Chronic administration of the neurotrophic agent cerebrolysin ameliorates the behavioral and morphological changes induced by neonatal ventral hippocampus lesion in a rat model of schizophrenia

Neonatal ventral hippocampal lesion (nVHL) in rats has been widely used as a neurodevelopmental model to mimic schizophrenia-like behaviors. Recently, we reported that nVHLs result in dendritic retraction and spine loss in prefrontal cortex (PFC) pyramidal neurons and medium spiny neurons of the nucleus accumbens (NAcc). Cerebrolysin (Cbl), a neurotrophic peptide mixture, has been reported to ameliorate the synaptic and dendritic pathology in models of aging and neurodevelopmental disorder such as Rett syndrome. This study sought to determine whether Cbl was capable of reducing behavioral and neuronal alterations in nVHL rats. The behavioral analysis included locomotor activity induced by novel environment and amphetamine, social interaction, and sensoriomotor gating. The morphological evaluation included dendritic analysis by using the Golgi-Cox procedure and stereology to quantify the total cell number in PFC and NAcc. Behavioral data show a reduction in the hyperresponsiveness to novel environment- and amphetamine-induced locomotion, with an increase in the total time spent in social interactions and in prepulse inhibition in Cbl-treated nVHL rats. In addition, neuropathological analysis of the limbic regions also showed amelioration of dendritic retraction and spine loss in Cbl-treated nVHL rats. Cbl treatment also ameliorated dendritic pathology and neuronal loss in the PFC and NAcc in nVHL rats. This study demonstrates that Cbl promotes behavioral improvements and recovery of dendritic neuronal damage in postpubertal nVHL rats and suggests that Cbl may have neurotrophic effects in this neurodevelopmental model of schizophrenia. These findings support the possibility that Cbl has beneficial effects in the management of schizophrenia symptoms.     

Combined administration of cerebrolysin and donepezil induces plastic changes in prefrontal cortex in aged mice

Cerebrolysin (Cbl) shows neurotrophic and neuroprotective properties while donepezil (Dnp) is a potent acetylcholinesterase (AChE) inhibitor, both drugs are prescribed for Alzheimer's disease (AD) treatment. Previous studies have shown that the Dnp and Cbl administered separately, modify dendritic morphology of neurons in the prefrontal cortex and hippocampus in senile rodents. Since the deficit of neurotrophic factor activity is implicated in the degeneration of cholinergic neurons of basal forebrain, a combination therapy of Dnp and Cbl has been tested recently in Alzheimer's patients. However, the plastic changes that may underlie this combined treatment have not yet been explored. We present here the effect of the combined administration of Cbl and Dnp on dendritic morphology in brain regions related to learning and memory in aged mice. The Golgi‐Cox staining protocol and Sholl analysis were used for studying dendritic changes. Cbl and Dnp were administrated daily for 2 months to 9‐months‐old mice. Locomotor activity was assessed, as well as the dendritic morphology of neurons in several limbic regions was analyzed. Results showed that Cbl and Dnp induced an increase in locomotor activity without synergistic effect. The Cbl or Dnp treatment modified the dendritic morphology of neurons from prefrontal cortex (PFC), dorsal hippocampus (DH), dentate gyrus (DG), and the shell of nucleus accumbens (NAcc). These changes show an increase in the total dendritic length and spine density, resulting in an improvement of dendritic arborization. Prominently, a synergistic effect of Cbl and Dnp was observed on branching order and total dendritic length of pyramidal neurons from PFC. These results suggest that Dnp and Cbl may induce plastic changes in a manner independent of each other, but could enhance their effect in target cells from PFC. Synapse 66:938–949, 2012. © 2012 Wiley Periodicals, Inc.     

A prospective multi-centre study of the value of FDG-PET as part of a structured diagnostic protocol in patients with fever of unknown origin

Purpose Since ¹⁸F-fluorodeoxyglucose (FDG) accumulates in neoplastic cells and in activated inflammatory cells, positron emission tomography (PET) with FDG could be valuable in diagnosing patients with fever of unknown origin (FUO). The aim of this study was to validate the use of FDG-PET as part of a structured diagnostic protocol in the general patient population with FUO. Methods From December 2003 to July 2005, 70 patients with FUO were recruited from one university hospital (n=38) and five community hospitals (n=32). A structured diagnostic protocol including FDG-PET was used. A dedicated, full-ring PET scanner was used for data acquisition. FDG-PET scans were interpreted by two staff members of the department of nuclear medicine without further clinical information. The final clinical diagnosis was used for comparison with the FDG-PET results. Results Of all scans, 33% were clinically helpful. The contribution of FDG-PET to the final diagnosis did not differ significantly between patients diagnosed in the university hospital and patients diagnosed in the community hospitals. FDG-PET contributed significantly more often to the final diagnosis in patients with continuous fever than in patients with periodic fever. FDG-PET was not helpful in any of the patients with normal erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Conclusion FDG-PET is a valuable imaging technique as part of a diagnostic protocol in the general patient population with FUO and a raised ESR or CRP.     

Incidence of epilepsies and epileptic syndromes among children in Navarre, Spain: 2002 through 2005

All incident cases of children living in Navarre, Spain, younger than 15 years of age with newly diagnosed epilepsy (2002-2005) were registered in a prospective study, with epidemiologic and clinical data and complementary study results collected. Based on International League Against Epilepsy criteria, 191 patients were diagnosed as having epilepsy. The overall incidence rate is 62.6 cases per 100 000, with the highest incidence (95.3 cases per 100 000) during the first year of life. Fifty-five percent of patients have focal epilepsies, 42.9% generalized epilepsies, and 2.1% undetermined epilepsies. Among infants, West syndrome (45.5%), epilepsies associated with specific syndromes (27.3%), and focal symptomatic epilepsies (13.6%) are the most prevalent syndromes. In early childhood, the main syndromes are focal symptomatic (22.7%) and cryptogenic (21.2%) epilepsies and Doose syndrome (13.6%). Among school-aged children, focal benign epilepsies (27.8%) and cryptogenic and absence epilepsies (18.5% for both) are the most prevalent, with focal cryptogenic epilepsies (26.5%) and benign epilepsies (18.4%) most prevalent among adolescents.     

Estimating the effects of co-medications on plasma olanzapine concentrations by using a mixed model

The purpose of this study was to estimate the effect sizes of drug interactions on plasma olanzapine concentrations while adjusting for potentially confounding factors such as smoking. The estimation was performed by using a mixed model, data from a series of previously published studies of lamotrigine, oxcarbazepine, topiramate, and mirtazapine, and unpublished data from patients under clinical therapeutic drug monitoring (TDM). The total sample included 163 adult patients (age>or=18 years) who provided both steady-state plasma olanzapine concentrations and smoking information. They provided a total of 360 olanzapine concentrations (1 to 11 measures per patient). Smoking and concomitant carbamazepine or lamotrigine use were found to have significant effects on median plasma olanzapine concentrations. The effects of lamotrigine on plasma olanzapine concentrations were modified by smoking. After adjusting for olanzapine dose and carbamazepine intake, plasma olanzapine concentrations were 10% lower in non-smokers who were taking lamotrigine than in non-smokers who were not taking lamotrigine; olanzapine concentrations were 35% higher in smokers who were taking lamotrigine than in smokers who were not taking lamotrigine; olanzapine concentrations were 41% lower in smokers who were not taking lamotrigine than in non-smokers who were not taking lamotrigine; and olanzapine concentrations were 11% lower in smokers who were taking lamotrigine than in non-smokers who were taking lamotrigine. After adjusting for olanzapine dose and taking carbamazepine, the correction factor comparing smokers taking lamotrigine versus non-smokers who were not taking lamotrigine was 1.3. Gender, age, and concomitant use of mirtazapine, valproic acid, lamotrigine, topiramate, lorazepam, citalopram or oxcarbazepine did not have significant effects on olanzapine concentrations. The main limitation of this clinical design is the unavoidable substantial "noise" that characterizes (uncontrolled) clinical environments, which may make it difficult to detect the effects of some variables. Other limitations were the small sample size of some drug sub-samples and the lack of testing for plasma olanzapine metabolites.     

Antigen targeting to dendritic cells elicits long-lived T cell help for antibody responses

Resistance to several prevalent infectious diseases requires both cellular and humoral immune responses. T cell immunity is initiated by mature dendritic cells (DCs) in lymphoid organs, whereas humoral responses to most antigens require further collaboration between primed, antigen-specific helper T cells and naive or memory B cells. To determine whether antigens delivered to DCs in lymphoid organs induce T cell help for antibody responses, we targeted a carrier protein, ovalbumin (OVA), to DCs in the presence of a maturation stimulus and assayed for antibodies to a hapten, (4-hydroxy-3-nitrophenyl) acetyl (NP), after boosting with OVA-NP. A single DC-targeted immunization elicited long-lived T cell helper responses to the carrier protein, leading to large numbers of antibody-secreting cells and high titers of high-affinity antihapten immunoglobulin Gs. Small doses of DC-targeted OVA induced higher titers and a broader spectrum of anti-NP antibody isotypes than large doses of OVA in alum adjuvant. Similar results were obtained when the circumsporozoite protein of Plasmodium yoelii was delivered to DCs. We conclude that antigen targeting to DCs combined with a maturation stimulus produces broad-based and long-lived T cell help for humoral immune responses.     

Cross-cultural adaptation and validation of the Spanish version of the Cumberland Ankle Instability Tool (CAIT): an instrument to assess unilateral chronic ankle instability

The Cumberland Ankle Instability Tool (CAIT) is a valid instrument to determine the presence of chronic ankle instability (CAI) and to assess its severity. Self-report test is very useful for researchers and clinical practice, and CAI is a widespread tool. Nevertheless, there is lack of measurement instruments validated into Spanish, which represents a major difficulty for research dealing with a Spanish-speaking population. The questionnaire was cross-culturally adapted into Spanish. The psychometric properties tested in the Spanish version of the CAIT were measured for internal consistency, test–retest reliability, construct validity, criterion validity, and responsiveness in 108 participants who were recruited from several fitness centers. The Spanish version of the CAIT had high internal consistency (Cronbach's α?=?0.766) and reliability (intraclass correlation coefficient?=?0.979, 95 % confidence interval (CI)?=?0.958–0.990). Correlation with the 36-item Short-Form Health Survey (SF-36) physical component summary score (rho?=?0.241, p?=?0.012) was greater than the SF-36 mental component summary score (rho?=??0.162, p?=?0.094). The construct validity shows three different factors in the questionnaire and good responsiveness with a mean change of ?2.43 (95 % CI?=??3.12 to 1.73, p?<?0.0001) and a size effect of Cohen's d?=?1.07. The Spanish version of the CAIT has been shown to be a valid and reliable instrument for measuring chronic ankle instability and constitutes a useful instrument for the measurement of CAI in the clinical setting in Spain.