Genetic and clinical evidence of mitochondrial dysfunction in autism spectrum disorder and intellectual disability.

Clinical conditions commonly associated with mitochondrial disorders (CAMDs) are often present in autism spectrum disorders (ASD) and intellectual disability (ID). Therefore, the mitochondrial dysfunction hypothesis has been proposed as a transversal mechanism that may function in both disorders. Here, we investigated the presence of conditions associated with mitochondrial disorders and mitochondrial DNA (mtDNA) alterations in 122 subjects who presented ASD with ID (ASD group), 115 subjects who presented ID but not ASD (ID group) and 112 healthy controls (HC group). We assessed in the three study groups the presence of the clinical conditions through a questionnaire and the mtDNA content of two mitochondrial genes, MT-ND1 and MT-ND4, by qPCR. The mtDNA sequences of 98 ASD and 95 ID subjects were obtained by mtDNA-targeted next generation sequencing and analysed through the MToolBox pipeline to identify mtDNA mutations. Subjects with ASD and ID showed higher frequencies of constipation, edema, seizures, vision alterations, strabismus and sphincter incontinence than HCs subjects. ASD and ID subjects showed significantly lower mtDNA content than HCs in both MT-ND1 and MT-ND4 genes. In addition, we identified 49 putative pathogenic variants with a heteroplasmy level higher than 60%: 8 missense, 29 rRNA and 12 tRNA variants. A total of 28.6% of ASD and 30.5% of ID subjects carried at least one putative pathogenic mtDNA mutation. The high frequency of CAMDs, the low mtDNA content and the presence of putative pathogenic mtDNA mutations observed in both ASD and ID subjects are evidence of mitochondrial dysfunction in ASD and ID.

Personality dimensions of schizophrenia patients compared to control subjects by gender and the relationship with illness severity.

BACKGROUND: Personality traits and schizophrenia present gender differences; however, gender has not been considered in most studies on personality and schizophrenia. This study aims to identify the different personality dimensions of schizophrenia patients and healthy control subjects by gender and to explore the relationship between personality dimensions and illness severity variables by analyzing data for males and females separately. METHODS: Temperament and Character Inventory-Revised dimensions were compared by gender between 161 schizophrenia patients and 214 healthy controls from a population-based sample using independent t-tests. We then investigated whether personality dimensions are related to illness severity variables using correlation analyses and bivariate logistic regression, also by gender. RESULTS: The patients had significantly higher scores for harm avoidance (HA) and self-transcendence (ST) and lower scores for reward dependence (RD), cooperativeness (C), and self-directedness (SD) than the controls. Similar results were obtained when the sample was stratified by gender, however the differences were higher and more significant for HA among males and for RD among females. The number of admissions to a psychiatric hospital positively correlated with novelty seeking (NS) in males and negatively with SD in females. In males, SD and ST negatively correlated with the number of suicide attempts. CONCLUSIONS: Male and female patients present difficulties for regulating and adapting behavior to achieve goals (SD) and for identifying and accepting others (C), as well as a great sense of spirituality and universe identification (ST). However, male patients are more characterized by being fearful, doubtful and easily fatigued (HA), while female patients are characterized by presenting difficulties maintaining and pursuing associated reward behaviors (RD). Furthermore, male and female patients who are frequently admitted to psychiatric hospitals and male patients who attempt suicide should be evaluated regarding their personality dimensions. Future studies assessing the relationship between personality dimensions and the clinical features of schizophrenia should consider gender differences.

Spanish adaptation of the Beck Cognitive Insight Scale (BCIS) for schizophrenia.

INTRODUCTION: The Beck Cognitive Insight Scale has been designed to evaluate the cognitive insight capacity, that is to say, the practice of self-reflectiveness as a meta-cognitive mechanism for examining and analysing the disorder's symptoms, it also permits a continuous re-evaluation of inadequate interpretations. METHODOLOGY: The aim of this study is to examine the psychometric properties, the dimensional structure and the internal validity of the Spanish version of Beck's Cognitive Scale of Insight (BCIS). In this paper we also analyse its relation with the Positive and Negative Symptoms Scale (PANSS). The Cognitive Insight Scale was translated and adapted to Spanish with 129 in- and out-schizophrenic patients. RESULTS: Principal component analysis showed a two-factor structure that was similar to the original one, recognizable as self-reflectiveness (R) and self-certainty (C) with similar reliability as the American version. Self-reflectiveness and the R-C index correlated with loss of insight of the PANSS scale. In general, BCIS showed significant associations with the PANSS subscales. Out patients scored self-reflectiveness and R-C index signicantly higher than in-patients and lower in self-certainty. CONCLUSION: Psychometric properties obtained with the adapted Spanish version of BCIS guarantee the adequate evaluation of cognitive insight.

Ulcerative colitis exacerbates lipopolysaccharide-induced damage to the nigral dopaminergic system: potential risk factor in Parkinson`s disease.

Peripheral inflammation could play a role in the origin and development of certain neurodegenerative disorders. To ascertain this possibility, a model of dopaminergic neurodegeneration based on the injection of the inflammatory agent lipopolysaccharide (LPS) within the substantia nigra was assayed in rats with ulcerative colitis (UC) induced by the ingestion of dextran sulphate sodium. We found an increase in the levels of inflammatory markers from serum (tumor necrosis factor-α, IL-1ß, IL-6 and the acute phase protein C-reactive protein) and substantia nigra (tumor necrosis factor-α, IL-1ß, IL-6, inducible nitric oxide synthase, intercellular adhesion molecule-1, microglial and astroglial populations) of rats with UC, as well as an alteration of the blood-brain barrier permeability and the loss of dopaminergic neurons. UC reinforced the inflammatory and deleterious effects of LPS. On the contrary, clodronate encapsulated in liposomes (ClodLip), which depletes peripheral macrophages, ameliorated the effect of LPS and UC. Peripheral inflammation might represent a risk factor in the development of Parkinson's disease.

[Prevalence of and predisposing factors for bundle branch block in patients starting dialysis]. / Análisis de la prevalencia y los factores predisponentes de los bloqueos de rama en los pacientes que inician diálisis.

INTRODUCTION AND OBJECTIVES: Although bundle branch block (BBB) is regarded as a frequent finding, data on its prevalence are scarce in the general population and nonexistent in patients on dialysis. The aims of this study were to determine the prevalence of complete BBB in patients starting dialysis, to identify factors associated with its presence and, secondarily, to explore its association with mortality and the occurrence of cardiovascular events. METHODS: The study involved patients who started dialysis at our institution between November 1, 2003 and December 31, 2006. All underwent cardiological evaluation at the start of treatment. The presence of BBB was determined and its relationship with clinical factors and biochemical and echocardiographic parameters was examined. Patients were followed up until November 30, 2007. RESULTS: The study included 211 patients (age 65.05+/-15.7 years; 56.4% male). Of these, 24 (11.4%) presented with BBB: 6 (2.8%) with left BBB and 18 (8.5%) with right BBB. Age (odds ratio [OR]=1.05; 95% confidence interval [CI], 1.008-1.113; P=.02) and body mass index (OR=1.12; 95% CI, 1.019-1.234; P=.02) were independently associated with BBB. During a mean follow-up period of 23.7+/-12.9 months, patients who presented with left BBB showed a clear trend towards a poorer outcome than those without a conduction defect. CONCLUSIONS: The prevalence of BBB was high in patients starting dialysis and greater than that observed in the general population. Its presence was independently associated with older age and obesity. During the mean follow-up period of 2 years, patients with left BBB demonstrated a trend towards a poor prognosis.

Enhanced CD4 down-modulation by late stage HIV-1 nef alleles is associated with increased Env incorporation and viral replication.

Three viral proteins participate in the down-modulation of CD4 in human immunodeficiency virus type 1 (HIV-1)-infected cells. The underlying mechanisms have been extensively investigated. However, the physiological relevance of this phenomenon remains poorly understood. To address the role of CD4 down-modulation in HIV-1 pathogenesis in vivo, we have characterized the functional properties of nef alleles isolated from seven HIV-1-infected patients at either the stage of AIDS (late alleles) or during the asymptomatic phase of infection (early alleles). HIV-1 variants carrying these nef alleles showed striking differences in CD4 down-modulation, virus infectivity, and replication properties. Infection of T cells with late strains resulted in production of viral particles with enhanced infectivity, as compared with variants carrying early nef alleles. These differences in infectivity were observed only when viruses were produced in cells with high levels of the viral receptor, suggesting a functional link between CD4 levels and the ability of Nef to down-modulate CD4 and to enhance viral infectivity. Similarly, late nef alleles were substantially more active than early nef genes in stimulating HIV-1 replication in high CD4-positive cells, including primary lymphocytes, but not in cells expressing low levels of the CD4 receptor. Single-round assays showed that differences in infectivity between late and early strains are largely reduced when evaluated in target cells with high levels of CD4, suggesting that the inhibitory effect occurs at the entry step. Supporting this, enhanced CD4 down-modulation by late nef alleles was associated with higher levels of envelope incorporation into viral particles, a phenomenon that likely accounted for the augmented infectivity. Our data suggest a mechanistic link between the Nef-mediated CD4 down-modulation and the enhancement of replication in CD4-positive lymphocytes. As progression to disease occurs, HIV-1 Nef variants with enhanced ability to down-modulate CD4 are selected. These strains efficiently overcome the deleterious effects of CD4 and replicate more aggressively in CD4-positive primary lymphocytes. These results highlight the importance of the virus-induced CD4 down-modulation in HIV-1 pathogenesis.

Increased early atherogenesis in young versus old hypercholesterolemic rabbits by a mechanism independent of arterial cell proliferation.

We sought to determine the relative importance of aging and hypercholesterolemia on atherosclerosis. Although plasma cholesterol levels increased similarly in young and old rabbits fed an atherogenic diet for 2 months, aortic atherosclerotic lesions were more prominent in young animals. This finding was associated with an age-dependent reduction in the DNA-binding activity of the proinflammatory nuclear factor kappaB (NF-kappaB) in aortic tissue. Atherosclerotic lesions consisted mostly of macrophages, which displayed a similar proliferative response in both age groups. Independently of the age, medial cell proliferation was low and increased as a function of intimal lesion size. Thus, higher atherogenicity in young rabbits exposed to extreme hypercholesterolemia compared to old counterparts is associated with higher activity of NF-kappaB in the juvenile vessel wall without apparent age-dependent changes in arterial cell proliferation.