Self-ordered pointing and visual conditional associative learning tasks in drug-free schizophrenia spectrum disorder patients

<p>Abstract</p> <p>Background</p> <p>There is evidence of a link between schizophrenia and a deficit of working memory, but this has been derived from tasks not specifically developed to probe working memory per se. Our aim was to investigate whether working memory deficits may be detected across different paradigms using the self-ordered pointing task (SOPT) and the visual conditional associative learning task (VCALT) in patients with schizophrenia spectrum disorders and healthy controls. The current literature suggests deficits in schizophrenia spectrum disorder patients versus healthy controls but these studies frequently involved small samples, broad diagnostic criteria, inclusion of patients on antipsychotic medications, and were not controlled for symptom domains, severity of the disorder, etc. To overcome some of these limitations, we investigated the self-monitoring and conditional associative learning abilities of a numerically representative sample of healthy controls and a group of non-deteriorated, drug-free patients hospitalized for a schizophrenia spectrum disorder with florid, mainly positive psychotic symptoms.</p> <p>Methods</p> <p>Eighty-five patients with a schizophrenia spectrum disorder (DSM-IV-TR diagnosis of schizophrenia (<it>n </it>= 71) or schizophreniform disorder (<it>n </it>= 14)) and 80 healthy controls entered the study. The clinical picture was dominated by positive symptoms. The healthy control group had a negative personal and family history of schizophrenia or mood disorder and satisfied all the inclusion and exclusion criteria other than variables related to schizophrenia spectrum disorders.</p> <p>Results</p> <p>Compared to controls, patients had worse performances on SOPT, VCALT and higher SOPT/VCALT ratios, not affected by demographic or clinical variables. ROC curves showed that SOPT, VCALT, and SOPT/VCALT ratio had good accuracy in discriminating patients from controls. The SOPT and VCALT scores were inter-correlated in controls but not in patients.</p> <p>Conclusion</p> <p>The selection of a clinically homogeneous group of patients, controlled for a number of potential confounding factors, and the high level of significance found in the different analyses confirm the presence of SOPT and VCALT abnormalities in a large preponderance of patients with schizophrenia spectrum disorder with positive symptoms. SOPT, VCALT, and SOPT/VCALT ratio showed good accuracy in discriminating patients from healthy controls. These conclusions cannot be extended to schizophrenia spectrum disorder patients with a different clinical profile from our patient population.</p

BRCA1-mutated and basal-like breast cancers have similar aCGH profiles and a high incidence of protein truncating TP53 mutations

<p>Abstract</p> <p>Background</p> <p>Basal-like breast cancers (BLBC) are aggressive breast cancers for which, so far, no targeted therapy is available because they typically lack expression of hormone receptors and HER2. Phenotypic features of BLBCs, such as clinical presentation and early age of onset, resemble those of breast tumors from <it>BRCA1</it>-mutation carriers. The genomic instability of <it>BRCA1</it>-mutated tumors can be effectively targeted with DNA-damaging agents and poly-(ADP-ribose) polymerase 1 (PARP1) inhibitors. Molecular similarities between BLBCs and <it>BRCA1</it>-mutated tumors may therefore provide predictive markers for therapeutic response of BLBCs.</p> <p>Methods</p> <p>There are several known molecular features characteristic for <it>BRCA1</it>-mutated breast tumors: 1) increased numbers of genomic aberrations, 2) a distinct pattern of genomic aberrations, 3) a high frequency of <it>TP53 </it>mutations and 4) a high incidence of complex, protein-truncating <it>TP53 </it>mutations. We compared the frequency of <it>TP53 </it>mutations and the pattern and amount of genomic aberrations between <it>BRCA1</it>-mutated breast tumors, BLBCs and luminal breast tumors by <it>TP53 </it>gene sequencing and array-based comparative genomics hybridization (aCGH) analysis.</p> <p>Results</p> <p>We found that the high incidence of protein truncating <it>TP53 </it>mutations and the pattern and amount of genomic aberrations specific for BRCA1-mutated breast tumors are also characteristic for BLBCs and different from luminal breast tumors.</p> <p>Conclusions</p> <p>Complex, protein truncating TP53 mutations in BRCA1-mutated tumors may be a direct consequence of genomic instability caused by BRCA1 loss, therefore, the presence of these types of TP53 mutations in sporadic BLBCs might be a hallmark of BRCAness and a potential biomarker for sensitivity to PARP inhibition. Also, our data suggest that a small subset of genomic regions may be used to identify BRCA1-like BLBCs. BLBCs share molecular features that were previously found to be specific for BRCA1-mutated breast tumors. These features might be useful for the identification of tumors with increased sensitivity to (high-dose or dose-dense) alkylating agents and PARP inhibitors.</p

Cross-species comparison of aCGH data from mouse and human BRCA1- and BRCA2-mutated breast cancers

Background: Genomic gains and losses are a result of genomic instability in many types of cancers. BRCA1- and BRCA2-mutated breast cancers are associated with increased amounts of chromosomal aberrations, presumably due their functions in genome repair. Some of these genomic aberrations may harbor genes whose absence or overexpression may give rise to cellular growth advantage. So far, it has not been easy to identify the driver genes underlying gains and losses. A powerful approach to identify these driver genes could be a cross-species comparison of array comparative genomic hybridization (aCGH) data from cognate mouse and human tumors. Orthologous regions of mouse and human tumors that are commonly gained or lost might represent essential genomic regions selected for gain or loss during tumor development. Methods: To identify genomic regions that are associated with BRCA1- and BRCA2-mutated breast cancers we compared aCGH data from 130 mouse Brca1?/?;p53?/?, Brca2?/?;p53?/? and p53?/? mammary tumor groups with 103 human BRCA1-mutated, BRCA2-mutated and non-hereditary breast cancers. Results: Our genome-wide cross-species analysis yielded a complete collection of loci and genes that are commonly gained or lost in mouse and human breast cancer. Principal common CNAs were the well known MYCassociated gain and RB1/INTS6-associated loss that occurred in all mouse and human tumor groups, and the AURKA-associated gain occurred in BRCA2-related tumors from both species. However, there were also important differences between tumor profiles of both species, such as the prominent gain on chromosome 10 in mouse Brca2?/?;p53?/? tumors and the PIK3CA associated 3q gain in human BRCA1-mutated tumors, which occurred in tumors from one species but not in tumors from the other species. This disparity in recurrent aberrations in mouse and human tumors might be due to differences in tumor cell type or genomic organization between both species. Conclusions: The selection of the oncogenome during mouse and human breast tumor development is markedly different, apart from the MYC gain and RB1-associated loss. These differences should be kept in mind when using mouse models for preclinical studies.MediamaticsElectrical Engineering, Mathematics and Computer Scienc

Mouse models of neurodegenerative disease: preclinical imaging and neurovascular component.

Neurodegenerative diseases represent great challenges for basic science and clinical medicine because of their prevalence, pathologies, lack of mechanism-based treatments, and impacts on individuals. Translational research might contribute to the study of neurodegenerative diseases. The mouse has become a key model for studying disease mechanisms that might recapitulate in part some aspects of the corresponding human diseases. Neurode- generative disorders are very complicated and multifacto- rial. This has to be taken in account when testing drugs. Most of the drugs screening in mice are very di cult to be interpretated and often useless. Mouse models could be condiderated a ‘pathway models’, rather than as models for the whole complicated construct that makes a human disease. Non-invasive in vivo imaging in mice has gained increasing interest in preclinical research in the last years thanks to the availability of high-resolution single-photon emission computed tomography (SPECT), positron emission tomography (PET), high eld Magnetic resonance, Optical Imaging scanners and of highly speci c contrast agents. Behavioral test are useful tool to characterize di erent ani- mal models of neurodegenerative pathology. Furthermore, many authors have observed vascular pathological features associated to the di erent neurodegenerative disorders. Aim of this review is to focus on the di erent existing animal models of neurodegenerative disorders, describe behavioral tests and preclinical imaging techniques used for diagnose and describe the vascular pathological features associated to these diseases

Factors associated with absenteeism-illness in rural workers in a timber company Factores asociados al absentismo-enfermedad de los trabajadores rurales de una empresa forestal Fatores associados ao absenteísmo-doença dos trabalhadores rurais de uma empresa florestal

The monitoring of absenteeism-illness has revealed its high prevalence, and a strong relationship with work. This study aimed to analyze the factors associated with absenteeism-illness among the rural workers in a timber company in Minas Gerais, Brazil. It is an analytical cross-sectional study, carried out among 883 workers. The medical certificates issued in the company over one year were surveyed. For the analysis, use was made of descriptive statistics and bi- and multivariable analyses. The strength of association was measured by the odds ratio (OR) with help from logistic regression (p<0.05). A prevalence of 54% of medical certificates was found in the population. Bivariate analysis revealed an association between job (forestry assistant (OR=13.1), carpenter (OR=15) and chainsaw operator (OR=39.6)), length of service in the company, departments and length of schooling with absenteeism-illness. In the multi-variate analysis, the association between length of schooling and being a carpenter disappeared, while the other associations remained. It is concluded that there is important evidence about the occupational and demographic factors and absenteeism-illness among forestry workers.<br>El acompañamiento del absentismo-enfermedad ha revelado altas prevalencias y fuerte relación con el trabajo. Se objetivó analizar los factores asociados al absentismo-enfermedad de los trabajadores rurales de una empresa forestal en Minas Gerais- Brasil. Se trata de un estudio transversal, analítico, realizado con 883 trabajadores. Fueron levantados los testificados médicos durante un año. Se utilizó para análisis estadístico descriptivo, análisis bi y multivariadas. La fuerza de asociación fue medida por el odds ratio (OR) con auxilio de la regresión logística (p<0,05). Fueron encontradas prevalencia del 54,0% de testificados en la población. El análisis bivariada reveló asociación entre la función (ayudante forestal (OR=13,1), ebanista (OR=15) y operador de motosierra (OR=39,6)), tiempo de trabajo, sectores y escolaridad con el absentismo-enfermedad. En la multivariada hubo desaparición de la asociación con el ebanista y con la escolaridad, siendo mantenidas las demás. Se concluye que hay evidencias importantes sobre la relación entre factores ocupacionales y demográficos y el absentismo-enfermedad de los trabajadores forestales.<br>O acompanhamento do absenteísmo-doença tem revelado altas prevalências e forte relação com o trabalho. Objetivou-se analisar os fatores associados ao absenteísmo-doença dos trabalhadores rurais de uma empresa florestal em Minas Gerais, Brasil. Trata-se de estudo transversal, analítico, realizado com 883 trabalhadores. Foram levantados os atestados médicos desses trabalhadores, durante um ano. Utilizaram-se, para análise estatística descritiva, análises bi e multivariadas. A força de associação foi medida pelo odds ratio (OR) com auxílio da regressão logística (p<0,05). Foi encontrada prevalência de 54,0% de atestados na população. A análise bivariada revelou associação entre a função (ajudante florestal (OR=13,1), marceneiro (OR=15) e operador de motosserra (OR=39,6)), tempo de trabalho, setores e escolaridade com o absenteísmo-doença. Na análise multivariada houve desaparecimento da associação com o marceneiro e com a escolaridade, sendo mantidas as demais. Conclui-se que há evidências importantes sobre a relação entre fatores ocupacionais e demográficos e o absenteísmo-doença dos trabalhadores florestais