Agomelatine Is Unable to Attenuate Kainic Acid-Induced Deficits in Early Life Communicative Behavior.

Early life seizures are associated with a variety of behavioral comorbidities. Among the most prevalent of these are deficits in communication. Auditory communicative behaviors in mice, known as ultrasonic vocalizations (USVs), can be used to assess potential treatments. Agomelatine is a melatonin agonist that effectively reduces behavioral comorbidities of seizures in adults; however, its ability to attenuate seizure-induced communicative deficits in neonates is unknown. To address this, we administered C57 mice either saline or kainic acid (KA) on postnatal day (PD) 10. The mice then received either agomelatine or saline 1-h post-status epilepticus. On PD 11, we assessed the quantity of USVs produced, the duration, peak frequency, fundamental frequency, and amplitude of the vocalizations, as well as the call type utilization. We found that KA increased vocal production and reduced USV variability relative to controls. KA also increased USV duration and amplitude and significantly altered the types of calls produced. Agomelatine did not attenuate any of the deficits. Our study is the first to assess agomelatine's efficacy to correct USVs and thus provides an important point of context to the literature, indicating that despite its high therapeutic efficacy to attenuate other behavioral comorbidities of seizures, agomelatine's ability to correct neonatal communicative deficits is limited.

Polimorfismo Ser326Cis de la 8-oxoguanina ADN glucosilasa 1 (OGG1) en hombres con teratozoospermia / Ser326Cys polymorphism of 8-oxoguanine DNA glycosylase 1 (OGG1) in men with teratozoospermia

Resumen Antecedentes: El incremento seminal de especies reactivas de oxígeno (ERO) se ha vinculado con la oxidación del ADN y anormalidades en la morfología espermática. La enzima 8-oxoguanina ADN glucosilasa 1 (OGG1) repara la oxidación del ADN. Sin embargo, la presencia del polimorfismo en la OGG1 que involucra cambio de citocina (C) por guanina (G), resultando la sustitución de una cisteína por una serina en el codón 326 (Ser326Cis), ha demostrado disminución en la reparación del ADN oxidado. Estudios del polimorfismo Ser326Cis en hombres españoles y asiáticos con infertilidad demostraron que el alelo G(Cis) incrementa las ERO, impactando en la infertilidad y en la teratozoospermia. Objetivo: Conocer la prevalencia del polimorfismo Ser326Cis de OGG1 en pacientes con teratozoospermia. Método: Se analizaron parámetros espermáticos y el polimorfismo Ser326Cis de OGG1 de 81 muestras de semen con teratozoospermia. Resultados: Los genotipos detectados fueron Ser326Ser(CC) 43%, Ser326Cis(CG) 41% y Cis326Cis(GG) 16%. La frecuencia del alelo G(Cis) fue de 0.4, valor mayor a la frecuencia reportada en las bases de datos disponibles para poblaciones americanas (0.21-0.29), los parámetros espermáticos no se relacionaron con el polimorfismo Ser326Cis. Conclusión: El alelo G(Cis) es un factor que contribuye a la infertilidad.

Abstract Background: The increase in seminal reactive oxygen species (ROS) has been linked to DNA oxidation and abnormalities in sperm morphology. The enzyme 8-oxoguanine DNA glycosylase 1 (OGG1) repairs DNA oxidation. However, the presence of the polymorphism in OGG1 that involves a change of cytokine (C) to guanine (G) resulting in the substitution of a cystine for serine at codon 326 (Ser326Cys) has shown a decrease in the repair of oxidized DNA. Studies of the Ser326Cys polymorphism in Spanish and Asian men with infertility demonstrated that the G(Cys) allele increases ROS, impacting infertility and teratozoospermia. Objective: To know the prevalence of the Ser326Cys polymorphism of OGG1 in patients with teratozoospermia. Method: Sperm parameters and the Ser326Cys polymorphism of OGG1 were analyzed from 81 semen samples. Results: The genotypes detected were Ser326Ser(CC) 43%, Ser326Cys(CG) 41%, and yis326Cys(GG) 16%. The frequency of the G allele (Cys) was 0.4, a value higher than the frequency reported in the databases available for American populations (0.21-0.29), the sperm parameters were not related to the Ser326Cys polymorphism. Conclusion: The G (Cys) allele is a factor that contributes to infertility.

Lipopolysaccharide-induced sickness behavior is not altered in male Fmr1-deficient mice.

OBJECTIVES: Fragile X syndrome is the main monogenetic cause of intellectual disability and autism. Alterations in the immune system are commonly found in these developmental disorders. We and others have demonstrated that Fmr1 mutant mice present an altered response to immune stimuli. However, whether this altered immune response can influence the Fmr1 mutant behavioral outcomes in response to inflammation has not been fully investigated. MATERIALS AND METHODS: In the current study, we examine the behavioral sickness response of male wildtype and knockout  mice to the innate immune stimulus lipopolysaccharide (LPS) (0.1 mg/kg) to determine if Fmr1 mutants have altered sickness behavior. We used an enzyme-linked immunosorbent assay (ELISA) to measure changes in the cytokine interleukin-6 (IL-6) to determine that inflammation was induced in the mice. Sickness behavior was assessed in a wheel-running paradigm, and a tail suspension test was used to assess the depressive-like phenotype that follows sickness behavior in response to LPS. RESULTS: The ELISA using blood serum confirmed a significant increase in IL-6 in mice that were treated with LPS. Treated Fmr1 mutants exhibited decreased distance traveled in the wheel running after LPS administration, similar to treated controls. Another cohort of animals treated with LPS were tested in the tail suspension test and exhibited no alterations in immobility time in response to LPS. CONCLUSION: Together, our data suggest that Fmr1 mutant mice do not have altered sickness behavior in response to a low dose of LPS.

Changing the Tendency to Integrate the Senses.

Integration of sensory signals that emanate from the same source, such as the visual of lip articulations and the sound of the voice of a speaking individual, can improve perception of the source signal (e.g., speech). Because momentary sensory inputs are typically corrupted with internal and external noise, there is almost always a discrepancy between the inputs, facing the perceptual system with the problem of determining whether the two signals were caused by the same source or different sources. Thus, whether or not multisensory stimuli are integrated and the degree to which they are bound is influenced by factors such as the prior expectation of a common source. We refer to this factor as the tendency to bind stimuli, or for short, binding tendency. In theory, the tendency to bind sensory stimuli can be learned by experience through the acquisition of the probabilities of the co-occurrence of the stimuli. It can also be influenced by cognitive knowledge of the environment. The binding tendency varies across individuals and can also vary within an individual over time. Here, we review the studies that have investigated the plasticity of binding tendency. We discuss the protocols that have been reported to produce changes in binding tendency, the candidate learning mechanisms involved in this process, the possible neural correlates of binding tendency, and outstanding questions pertaining to binding tendency and its plasticity. We conclude by proposing directions for future research and argue that understanding mechanisms and recipes for increasing binding tendency can have important clinical and translational applications for populations or individuals with a deficiency in multisensory integration.

Estimating the number of deaths averted from 2008 to 2020 within the Ethiopian CMAM programme.

The management of wasting in Ethiopia is heavily reliant on the Community-based Management of Acute Malnutrition (CMAM) programme that has been implemented in more than 18,000 service delivery points scattered across the country. Despite the full-scale implementation of the CMAM, the number of child death averted, and the cost per child death averted remains unknown. This study aimed to estimate the cost and the number of child death averted by the CMAM programme between 2008 and 2020. Using data from routine monitoring of the CMAM programme, we estimated the excess mortality averted by the programme and estimated the cost per averted child death based on supply and labour. Over the past 13 years between 2008 and 2020, 3.6 million children under 5 years were admitted to the Ethiopian CMAM programme. The yearly average admission of 317,228 was achieved since 2011. On average, ~34,000 child deaths were averted yearly. The CMAM programme was estimated to have saved 437,654 (95% confidence interval [CI]: 320,161; 469,932) child deaths between 2008 and 2020, approximately 12% of the admitted cases. The average cost of the programme per adverted death was estimated at US$762/child death averted (95% CI = 639; 1001). The CMAM programme in Ethiopia is cost-effective and has continued to avert a significant number of child death. Given the high short- and long-term economic and health consequences of child wasting, concerted multi-sectoral efforts are needed to accelerate progress not only in its treatment but also in its prevention.

Rapamycin, but not minocycline, significantly alters ultrasonic vocalization behavior in C57BL/6J pups in a flurothyl seizure model.

Epilepsy is one of the most common neurological disorders, with individuals having an increased susceptibility of seizures in the first few years of life, making children at risk of developing a multitude of cognitive and behavioral comorbidities throughout development. The present study examined the role of PI3K/Akt/mTOR pathway activity and neuroinflammatory signaling in the development of autistic-like behavior following seizures in the neonatal period. Male and female C57BL/6J mice were administered 3 flurothyl seizures on postnatal (PD) 10, followed by administration of minocycline, the mTOR inhibitor rapamycin, or a combined treatment of both therapeutics. On PD12, isolation-induced ultrasonic vocalizations (USVs) of mice were examined to determine the impact of seizures and treatment on communicative behaviors, a component of the autistic-like phenotype. Seizures on PD10 increased the quantity of USVs in female mice and reduced the amount of complex call types emitted in males compared to controls. Inhibition of mTOR with rapamycin significantly reduced the quantity and duration of USVs in both sexes. Changes in USVs were associated with increases in mTOR and astrocyte levels in male mice, however, three PD10 seizures did not result in enhanced proinflammatory cytokine expression in either sex. Beyond inhibition of mTOR activity by rapamycin, both therapeutics did not demonstrate beneficial effects. These findings emphasize the importance of differences that may exist across preclinical seizure models, as three flurothyl seizures did not induce as drastic of changes in mTOR activity or inflammation as observed in other rodent models.

Diffusion and Monod kinetics model to determine in vivo human corneal oxygen-consumption rate during soft contact lens wear.

PURPOSE: We present an analysis of the corneal oxygen consumption Qc from non-linear models, using data of oxygen partial pressure or tension (P(O2) ) obtained from in vivo estimation previously reported by other authors. (1) METHODS: Assuming that the cornea is a single homogeneous layer, the oxygen permeability through the cornea will be the same regardless of the type of lens that is available on it. The obtention of the real value of the maximum oxygen consumption rate Qc,max is very important because this parameter is directly related with the gradient pressure profile into the cornea and moreover, the real corneal oxygen consumption is influenced by both anterior and posterior oxygen fluxes. RESULTS: Our calculations give different values for the maximum oxygen consumption rate Qc,max, when different oxygen pressure values (high and low P(O2)) are considered at the interface cornea-tears film. CONCLUSION: Present results are relevant for the calculation on the partial pressure of oxygen, available at different depths into the corneal tissue behind contact lenses of different oxygen transmissibility.

Nicotine and estrogen synergistically exacerbate cerebral ischemic injury.

The greater incidence of myocardial infarction, cardiac arrest, and ischemic stroke among women who smoke and use oral contraception (OC) compared to women who do not smoke and who do or do not use OC may be due in part to how nicotine influences endocrine function in women. For example, we recently demonstrated that chronic exposure to nicotine, the addictive agent in tobacco smoke responsible for the elevated risk of cardiac arrest, abolishes the endogenous or exogenous 17ß-estradiol-conferred protection of the hippocampus against global cerebral ischemia (a potential outcome of cardiac arrest) in naive or ovariectomized female rats. In the current study we examined the hypotheses that (1) a synergistic deleterious effect of nicotine plus oral contraceptives exacerbates post-ischemic hippocampal damage in female rats, and (2) nicotine directly inhibits estrogen-mediated intracellular signaling in the hippocampus. To test first hypothesis and to simulate smoking behavior-induced nicotine levels in the human body, we implanted osmotic pumps containing nicotine in the female rats for 16 days. Furthermore, we mimicked the use of oral contraceptives in females by administering oral contraceptives orally to the rat. Rats exposed to either nicotine alone or in combination with oral contraceptives were subjected to an episode of cerebral ischemia and the resultant brain damage was quantified. These results showed for the first time that nicotine with oral contraceptives did indeed exacerbate post-ischemic CA1 damage as compared to nicotine alone in naive female rats. In ex vivo hippocampal slice cultures, we found that nicotine alone or with 17ß-estradiol directly hinders estrogen receptors-mediated phosphorylation of cyclic-AMP element binding protein, a process required for neuronal survival and also exacerbates ischemic damage. Thus, nicotine can affect the outcome of cerebral ischemia by influencing brain endocrine function directly rather than through indirect systemic effects.

Derangements of post-ischemic cerebral blood flow by protein kinase C delta.

Cerebral ischemia causes blood flow derangements characterized by hyperemia (increased cerebral blood flow, CBF) and subsequent hypoperfusion (decreased CBF). We previously demonstrated that protein kinase C delta (δPKC) plays an important role in hippocampal neuronal death after ischemia. However, whether part of this protection is due to the role of δPKC on CBF following cerebral ischemia remains poorly understood. We hypothesized that δPKC exacerbates hyperemia and subsequent hypoperfusion resulting in CBF derangements following ischemia. Sprague-Dawley (SD) rats pretreated with a δPKC specific inhibitor (δV1-1, 0.5 mg/kg) exhibited attenuation of hyperemia and latent hypoperfusion characterized by vasoconstriction followed by vasodilation of microvessels after 2-vessel occlusion plus hypotension measured by 2-photon microscopy. In an asphyxial cardiac arrest model (ACA), SD rats treated with δV1-1 (pre- and post-ischemia) exhibited improved perfusion after 24 h and less hippocampal CA1 neuronal death 7 days after ACA. These results suggest possible therapeutic potential of δPKC in modulating CBF and neuronal damage after cerebral ischemia.

En primera persona: investigando mundos de los que somos partes / Em primeira pessoa: investigando mundos dos quais somos parte / Investigating worlds we are part of: in first person

El escrito propone algunas reflexiones en torno a los desafíos e interrogantes que se le presentan a los investigadores cuando se arriesgan a abandonar la ilusión de seguridad de colocarse “por fuera” de las dramáticas de su investigación. Los enfoques metodológicos de corte participativo y cooperativo cuestionan la posibilidad y el sentido de protegerse en la neutralidad u objetividad a fin de conseguir rigor y fiabilidad e invitan a considerar el encuentro de investigación sobre otras bases. En este escrito, revisamos algunos de los presupuestos epistemológicos y las dificultades metodológicas y técnicas que se presentan al investigador cuando intenta envolverse en la co-construccion de la investigación, arriesgándose a considerar a los “sujetos” como co-investigadores. Asimismo, se revisan algunas consecuencias de esta mirada sobre la formación de investigadores y se insinúan algunos caminos para cuidar - a la vez - del rigor metodológico y de una ética relacional

Esse trabalho propõe algumas reflexões acerca dos desafios e questões que se apresentam aos pesquisadores quando se arriscam a abandonar a ilusão de segurança de não estarem envolvidos nas tramas de suas investigações. Os enfoques metodológicos de tipo participativo e cooperativo questionam a possibilidade e o sentido de proteger-se na neutralidade ou objetividade a fim de alcançar rigor e confiabilidade e convidam a considerar o encontro entre “pesquisador/pesquisado” em outras bases. Nesse trabalho, revisamos alguns pressupostos epistemológicos e as dificuldades metodológicas e técnicas que se apresentam ao investigador ao tentar envolver-se na construção da investigação e considerar os “sujeitos” como partícipes dessa construção. Nesse sentido, buscamos discutir as conseqüências de tal perspectiva na formação de pesquisadores e indicamos alguns caminhos que articulam a um só tempo rigor metodológico e ética relacional

This article proposes some reflections around the challenges and questions that are presented to researchers when they take the risk to abandoning the illusion of security coming from positioning "outside" of their research. Participatory and collaborative methodological approaches questioned the possibility and the sense to protect the neutrality or objectivity in order to achieve accuracy and reliability and invited to consider the research encounter on other bases. In this paper, we review the basis of some epistemological, methodological and technical difficulties confronted for the researcher when he tries to get involved in the co-construction of research, taking the risk of considered the "subjects" as co-researchers. It also reviews some implications of this view on the training of investigators and we suggest some ways to look for a relational ethics and the methodological conditions

Pretreatment with a single estradiol-17beta bolus activates cyclic-AMP response element binding protein and protects CA1 neurons against global cerebral ischemia.

Estradiol-17beta is released from the ovaries in a cyclic manner during the normal estrous cycle in rats. During the transition from the diestrous to proestrous stage, the 17beta-estradiol increases in blood circulation. We hypothesized that a higher serum level of endogenous 17beta-estradiol would protect hippocampal pyramidal neurons against global cerebral ischemia via activation of the cyclic-AMP response element binding protein (CREB)-mediated signaling cascade. Furthermore, we asked if a single 17beta-estradiol bolus provides protection against ischemia in the absence of endogenous estradiol. To test these hypotheses, rats were subjected to global cerebral ischemia at different stages of the estrous cycle. Ischemia was produced by bilateral carotid occlusion and systemic hypotension. Brains were examined for histopathology at 7 days of reperfusion. Higher serum levels of 17beta-estradiol (at proestrus and estrus stages) correlated with increased immunoreactivity of pCREB in hippocampus and ischemic tolerance. At diestrus, when circulating gonadal hormone concentrations were lowest, the pCREB protein content of hippocampus was reduced and showed the least number of normal neurons after ischemia compared to other stages of the estrous cycle. A similar phosphorylation pattern was also observed for mitogen-activated protein kinase (MAPK) and calcium-calmodulin-dependent protein kinase (CaMKII) in hippocampus. The cyclic variation in ovarian hormones did not reflect phosphorylation of protein kinase B (Akt). To test the efficacy of a single bolus of 17beta-estradiol before ischemia, ovariectomized rats were treated with 17beta-estradiol (5/10/50 microg/kg) or vehicle (oil) and 48/72/96 h later rats were exposed to cerebral ischemia. A single 17beta-estradiol bolus treatment in ovariectomized rats significantly increased CREB mRNA activation and protected CA1 pyramidal neurons against ischemia. These results suggest that an exogenous bolus of 17beta-estradiol to ovariectomized rats protects hippocampus against ischemia via activation of the CREB pathway in a manner similar to the endogenous estrous cycle.

A intimidade nas relações de casal: desafios para a criação de mundos singulares na pós-modernidade / Intimacy in couples´relationships: challenges for the creation of singular worlds in post-modernity

Este artigo apresenta um recorte dos resultados de uma pesquisa sobre as conversações que os casais mantêm nos momentos críticos de sua relação.Este trabalho focaliza – particularmente – no papel que cabe à intimidade na construção da relação amorosa e suas vicissitudes na posmodernidade. Da mesma forma são considerados os desafios que propõe a busca simultânea de autonomia e proximidade, prototípicos da época atual, que colocam a intimidade no centro das conversações, já que suas possibilidades de reconstrução condicionam as opções que os casais terão no momento de reformular o desenho de sua relação. Também são esboçadas as interseções da intimidade, com os dois núcleos de sentido que conformam o sistema auto-organizado dos significados postos em jogo diante das situações críticas.

This article presents some aspects of the results of a research on the conversations the couples keep at the critical moments of their relationship. It focuses particularly on the role of intimacy in the construction of the loving relation and its contingency in the post modernity. Moreover, the challenges which the concurrent search for autonomy and proximity implies will be considered. Both are typical of the current time and place intimacy in the center of the conversations because the possibilities of reconstruction condition the options that couples will have at the moment of reformulating the design of their relationship. Also, the textures of privacy are sketched, with the two nuclei of sense that tune the auto-organized system of meanings facing critical situations.

Análisis biomecánico del uso de cianocrilatos en la reparación meniscal: estudio experimental en modelo animal / Biomechanical analysis of the cyanoacrylates in the meniscal repair: experimental study

Se midió la resistencia hasta la falla de 5 métodos para reparación meniscal. Sesenta meniscos mediales de origen bovino se dividieron en 5 grupos. Se hizo una lesión artificial a 3 mm desde el borde periférico. Las técnicas evaluadas fueron: sutura horizontal con adición de cianoacrilatos (grupo 1), dardos meniscales con cianoacrilato (grupo 2), sutura con técnica horizontal (grupo 3), dardos meniscales (grupo 4), y cianoacrilatos unicamente (grupo 5). Una prueba de tensión hasta la falla se hizo, usando el analizador universal Instron 1122. El promedio de la carga de falla en el grupo 1 fue 110N, en el grupo 2: 89,8N, en el grupo 3: 97N, en el grupo 4: 82.7N y en el último grupo 48.5N. No se encontró diferencia estadisticamente significativa en la carga de falla entre los grupos 2 y 3. La falla para los dardos con cianoacrilato en meniscos bovinos es comparable con la sutura horizontal.

Ischemic preconditioning preserves mitochondrial function after global cerebral ischemia in rat hippocampus.

Ischemic tolerance in brain develops when sublethal ischemic insults occur before "lethal" cerebral ischemia. Two windows for the induction of tolerance by ischemic preconditioning (IPC) have been proposed: one that occurs within 1 hour after IPC, and another that occurs 1 or 2 days after IPC. The authors tested the hypotheses that IPC would reduce or prevent ischemia-induced mitochondrial dysfunction. IPC and ischemia were produced by bilateral carotid occlusions and systemic hypotension (50 mm Hg) for 2 and 10 minutes, respectively. Nonsynaptosomal mitochondria were harvested 24 hours after the 10-minute "test" ischemic insult. No significant changes were observed in the oxygen consumption rates and activities for hippocampal mitochondrial complexes I to IV between the IPC and sham groups. Twenty-four hours of reperfusion after 10 minutes of global ischemia (without IPC) promoted significant decreases in the oxygen consumption rates in presence of substrates for complexes I and II compared with the IPC and sham groups. These data suggest that IPC protects the integrity of mitochondrial oxidative phosphorylation after cerebral ischemia.

Transient changes of brain-derived neurotrophic factor (BDNF) mRNA expression in hippocampus during moderate ischemia induced by chronic bilateral common carotid artery occlusions in the rat.

Chronic bilateral common carotid artery occlusion (BCCAO) induces moderate ischemia (oligemia) in the rat forebrain in the absence of overt neuronal damage. In situ hybridization for brain-derived neurotrophic factor (BDNF) mRNA was used to search for a molecular response to moderate ischemia. BDNF mRNA was significantly increased in the hippocampal granule cells at 6 h of occlusion (ANOVA, Tukey test P<0.05). At 1, 7 and 14 days BDNF mRNA levels returned to control levels. The frequency of BDNF gene expression at 6 h was 83%, which was significantly higher than the 7% incidence of histological injury in the hippocampus (Fisher's exact test, P<0.002). Cerebral blood flow was reduced to 75% of control levels in the hippocampus after 1 week of BCCAO when measured with the autoradiographic method. Measurements of tissue flow with a microprobe for laser Doppler flow excluded decreases into the ischemic range during the period when elevated gene expression was observed. Prolonged moderate ischemia (oligemia) is a sufficient stimulus for BDNF gene expression in the hippocampus. These molecular studies provide direct evidence for an involvement of the hippocampus in the BCCAO model.

The effect of bone morphogenetic protein-7 (BMP-7) on functional recovery, local cerebral glucose utilization and blood flow after transient focal cerebral ischemia in rats.

Bone morphogenetic protein-7 (BMP-7) has been shown to enhance dendritic growth and improve functional recovery after experimental stroke. In this study, we examined the effect of BMP-7 on functional recovery, local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCMRglu) following transient middle cerebral artery occlusion. Sprague--Dawley rats (n=29) were anesthetized with halothane/nitrous oxide and received 2-h middle cerebral artery occlusion (MCAo) by poly-L-lysine-coated intraluminal suture. Rectal and cranial temperatures were regulated at 37.0--37.5 degrees C. BMP-7 or vehicle (volume, 25 microl) was administered intracisternally in a blinded fashion at 24 h after MCAo. Neurological status was evaluated during occlusion (60 min) and daily for 2 days after MCAo. In matched animal groups, LCMRglu was measured autoradiographically with [(14)C]2-deoxyglucose (2-DG) and LCBF with [(14)C]iodoantipyrine 48 h after MCAo. Four animals groups were studied: LCMRglu series (BMP-7, n=7; vehicle, n=8); LCBF series (BMP-7, n=6; vehicle, n=8). Average three-dimensional image data sets were constructed for each group and were compared by pixel-based statistical methods. Rectal and cranial temperatures, mean blood pressure, plasma glucose and blood gases were similar among groups. BMP-7 significantly improved the total neurological score compared to vehicle at 48 h after MCAo (7.3+/-0.4 vs. 9.0+/-0.2, respectively; P<0.0003). Compared to vehicle-rats, BMP-7 enhanced glucose utilization in the basal ganglia ipsilateral to stroke and improved LCBF in ipsilateral subthalamus, but decreased LCBF and LCMRglu in contralateral cortical regions.

Neuroprotective effect of high-dose albumin therapy against global ischemic brain injury in rats.

The purpose of this study was to determine whether treatment with high-dose human serum albumin (HSA) would offer protection in a model of high-grade transient forebrain ischemia. Twenty-six fasted Wistar rats underwent bilateral common carotid artery occlusion and severe hypotension (50 mmHg) for 10 min. The agent (25% HSA) or vehicle (0.9% NaCl) was administered i.v. 5 min after termination of ischemia. HSA-treated rats showed significantly improved neurological deficits throughout a 7-day survival period. Histologically, HSA-treated rats showed 2.4- to 5.3-fold increases in numbers of surviving CA1 hippocampal pyramidal neurons compared to saline-treated animals. These results document that high-dose albumin therapy instituted 5 min after global ischemia significantly improves neurological score and reduces histological damage.

The effect of high-dose albumin therapy on local cerebral perfusion after transient focal cerebral ischemia in rats.

We have shown that high-concentration albumin therapy is markedly neuroprotective in focal cerebral ischemia. The present study was conducted to ascertain the degree to which hemodynamic alterations are responsible for this therapeutic effect. Normothermic, physiologically regulated male Sprague-Dawley rats received a 2-h period of middle cerebral artery occlusion (MCAo) by insertion of an intraluminal suture coated with poly-L-lysine. Albumin (25% human serum albumin solution) or vehicle (0.9% sodium chloride) was administered intravenously at a dose of 1% of body weight immediately after suture withdrawal following 2-h MCAo. Local cerebral blood flow (LCBF) was measured autoradiographically with 14C-iodoantipyrine after 1 h of recirculation. Novel image-processing methods were used to compare average LCBF data sets against previously obtained infarction-frequency data on a pixel-by-pixel basis. Albumin therapy reduced mean hematocrit by 42% but produced no other systemic alterations. Pixel-based histopathological analysis revealed large, consistent cortical and subcortical infarcts in saline-treated rats with MCAo; albumin therapy reduced mean cortical infarct volume by 85%. Within regions showing albumin-associated neuroprotection, numbers of pixels having LCBF in the upper ischemic-core flow range (0.12-0.24 ml g-1 min-1) were reduced by 8.6-fold by albumin therapy when compared to saline-treated rats; and numbers of pixels with LCBF in the lower penumbral flow range (0.24-0.36 ml g-1 min-1) were reduced by 3. 1-fold in albumin-treated rats (p=0.04 by repeated-measures analysis of variance). Analysis of the [albumin-saline] 3-dimensional difference-image data set revealed a circumferential zone of statistically significant albumin-associated LCBF increase within the posterior portion of the ischemic hemisphere, surrounding the core-region of prior ischemia. Thus, high-concentration albumin therapy improves local perfusion to regions of critical LCBF reduction. The spatial extent of this LCBF effect, however, appears too small to account fully for the marked neuroprotective efficacy of this therapy. We suggest that other, non-hemodynamic mechanisms may also be contributory.