Single-Molecule Insight Into Target Recognition by CRISPR-Cas Complexes.

Ribonucleoprotein (RNP) complexes from CRISPR-Cas systems have attracted enormous interest since they can be easily and flexibly reprogrammed to target any desired locus for genome engineering and gene regulation applications. Basis for the programmability is a short RNA (crRNA) inside these complexes that recognizes the target nucleic acid by base pairing. For CRISPR-Cas systems that target double-stranded DNA this results in local DNA unwinding and formation of a so-called R-loop structure. Here we provide an overview how this target recognition mechanism can be dissected in great detail at the level of a single molecule. Specifically, we demonstrate how magnetic tweezers are applied to measure the local DNA unwinding at the target in real time. To this end we introduce the technique and the measurement principle. By studying modifications of the consensus target sequence, we show how different sequence elements contribute to the target recognition mechanism. From these data, a unified target recognition mechanism can be concluded for the RNPs Cascade and Cas9 from types I and II CRISPR-Cas systems. R-loop formation is hereby initiated on the target at an upstream element, called protospacer adjacent motif (PAM), from which the R-loop structure zips directionally toward the PAM-distal end of the target. At mismatch positions, the R-loop propagation stalls and further propagation competes with collapse of the structure. Upon full R-loop zipping conformational changes within the RNPs trigger degradation of the DNA target. This represents a shared labor mechanism in which zipping between nucleic acid strands is the actual target recognition mechanism while sensing of the R-loop arrival at the PAM-distal end just verifies the success of the full zipping.

Elevated C-reactive protein levels in schizophrenia inpatients is associated with aggressive behavior.

BACKGROUND: An association between inflammation and behavioral domains of mental disorders is of growing interest. Recent studies reported an association between aggression and inflammation. In this study, we investigated the association between aggressive behavior and inflammatory markers in schizophrenia inpatients. METHODS: Adult schizophrenia inpatients without affective symptoms (n=213) were retrospectively identified and categorized according to their C-reactive protein measurement at admission as either elevated (CRP>1 mg/dL; n=57) or normal (CRP<1 mg/dL; n=156). The following indicators of aggression were compared: PANSS excitement component (PANSS-EC), restraints and suicidal behavior during hospitalization. Univariate comparisons between elevated and normal CRP levels were performed and multivariate analysis was conducted to control for relevant covariates. RESULTS: CRP levels significantly correlated with other laboratory markers indicating increased inflammation including leukocyte count and neutrophil to lymphocyte ratio (r=0.387, P<0.0001 and r=0.356, P<0.0001) respectively. Inpatients with elevated C-reactive protein displayed increased aggressive behavior compared to patients with normal CRP levels (<1 mg/dL). This was manifested by higher rates of restraint during hospitalization (χ(2)=5.22, P=0.031) and increased PANSS-EC score (U=5410.5, P=0.012). Elevated CRP levels were not associated with suicidal behavior. Multivariate analysis revealed that higher PANSS-EC score was associated with elevated CRP after controlling for the covariates age, sex, BMI and smoking. CONCLUSION: This study identified a potential biological correlate (inflammation) of a specific behavioral endophenotype (aggression) in schizophrenia inpatients.

Age of onset group characteristics in forensic patients with schizophrenia.

This study aims to empirically identify age of onset groups and their clinical and background characteristics in forensic patients with schizophrenia. Hospital charts were reviewed of all 138 forensic patients with schizophrenia admitted to Geha Psychiatric Hospital that serves a catchment area of approximately 500,000 people, from 2000 to 2009 inclusive. Admixture analysis empirically identified early- (M=19.99, SD=3.31) and late-onset groups (M=36.13, SD=9.25). Early-onset was associated with more suicide attempts, violence before the age of 15, and early conduct problems, whereas late-onset was associated with a greater likelihood of violence after the age of 18 and marriage (P<0.01). The current findings provide clinicians with a unique direction for risk assessment and indicate differences in violence between early- and late-onset schizophrenia, particularly co-occurrence of harmful behavioral phenotypes.

Religiosity is a protective factor against self-injurious thoughts and behaviors in Jewish adolescents: findings from a nationally representative survey.

PURPOSE: Few studies have investigated the association between religiosity and self-injurious thoughts and behaviors specifically in adolescents, yielding inconsistent results. To date, no study has examined this relationship in a Jewish adolescent cohort. METHODS: Self-injurious thoughts and behaviors, as well as depression, were assessed in a nationally representative sample of Jewish adolescents (n=620) and their mothers, using the Development and Well-Being Assessment Inventory (DAWBA) structured interview. Degree of religiosity was obtained by a self-report measure. RESULTS: Using multivariate analysis, level of religiosity was inversely associated with self-injurious thoughts and behaviors (Wald χ(2)=3.95, P=0.047), decreasing the likelihood of occurrence by 55% (OR=0.45, 95% CI 0.2-0.99), after adjusting for depression and socio-demographic factors. This model (adjusted R(2)=0.164; likelihood ratio χ(2)=7.59; df=1; P<0.047) was able to correctly classify 95.6% of the patients as belonging either to the high or low risk groups. CONCLUSION: This is the first study demonstrating religiosity to have a direct independent protective effect against self-injurious thoughts and behaviors in Jewish adolescents. This finding has clinical implications regarding risk assessment and suicide prevention. Further research can potentially elucidate the complex relationship between religiosity, self-injury and suicide in this population.

The interaction of subjective experience and attitudes towards specific antipsychotic-related adverse effects in schizophrenia patients.

BACKGROUND: Discontinuation of antipsychotic drugs in schizophrenia patients is a major concern, since it results in relapse and re-hospitalizations. Non-adherence is strongly associated with negative-subjective response to antipsychotics, which is composed of the subjective experience of negative drug effects and attitude towards the treatment. OBJECTIVE: To investigate the elements of subjective experience and subjective attitude towards specific drug-related adverse effects, leading to a generally negative-subjective attitude towards antipsychotics. METHODS: Schizophrenia inpatients (n=84) were administered a questionnaire measuring attitude and experience on eight subscales: weight gain, sedation, sexual anhedonia, extra-pyramidal syndrome, affective flattening, excessive sleep, diminished sociability and metabolic syndrome. DAI-30 was used to measure attitude towards drugs, and PANSS to assess psychopathology. RESULTS: Weak correlation was found between subjective experience and attitude on most of the subscales. The only strong, albeit inverse, correlation between experience and attitude that was found was with regard to affective flattening, experienced by 37% of the sample, and it also predicted negative drug attitude as measured by the DAI-30, RR: 1.87 (95% CI: 1.06-3.3, df=1, χ(2)=4.525, P<0.05). CONCLUSION: Negative attitude towards most adverse drug effects did not correlate with personal experience. Drug-related affective flattening should be evaluated routinely, since experiencing it may predict negative attitude towards drugs, potentially leading to poor compliance and relapse.

The use of mental health services by adolescent smokers: a nationwide Israeli study.

In this study, we aimed to evaluate the utilization of mental health services by adolescent smokers, the presence of untreated mental disorders in this young population and the associated emotional and behavioral difficulties. We performed a nationwide survey study of an Israeli representative sample of 906 adolescents and their mothers. Mental disorders were assessed using the Development and Well-Being Assessment (DAWBA) Inventory. Emotional and behavioral difficulties were evaluated using the Strengths and Difficulties Questionnaire (SDQ). Mental health services use and smoking habits were evaluated by relevant questionnaires. Adolescent smokers were using significantly more mental health services than non-smokers (79% vs. 63%, respectively, P<0.001), independently of their mental health status or ethnic group. Adolescent smokers also reported more emotional and behavioral difficulties in most areas (P<0.001), which are consistent with their mothers' reports, except in the area of peer relationships. The treatment gap for the smoking adolescents was 53% compared to 69% in the non-smokers (P<0.001). This is the first study characterizing the use of mental health services and the related emotional and behavioral difficulties in a nationally-representative sample of adolescents. The findings of a wide treatment gap and the rates of the associated emotional and behavioral difficulties are highly relevant to the psychiatric assessment and national treatment plans of adolescent smokers.

Anatomía dinámica del atlas / Dynamic anatomy atlas

El abordaje multidisciplinario de la región cérvicooccipital por neurocirujanos, ortopedistas y quienes se ocupan de los abordajes posteriores de la base del cráneo han puesto en el tapete la revisión de los conceptos clásicos y agregarles las nuevas adquisiciones que la anatomía enfocada desde las necesidades clínicas producen. Se revisa la anatomía funcional, conceptos biomecánicos y enfoque de la cirugía de base

Craneofaringioma en el Hospital de Niños "J.M. de Los Ríos": IV reporte (1985-1995) / Craneopharygiomas in the Hospital de Niños J.M. de Los Ríos: IV report (1985-1995)

Doscientos cincuenta y un casos de tumores cerebrales verificados anatomopatológicamente, durante los años 1985-1995, mostraron la presencia de 15 craneofaringiomas, cuyo estudio integral, clínico, imagenológico, endocrinológico, terapéuticos quirúrgicos y tratamientos radiantes se revisan

Revascularización cerebral mediante encéfalo arterio sinangiosis en el tratamiento de accidentes cerebrovasculares isquémicos: experiencia del Hospital de Niños J. M de Los Ríos: reporte de cuatro casos / Sinangiosis artherio brain in the treatment of ischemic cerebrovascular accidents: experience of the J. M de Los Ríos Hospital: report of 4 cases

Se reportaron los resultados de la encéfalo-arterio-sinangiosis en el tratamiento quirúrgico de la isquemia cerebral en el Hospital de Niños "J.M de Los Ríos". Caracas. Es liberada una arteria del cuero cabelludo (arteria temporal superficial) y puesta en contacto con la corteza cerebral, después de una craneotomía y apertura de la duramadre. Cuatro cirugías fueron realizadas en un período de dos años. Se analizaron los resultados, ventajas e indicaciones de este tipo de cirugía

Tumores supratentoriales infantiles / Tumors supratentorials in children

Se revisan los tumores del sistema nervioso central (S.N.C) en el lapso comprendido entre 19644-1992 del Hospital de niños de Caracas. La estadística demuestra que en 17 años (1964-80), época pre-tomográfica se trataron quirúrgicaamente 159 casos (9,35 casos anuales). En 12 años (1981-92) se atendieron 341 casos el doble en menos tiempo (28,40 casos por año) gracias a la tomografía. El total de 29 años fue de 510 casos o sea 17,8 casos por año, cifra inferior a la demanda. Supratentorial: 194 casos (38,09 por ciento) e infratentoriales 283 (55,6 por ciento); espinales: 33 (6,47 por ciento). El aspecto tentorial supratentorial fue lo siguiente: Astrocitomas: 52 casos (10 por ciento), craniofaringioma 22 (4,10 por ciento), Ependinomas: 16 (3,13 por ciento), Pinealomas: 12 (2,34 por ciento), Nervio y Quiasma óptico: 12 (2,34 por ciento), Neuroectodérmico primitivo: 10 (1,96 por ciento), Plexo Coroide: 9 (1,76 por ciento), Teratoma: 6 (1,17 por ciento), Glioblastoma multiforme: 4 (0,78 por ciento), Meningioma: 4 (0,78 por ciento), Oligodendroglioma: 3 (0,58 por ciento), Hemangioma: 3 (0,58 por ciento), Sarcoma: 3 (0,58 por ciento), Esponglioblastoma: 1 (0,19 por ciento). Localización: Hemisféricos: 82 (16,04 por ciento), Ventriculares 14 2,74 por ciento. Los postulados oncológicos rigen la conducta quirúrgica de estas lesiones: a) Eliminación de los síntomas, b) Preservación anatómica, c)Reducción al máximo o eliminación de población tumoral, d) Eliminación de tejidos necroticos con células. Toda lesión, no importa su ubicación, debe tener biopsia donde la estereotaxia encuentra su aplicación en lesiones profundas y de tallo cerebral