Atrial fibrillation is not uncommon among patients with ischemic stroke and transient ischemic stroke in China

Background

Atrial fibrillation (AF) is reported to be a less frequent cause of ischemic stroke in China than in Europe and North America, but it is not clear whether this is due to underestimation. Our aim was to define the true frequency of AF-associated stroke, to determine the yield of 6-day Holter ECG to detect AF in Chinese stroke patients, and to elucidate predictors of newly detected AF.

Methods

Patients with acute ischemic stroke or transient ischemic attack (TIA) were enrolled in a prospective, multicenter cohort study of 6-day Holter monitoring within 7 days after stroke onset at 20 sites in China between 2013 and 2015. Independent predictors of newly-detected AF were determined by multivariate analysis.

Results

Among 1511 patients with ischemic stroke and TIA (mean age 63 years, 33.1% women), 305 (20.2%) had either previously known (196, 13.0%) or AF newly-detected by electrocardiography (53, 3.5%) or by 6-day Holter monitoring (56/1262, 4.4%). A history of heart failure (OR?=?4.70, 95%CI, 1.64–13.5), advanced age (OR?=?1.06, 95%CI, 1.04–1.09), NIHSS at admission (OR?=?1.06, 95%CI, 1.02–1.10), blood high density lipoprotein (HDL) (OR?=?1.52, 95%CI, 1.09–2.13), together with blood triglycerides (OR?=?0.64, 95%CI, 0.45–0.91) were independently associated with newly-detected AF.

Conclusions

Contrary to previous reports, AF-associated stroke is frequent (20%) in China if systemically sought. Prolonged noninvasive cardiac rhythm monitoring importantly increases AF detection in patients with recent ischemic stroke and TIA in China. Advanced age, history of heart failure, and higher admission NIHSS and higher level of HDL were independent indicators of newly-detected AF.

Trial registration

NCT02156765 (June 5, 2014).

     

Effects of combining methylprednisolone with rolipram on functional recovery in adult rats following spinal cord injury

Methylprednisolone (MP) has been widely used as a standard therapeutic agent for the treatment of spinal cord injury (SCI). Because of its controversial beneficial effects, the combination of MP and other pharmacological agents aimed at enhancing functional recovery is desirable. The phosphodiesterase 4 (PDE4) inhibitor rolipram has been implicated in promotion of regeneration due to elevating cAMP. In the present study, we sought to determine the effects of MP and rolipram, administered in combination, after spinal cord injury (SCI) in adult rats. Here we show that in vitro administration of rolipram and MP significantly increased neuron survival and promoted neurite outgrowth of neurons on the inhibitory substrate CSPGs by upregulation of MMP-2 expression; in vivo administration of rolipram and MP inhibited CSPG expression and increase CSPG digestion after rat SCI. Rolipram and MP combining treatment promoted significant neuroprotection through reduced motoneuron death, minimized lesion cavity, and increased regeneration of lesioned corticospinal tract (CST) axons beyond the lesion site after SCI. Enhanced functional recovery was also observed. Overall, our study strongly suggested that the combination treatment of MP and rolipram may represent a promising strategy for clinically applicable pharmacological therapy for rapid initiation of neuroprotection after SCI.     

Craniofacial alterations in adult rats prenatally exposed to ethanol

The rat was studied to determine whether gestational exposure to moderate amounts of ethanol produces permanent craniofacial malformations. Pregnant Long-Evans rats were fed a liquid diet containing 35% ethanol-derived calories or an isocaloric liquid diet between gestation days 6 and 20. Various dimensions of skulls and mandibles from adult male offspring were measured. All measurements taken in the parasagittal and coronal planes were significantly smaller in the ethanol-exposed rats than in the offspring of pair-fed controls. None of the vertical measurements was significantly altered. This report demonstrates that gestational exposure to ethanol in rats, at doses which produce lasting behavioral effects, also produces a specific constellation of craniofacial dysmorphisms without concomitant decreases in body weight.     

Omega-3 effects on electrocorticographic patterns of adult Wistar rats exposed to ionizing radiation

This study aimed to assess the effect of supplementation with omega-3 in Wistar rats exposed to ionizing radiation in a dose of 18 Gy on the cortical electrical activity, using mathematical methods such as the power spectrum (PS) and the detrended fluctuation analysis (DFA) in the evaluation of the electrocorticogram (ECoG) record. The PS analysis showed that in non-irradiated animals but supplemented with omega-3 there was a decrease in the power of the beta rhythm, while the DFA applied to different frequency ranges of the ECoG showed a significant increase in the long-range correlation only for the theta wave when compared with non-supplemented animals. In the evaluation of the radiation effect through the PS, an increase in the power of the theta rhythm was observed in both groups (non-supplemented and supplemented animals) only when they were evaluated one week after irradiation. The DFA method also showed difference in this wave. The PS and DFA methods applied to the ECoG record allowed a quantitative analysis of the cortical electrical activity in rats in response to the omega-3 effects, ionizing radiation, or both.     

Acute connexin43 temporal and spatial expression in response to ischemic stroke

Connexin43 (Cx43) gap junctions expressed in astrocytes can significantly impact neuronal survival in stroke. However, little is known regarding Cx43 spatial and temporal expression during the initial stages of brain ischemia. Using immunohistochemistry and Western blot analysis, we examined Cx43 spatial and temporal expression as a function of neuronal injury within the first 24 h after permanent middle cerebral artery occlusion (pMCAO). Western blot analysis showed a significant increase in Cx43 protein expression in the core ischemic area at 2 and 3 h after pMCAO. However, after 6 h of pMCAO Cx43 levels were significantly reduced. This reduction was due to cell death and concomitant Cx43 degradation in the expanding focal ischemic region, while the peri-infarct zone revealed intense Cx43 staining. The neuronal cell-death marker Fluoro-Jade C labeled injured neurons faintly at 1 h post-pMCAO with a time-dependent increase in both intensity and size of punctate staining. In addition, decreased microtubule-associated protein 2 (MAP2) immunoreactivity and thionin staining similarly indicated cell damage beginning at 1 h after pMCAO. Taken together, Cx43 expression is sensitive to neuronal injury and can be detected as early as 2 h post-pMCAO. These findings underscore Cx43 gap junction as a potential early target for therapeutic intervention in ischemic stroke.     

Enhanced sensitivity to methadone in adult rats perinatally exposed to methadone

Adult rats, maternally exposed to methadone during gestation and/or lactation, were evaluated for thermoregulatory and nociceptive responsiveness following a challenge with 5 mg/kg (i.p.) methadone. Prior to drug administration, female rats in the gestation and gestation-lactation groups and all male rats perinatally exposed to methadone were subnormal in body temperature. One hour after acute methadone injection, male control rats were hypothermic. All groups of methadone-treated offspring exhibited a marked lowering in body temperature with respect to their pre-injection levels, as well as in regard to values of methadone-administered control animals. Prior to drug administration, male rats of the gestation-lactation group and female rats of the gestation and lactation groups had elevated nociceptive thresholds. Except for male rats in the lactation group, animals treated with methadone perinatally had longer latencies in response to the hot-plate relative to their pre-injection values, as well as to levels of methadone-injected controls. Three days after acute methadone administration, some groups of rats subjected to this drug during gestation and/or lactation were found to be hypothermic and hypalgesic in respect to their pre-injection values, and also relative to control rats. These results suggest that exposure to methadone early in life can have a profound influence on drug response in adulthood.     

Behavioral changes in adult rats exposed to ELF magnetic fields

In two experiments, male rats that had been exposed to an ELF (0.5 Hz), 3–50 gauss rotating magnetic field (RMF) for 21–30 days, displayed significantly (p < 0.05) greater ambulatory behavior (activity) than the control group in an open field test, when removed from the RMF. In a third experiment rats were exposed to a different RMF apparatus (3–30 gauss), and tested in a different open field for longer duration. Again the RMF-exposed group displayed greater activity (p < 0.10) than the control group.

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Zusammenfassung In zwei Untersuchungen zeigten männliche Ratten,die einem ELF (0,5 Hz) 3–50 Gauss rotierenden magnetischen Feld (RMF) für 21–30 Tage ausgesetzt wurden, in einem Open-Field Test signifikant (p < 0,05) mehr Bewegungsaktivität als die Kontrollgruppe,nachdem sie von dem RMF entfernt wurden. In einer dritten Untersuchung wurden Ratten in einem anderen RMF Gerät gehalten und in einem anderen Open-Field für längere Zeit getestet. Wieder zeigte die Gruppe, die dem RMF ausgesetzt war, mehr Bewegungsaktivität (p < 0,10) als die Kontrollgruppe.

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Resume Lors de deux essais, on a placé des rats mâles dans un champ magnétique tournant (CMT) de 3 à 50 gauss et des très basse fréquence (FTB) (0,5 Hz). Après 21 à 30 jours de ce traitement, on les a remis dans des conditions normales. Leur activité (marche) était plus élevée que celle d'un groupe de contrôle et cela de façon significative (p < 0,05). Dans un troisième essai, d'autres rats furent placés dans un autre appareil (3 à 30 gauss) et examinés ensuite dans un autre champ ouvert sur une plus longue période. Le groupe traité a déployé dans ce cas également une plus grande activité qu'un groupe de contrôle (p < 0,10).

     

Molecular and functional resistance to insulin in hypothalamus of rats exposed to cold

Insulin and leptin act in the hypothalamus, providing robust anorexigenic signals. The exposure of homeothermic animals to a cold environment leads to increased feeding, accompanied by sustained low levels of insulin and leptin. In the present study, the initial and intermediate steps of the insulin-signaling cascade were evaluated in the hypothalamus of cold-exposed Wistar rats. By immunohistochemistry, most insulin receptor (IR) and insulin receptor substrate-2 (IRS-2) immunoreactivity localized to the arcuate nucleus. Basal levels of tyrosine phosphorylation of IR and IRS-2 were increased in cold-exposed rats compared with rats maintained at room temperature. However, after an acute, peripheral infusion of exogenous insulin, significantly lower increases of IR and IRS-2 tyrosine phosphorylation were detected in the hypothalamus of cold-exposed rats. Insulin-induced association of p85/phosphatidylinositol 3-kinase with IRS-2, Ser473 phosphorylation of Akt, and tyrosine phosphorylation of ERK was significantly reduced in the hypothalamus of cold-exposed rats. To test the hypothesis of functional impairment of insulin signaling in the hypothalamus, intracerebroventricularly cannulated rats were acutely treated with insulin, and food ingestion was measured over a period of 12 h. Cold-exposed animals presented a significantly lower insulin-induced reduction in food consumption compared with animals maintained at room temperature. Hence, the present studies reveal that animals exposed to cold are resistant, both at the molecular and the functional level, to the actions of insulin in the hypothalamus.     

Statins in prevention and treatment of ischemic stroke

Based on the published data, including the results of large-scale, randomized, placebo-controlled trials, the article presents current strategies for the use of statins in primary and secondary prevention of ischemic stroke. Special attention is paid to the efficacy and advanced applications of statins in acute stroke. Based on the gross data, recommendations for the use of statins in prevention and treatment of ischemic stroke are presented.     

Non-selective cation channels, transient receptor potential channels and ischemic stroke

Several pathways to neural cell death are involved in ischemic stroke, and all require monovalent or divalent cation influx, implicating non-selective cation (NC) channels. NC channels are also likely to be involved in the dysfunction of vascular endothelial cells that leads to formation of edema following cerebral ischemia. Two newly described NC channels have emerged as potential participants in ischemic stroke, the acid sensing ion channel (ASIC), and the sulfonylurea receptor-1 (SUR1)-regulated NC(Ca-ATP) channel. Non-specific blockers of NC channels, including pinokalant (LOE 908 MS) and rimonabant (SR141716A), have beneficial effects in rodent models of ischemic stroke. Evidence is accumulating that NC channels formed by members of the transient receptor potential (TRP) family are also up-regulated in ischemic stroke and may play a direct role in calcium-mediated neuronal death. The nascent field of NC channels, including TRP channels, in ischemic stroke is poised to provide novel mechanistic insights and therapeutic strategies for this often devastating human condition.     

Persistent functional and structural retinal anomalies in newborn rats exposed to hyperoxia.

Previous studies have shown that newborn rats exposed postnatally to hyperoxia will develop a permanent impairment of the retinal function as determined with the electroretinogram (ERG). The purpose of our study was to examine whether postnatal hyperoxia equally alters the light- and dark-adapted ERGs and oscillatory potentials (OPs) as well as leads to permanent structural modification of the retina. During the first 14 days of life, cohorts of Sprague-Dawley rats were exposed to a hyperoxic environment, and ERGs were recorded at mean ages of approximately 25 and 55 days. Our results indicate that both light- and dark-adapted ERGs and OPs are already significantly altered within a few days following exposure to hyperoxia. None of the ERG and (or) OP parameters, with the exception of the a-wave, returned to normal values by 55 days of age. In fact some dark-adapted OPs were completely abolished following postnatal O2 exposure. Histological analysis revealed that the retina of rats exposed to hyperoxia failed to develop an outer plexiform layer and had a reduced count of horizontal cells, consistent with the permanent postreceptoral anomalies seen in the ERG responses. Our results suggest that postnatal hyperoxia causes a generalized retinal disorder leading to permanent structural modifications of the retinal cytoarchitecture and lasting anomalies of the rod and cone functions.     

Physiological changes in adult rats exposed to an ELF rotating magnetic field

In three Experiments (I, II, IV), adult male rats, between 115 and 150 days of age were exposed to either a 0.5–3 or 3–30 gauss ELF (0.5 Hz) rotating magnetic field (RMF), for 5, 10, or 26 days. The rats exposed to the RMF for 10 and 26 days averaged significantly (p< 0,05) greater water consumption than controls. The group exposed to the RMF for 5 days also consumed more water, although the difference was not significant. ELF-RMF-exposed rats also showed a progressive decrease (p <0.02) in relative thyroid weights, but increase in body weight gain (p <0.001) up to 10 days of exposure, and increase in testicle weights (p < 0.05) up to 26 days of exposure. No significant differences were found between groups for circulating blood eosinophil counts or relative adrenal weights, although again the differences did increase with duration of exposure. In a fourth Experiment (III), rats that were 80 days of age at the beginning of 21 days of exposure did not show any significant differences in the above measures from the control group. The changes in behavior and physiology associated with ELF exposure is discussed in terms of its effects upon the thyroid and its probable liquid crystalline properties.

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Zusammenfassung In drei Untersuchungen (I, II, IV) wurden männliche, 115–150 Tage alte Ratten entweder einem 0,5–3 oder einem 3–30 Gauss ELF (0,5 Hz) rotierenden magnetischen Feld (RMF) für 5, 10 oder 26 Tage ausgesetzt. Die Ratten, die dem RMF für 10 und 26 Tage ausgesetzt waren, hatten einen signifikant (p < 0,05) höheren Wasserkonsum als die Kontrollgruppe. Auch die Tiere, die dem RMF für 5 Tage ausgesetzt waren, tranken mehr Wasser (p > 0,05). Die exponierten Tiere zeigten auch eine fortschreitende Abnahme (p < 0,02) des relativen Schilddrüsengewichts, dagegen eine grössere Gewichtszunahme (p < 0,001) bei bis zu 10 Tagen Exponierung und Zunahme des relativen Hodengewichts (p < 0,05) bei bis zu 26 Tagen Exponierung. Die Unterschiede in der Zahl der zirkulierenden Esinophilen und im relativen Nebennierengewicht waren nicht signifikant. In der vierten Untersuchung (III) mit Ratten die bei Versuchsbeginn 80 Tage alt waren fanden sich nach 21 Tagen Exponierung keine Unterschiede beim Vergleich mit der Kontrollgruppe. Die physiologischen Veränderungen durch ELF-Exponierung, werden über eine Wirkung auf der Schilddrüse und ihre möglichen flüssigen und kristallinen Eigenschaften erklärt.

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Resume Lors de trois essais (I, II et IV), on a exposé des rats mâles, adultes, âgés de 115 à 150 jours à un champ magnétique tournant (CMT) d'une très basse fréquence (FTB) — de 0,5 Hz — soit de 0,5 à 3 Gauss, soit de 3 à 30 gauss, et cela durant 5, 10 ou 26 jours. Les rats exposés au CMT durant 10 ou 26 jours ont bu plus d'eau que des rats de contrôle et cela de façon significative (p < 0,05). Le groupe exposé au CMT durant 5 jours seulement a aussi bu davantage d'eau, mais la différence n'est alors pas significative. Les rats exposés à la fois au CMT et au FTB ont aussi montré une diminution significative (p < 0,02) du poids relatif de la glande thyroïde, une augmentation du poids du corps (p< 0,001) jusqu'au 10ème jour d'exposition et une augmentation du poids des testicules pour 26 jours d'exposition. On n'a par contre pas constaté de différences significatives entre les groupes quant au nombre d'oesinophiles circulant dans le sang, ni quant au poids des glandes surrénales, bien que ces différences augmentassent avec la durée d'exposition. Dans un quatrième essai (III), des rats âgés de 80 jours au début d'une période d'exposition de 21 jours n'ont présenté aucune différence quant aux paramètres mentionnés ci-dessus. Les changements du comportement et de la physiologie dûs à une exposition au FTB sont discutés par rapport aux répercussions d'une telle exposition sur la thyroïde et ses propriétés liquides et cristalline.

     

Acute but not chronic tempol treatment increases ischemic and reperfusion ventricular arrhythmias in open-chest rats

The effect of the chronic and acute antioxidant tempol (superoxide dismutase mimetic) treatment on cardiac ischemic tolerance was investigated in adult male Wistar rats. The first experimental group was given tempol (1 mM) in drinking water for three weeks, the second group received tempol (100 mg/kg, i.v.) 10 min before test ischemia, and control rats received the same volume of solvent. Anesthetized open-chest animals (pentobarbitone 60 mg/kg, i.p.) were subjected to 20-min coronary artery occlusion and 3-h reperfusion for infarct size determination. Ventricular arrhythmias were monitored during ischemia and at the beginning (5 min) of reperfusion. Acute tempol administration shifted the time profile of ischemic arrhythmias to the later phase and significantly increased the number of ischemic and reperfusion premature ventricular complexes, respectively (504+/-127 and 84+/-21) as compared with the chronically treated group (218+/-36 and 47+/-7) or controls (197+/-26 and 31+/-7). Acute tempol-treated rats exhibited a tendency to decrease infarct size (P = 0.087). The mechanism of proarrhythmic tempol action during ischemia and reperfusion remains to be elucidated.     

Pulmonary vascular resistance in adult rats exposed to hypoxia in the neonatal period

Newborn rats were exposed to hypoxia (10% O2 + N2) from 24 h to day 6 of neonatal life and then returned to room air until 45 days of age (experimental). The rats were anaesthetized, heparinized, and exsanguinated. The chest was opened and the lungs were perfused with diluted autologous blood at a constant flow rate (Q). The pulmonary arterial pressure (Pa) and venous pressure (Pv) were monitored. The properties of the pulmonary vasculature were assessed by measuring baseline vascular resistance, PVR = (Pa-Pv)/Q, segmental pressure gradients (double occlusion technique), pressure-flow relationship, hypoxic pressor response (HPR, 3% O2), and the response to 0.5 microgram bolus of angiotensin II (AII). These were compared with similar measurements on age-matched control animals never exposed to hypoxia. The perfusate hematocrit and gases were not significantly different between the two groups. The PVR normalized to body weight was 30% higher in the experimental groups (p less than 0.005). The double occlusion results (obtained at a flow rate of 13 mL/min) revealed that this increase in resistance was primarily due to the increase in the postcapillary resistance. HPR was primarily in the upstream segment in both groups but was larger in the experimental group. In contrast, the response to AII occurred in both the upstream as well as in the downstream vascular segments and did not differ between the two groups. We conclude that adult rats exposed to hypoxia in the neonatal period have elevated pulmonary vascular resistance and increased vascular reactivity to hypoxia.     

Mesenchymal stem cell therapy of brain ischemic stroke in rats

Mesenchymal stem cell (MSCs)-based therapy is a promising attempt to improve the recovery after stroke. Our experiments were carried out on inbred Wistar-Kyoto rats. MSCs were isolated, expanded in culture, and labeled with vital fluorescent dye PKH-26. Animals were subjected to middle cerebral artery occlusion (MCAO). After three days, MCAO 5 × 10⁶ isolated MSCs were injected into the tail vein of the experimental rats. The control animal group received PBS injections (negative control). Therapy results were evaluated by the following parameters: behavioral and neurological testing, the inured brain areas, damaged brain structures, neuron state, and vessel quantity in the region close to with necrosis zone. It was shown that control animals (PBS injection) did not return to their initial behavioral and neurological state within 6 weeks, while the experimental animals (MSCs injection), within 2–3 weeks after MCAO, had parameters like intact rats. The size of the damaged region in the control group was larger than in the experimental group by a factor of approximately 1.3. The damage in MSC-treated rats was limited to the neocortex; caudate nucleus, capsula externa and piriform cortex remained uninjured. The small vessel quantity in the “border” regions was twice as high as compared to the control group and approximately equal to the number of vessels in an intact brain. For the first time, we demonstrated that the vessel quantity in the neocortex and caudate nucleus of the contralateral hemisphere after MSC transplantation was twice as high as in control rats. It is concluded that the MSC transplantation exerts a beneficial influence upon the brain tissue reparation after stroke.     

Time-dependent contribution of non neuronal cells to BDNF production after ischemic stroke in rats

Although brain-derived neurotrophic factor (BDNF) plays a central role in recovery after cerebral ischemia, little is known about cells involved in BDNF production after stroke. The present study testes the hypothesis that neurons are not the unique source of neosynthesized BDNF after stroke and that non neuronal-BDNF producing cells differ according to the delay after stroke induction. For this purpose, cellular localization of BDNF and BDNF content of each hemisphere were analysed in parallel before and after (4h, 24h and 8d) ischemic stroke in rats. Stroke of different severities was induced by embolization of the brain with variable number of calibrated microspheres allowing us to explore the association between BDNF production and neuronal death severity. The main results are that (a) unilateral stroke increased BDNF production in both hemispheres with a more intense and long-lasting effect in the lesioned hemisphere, (b) BDNF levels either of the lesioned or unlesioned hemispheres were not inversely correlated to neuronal death severity whatever the delay after stroke onset, (c) in the unlesioned hemisphere, stroke resulted in increased BDNF staining in neurons and ependymal cells (at 4h and 24h), (d) in the lesioned hemisphere, beside neurons and ependymal cells, microglial cells (at 24h), endothelial cells of cerebral arterioles (at 4h and 24h) and astrocytes (at 8d) exhibited a robust BDNF staining as well. Taken together, overall data suggest that non neuronal cells are able to produce substantial amount of BDNF after ischemic stroke and that more attention should be given to these cells in the design of strategies aimed at improving stroke recovery through BDNF-related mechanisms.