerning both the pathophysiology and prevention of MI-related stroke.

Neurotoxicity of cysteine : interaction with glutamate

L-Cysteine produces excitotoxic brain damage but its chemical structure differs from that of other excitotoxins. Although it is an NMDAmimetic, its mode of action is complex and may encompass antiexcitotoxic components. The purpose of the present study was to investigate whether cysteine kills neurons by potentiating the effects of glutamate and/or by releasing glutamate. In primary cultures of cortical neurons, 24 h of exposure to glutamate caused a concentration-dependent, dizocilpine-sensitive cell death as measured by release of lactate dehydrogenase. Cysteine was also toxic but higher concentrations were required. In addition, N-acetylcysteine produced mild toxicity at 1 mM. There was no general potentiation between either glutamate and cysteine or glutamate and N-acetylcysteine although some combinations acted synergistically. In no case did the thiols inhibit glutamate toxicity. The interaction between glutamate and cysteine toxicity was also assessed in the immature rat arcuate nucleus in vivo. When given at a dose (0.5 mg/g) that did not cause any toxicity per se, cysteine enhanced the toxicity of glutamate (0.3-0.8 mg/g). Cortical microdialysis was carried out in anesthetized rats (8-10 days old) administered a toxic dose of cysteine (1 mg/g). The levels of taurine were elevated 15-fold, phosphoethanolamine 3-fold and alanine 2-fold. Despite the observation that glutamine decreased markedly and rapidly, there was only a delayed doubling of glutamate concentrations. It is therefore unlikely that cysteine induces neurotoxicity by releasing glutamate. Taken together, the results suggest that there is a synergistic effect between cysteine and glutamate. Speculatively, this potentiation may be produced by reduction by cysteine of the redox site of the glutamate-activated NMDA receptor-ionophore complex.

Reassessment of valve area determinations in mitral stenosis by the pressure half-time method: Impact of left ventricular stiffness and peak diastolic pressure difference

Estimation of the orifice area is of major importance in the timing of valve dilation or surgery in patients with mitral stenosis. Determination of the area has traditionally been accomplished at cardiac catheterization by the Gorlin equation. The valve area can also be estimated noninvasively with Doppler echocardiographic measurements of the pressure half-time, which is inversely proportional to the area. This method has gained widespread acceptance, but its accuracy has recently been questioned and factors other than reduction of orifice area appear to modify the pressure half-time. In the present study, the influence of left ventricular stiffness (defined as diastolic pressure rise per milliliter of mitral flow) and peak atrioventricular pressure difference on the pressure half-time was examined both in a hydraulic model and by review of data from 35 patients with mitral stenosis. Left ventricular stiffness less than 0.13 mm Hg/ml was considered normal. In the model study, the orifice area correlated only moderately with inverted pressure half-time (1/PHT) (r = 0.67). By multiple linear regression, inverted pressure half-time was shown to be dependent on valve area, chamber stiffness and peak pressure difference (R = 0.89), area and stiffness being most important (R = 0.85). In the clinical study, an increased ventricular stiffness was found in 22 of the 35 patients. The pressure half-time method overestimated the Gorlin-derived area by an average of 72% in these patients compared with only 10% in 13 patients with normal stiffness (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Ischemic Stroke Impact of a Recent Myocardial Infarction

BACKGROUND AND PURPOSE The risk of ischemic stroke is increased after a myocardial infarction. We quantified the stroke risk and evaluated ischemic stroke characteristics after an acute myocardial infarction. METHODS A case-control study including patients with first-ever stroke was undertaken. Cases (n=103) were recorded prospectively in the population-based Northern Sweden World Health Organization Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study. Two controls per case with a stroke but without a recent myocardial infarction were matched for age, sex, and year of stroke onset. RESULTS The sudden onset of neurological symptoms (76.7% versus 54.9%, P<0.001), impairment of consciousness (35.0% versus 18.4%, P<0.01), and a progression in neurological deficits (19.4% versus 8.7%, P<0.01) were more common in cases, while the onset of stroke during sleep was rarer in cases (6.8% versus 21.4%, P<0.01). In cases and controls, the clinical subclasses of stroke were as follows: total anterior circulation infarcts, 51.5% versus 37.9% (P<0.05); partial anterior circulation infarcts, 28.2% versus 26.7% (P=NS); lacunar infarcts, 4.8% versus 27.2% (P<0.001); and posterior circulation infarcts, 15.5% versus 8.2% (P=0.051). During the first 28 days after myocardial infarction, the daily rate of stroke declined rapidly from approximately 9 to 1 stroke per 10 000 myocardial infarction patients compared with an age-adjusted average daily stroke rate of 0.14 per 10 000 in the MONICA population. CONCLUSIONS We conclude that the clinical characteristics of the stroke differ between patients with and without a recent myocardial infarction. The risk of a first-ever ischemic stroke is highest during the first few days after a myocardial infarction, but it then declines rapidly, and the absolute number of stroke events is low.

Kappa-opioid receptors on astrocytes stimulate L-type Ca2+ channels.

Cultured astrocytes from the cerebral cortex of the rat respond to opioid kappa-receptor stimulation with a substantial elevation of the cytoplasmic free calcium, visualized through the use of the fluorescent calcium indicator Fura-2. The stimulation of kappa-receptors with U-50488H increases the level of calcium through a dose-related stimulatory effect on the transmembrane calcium influx. The kappa-receptor stimulation was completely blocked by the selective kappa-receptor blocker nor-binaltorphimine. Furthermore, the transmembrane calcium influx was completely blocked by nifedipine, indicating the involvement of L-type channels. The presence of L-type channels was verified by stimulation of L-type channels with Bay K8644. The effects of Bay K8644 were completely blocked by nifedipine. L-type channel-coupled kappa-receptors on astrocytes might represent a novel mechanism contributing to the depressant action of opioids on synaptic transmission via decreasing the availability of extracellular calcium necessary for presynaptic transmitter release.

Mu and delta opiate receptors in neuronal and astroglial primary cultures from various regions of the brain—coupling with adenylate cyclase, localisation on the same neurones and association with dopamine (D1) receptor adenylate cyclase

Primary cultures, enriched in neurones or astroglial cells, from three phylogenetically different regions of the brain of the rat, the cerebral cortex, the striatum and the brain stem, were used to investigate the presence of opiate receptors, coupled to adenylate cyclase. Morphine was used as a mu-receptor agonist and [D-Ala2, D-Leu5]-enkephalin (DADLE) was used as a delta-receptor agonist. In the neuronal cultures, both ligands inhibited the prostaglandin (PG)E1-stimulated intracellular accumulation of cyclic AMP dose-dependently, with the most prominent effects seen in the cultures of striatum and with DADLE being more potent than morphine. The opiate receptor antagonist, naloxone reversed the effects. Morphine and DADLE, added together, inhibited the PGE1-stimulated accumulation of cyclic AMP, less than the sum of the effects of each drug. Therefore, it might be that these opioid receptors are localized together on the same neurone. Striatal neurones contained dopamine receptors coupled to cyclic AMP, as second messenger. It was shown that the D1 (dopamine) receptor-stimulated activity of adenylate cyclase was inhibited by the mu and delta opioid receptor ligands. Thus, interactions at the level of adenylate cyclase seem to exist between D1, mu and delta opiate receptors. In the astroglial enriched cultures, DADLE inhibited the PGE1-induced accumulation of cyclic AMP, however, with a less prominent effect in the brain stem cultures.(ABSTRACT TRUNCATED AT 250 WORDS)