Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors

Chronic myeloid leukemia in chronic phase (CML-CP) is induced by BCR-ABL1 oncogenic tyrosine kinase. Tyrosine kinase inhibitors eliminate the bulk of CML-CP cells, but fail to eradicate leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) displaying innate and acquired resistance, respectively. These cells may accumulate genomic instability, leading to disease relapse and/or malignant progression to a fatal blast phase. In the present study, we show that Rac2 GTPase alters mitochondrial membrane potential and electron flow through the mitochondrial respiratory chain complex III (MRC-cIII), thereby generating high levels of reactive oxygen species (ROS) in CML-CP LSCs and primitive LPCs. MRC-cIII-generated ROS promote oxidative DNA damage to trigger genomic instability, resulting in an accumulation of chromosomal aberrations and tyrosine kinase inhibitor-resistant BCR-ABL1 mutants. JAK2(V617F) and FLT3(ITD)-positive polycythemia vera cells and acute myeloid leukemia cells also produce ROS via MRC-cIII. In the present study, inhibition of Rac2 by genetic deletion or a small-molecule inhibitor and down-regulation of mitochondrial ROS by disruption of MRC-cIII, expression of mitochondria-targeted catalase, or addition of ROS-scavenging mitochondria-targeted peptide aptamer reduced genomic instability. We postulate that the Rac2-MRC-cIII pathway triggers ROS-mediated genomic instability in LSCs and primitive LPCs, which could be targeted to prevent the relapse and malignant progression of CML.     

Smoking in non-student Mexican adolescents with asthma: relation with family structure, educational level, parental approval of smoking, parents who smoke, and smoking friends

Introduction

The association between some factors of the familial and social environment with smoking in non-student adolescents with asthma has not been explored. The aim of the study was to determine the association between family structure, educational level, parental approval of smoking, parents who smoke, and smoking friends with smoking in non-student adolescents with asthma.

Subjects and methods

In a cross-sectional study, data were obtained by means of a structured questionnaire applied to 4,778 non-student adolescents aged 13–18 years. Diagnosis of asthma was performed using a questionnaire based on the International Study of Asthma and Allergy in Childhood questionnaire. The smoking habit was determined by application of a self-administered questionnaire. Odds ratios (OR) were determined for smoking using logistic regression.

Results

From the total sample, asthma prevalence was 6.6% and of active smoking, 34.2%. Age at initiation of asthma symptoms was 5.15 ± 3.52 years, and that of active smoking was 13.65 ± 2.07 years. Percentage of non-intact family (40.1 vs. 32.7%) was greater in the group of adolescents with asthma. Logistic regression models show that parental approval of smoking (adjusted OR = 5.57; 95% confidence interval = 2.48–12.51) and smoking friends (adjusted OR = 2.92; 95% confidence interval = 1.04–8.19) are associated with smoking in non-student adolescents with asthma.

Conclusion

In this study, parental approval of smoking and having friends who smoke appear to be associated with smoking among non-student adolescents with asthma.     

A Randomized Trial Investigating the Influence of Strength Training on Quality of Life in Ischemic Stroke

Background: Strength training post stroke is widely acknowledged as an important part of a rehabilitation program. Muscle strength has been shown to be a significant contributor to physical disability after stroke, which in turn has an immense impact on the reintegration of patients into society, affecting their quality of life.

Objective: This was a randomized intervention trial to determine the effect of a resistance training program on the quality of life in patients with stroke.

Methods: An experimental group (EG), consisting of 11 subjects aged 51.7 ± 8.0 years, and a control group (CG), consisting of 13 subjects aged 52.5 ± 7.7 years, were studied before and after 12 weeks. EG underwent 12 weeks of strength training three times a week. The CG did not undergo strength training during the 12-week study period.

Results: There was a significant increase in quality of life from pre-test to post-test (Δ% = 21.47%; p = 0.021) in EG. There were significant differences in all indicators of quality of life between groups at 12 weeks. There were greater gains in strength in EG than in CG (p ≤ 0.05). There was a negative correlation between the strength gains as determined with the 1RM test and the quality of life, especially in lower limb exercises.

Conclusion: The results of this study indicate that there was an improvement in the measures of strength in EG, and that there was a correlation between improvements in strength and quality of life in these patients who had previously suffered a stroke at least one year prior to study.     

Maturational changes in connexin 43 expression in the seminiferous tubules may depend on thyroid hormone action

Introduction

Connexin 43 (Cx43) mediates the effect of thyroid hormone on Sertoli cell maturation in vitro. We investigated the influence of triiodothyronine (T3) administration on Cx43 expression in relation to the progress in seminiferous tubule maturation.

Material and methods

Male rats were daily injected with 100 µg T3/kg body weight from birth until postnatal day (pnd) 5 (transient treatment – tT3) or until pnd 15 (continuous treatment – cT3) or solvent – control (C). On pnd 16 serum hormone levels, body and testes weight, seminiferous tubule morphometry, Cx43 immunostaining and germ cell degeneration were investigated. Cx43 expression was also assessed in six 50-day-old adult untreated rats.

Result

tT3 increased 2.6-fold serum level of T3, testes weight, and seminiferous tubule diameter, and induced maturation-like dislocation of Cx43 expression from the apical to the peripheral region of Sertoli cell cytoplasm. In addition, incidence of Cx43-positive tubules declined from 86% in C to 46% after tT3, being similar to the adult value (30% of tubules Cx43-positive). In turn, cT3 increased serum T3 level 12-fold, and decreased body weight. Seminiferous tubules became shortened and distended, Sertoli cell cytoplasm vacuolated, Cx43 expression had minimal intensity and germ cell degeneration increased.

Conclusions

Cx43 might intermediate a short and transient stimulatory effect of T3 on seminiferous tubule maturation that disappeared together with exposure to the toxic effect of a continuously high level of the hormone.     

Neuroanatomical consequences of very preterm birth in middle childhood

Individuals born preterm can demonstrate reductions in brain volume, cortical surface area and thickness. However, the extent of these neuroanatomical deficits and the relation among these measures in middle childhood, a critical developmental period, have not been determined. We assessed differences in brain structure by acquiring high-resolution T₁-weighted scans in 25 children born very preterm (<32 weeks gestational age) without significant post-natal neurological sequelae and 32 age-matched term-born children (7–10 years). Children born very preterm had decreased brain volume, surface area and cortical thickness compared to term-born children. Furthermore, children born preterm did not display the robust relation between total brain volume and basal ganglia and thalamic volume apparent in the term-born children. Cortical thickness analyses revealed that the cortex was thinner for children born preterm than term-born children in the anterior cingulate cortex/supplementary motor area, isthmus of the cingulate gyrus, right superior temporal sulcus, right anterior insula, postcentral gyrus and precuneus. Follow-up analyses revealed that right precuneus thickness was correlated with gestational age. Thus, even without significant postnatal medical sequelae, very preterm-born children showed atypical brain structure and developmental patterns in areas related to higher cognitive function. Disruptions of the typical neurodevelopmental trajectory in the third trimester of pregnancy likely underlie these differences persisting into middle childhood.     

Frontotemporoparietal asymmetry and lack of illness awareness in schizophrenia

Introduction: Lack of illness awareness or anosognosia occurs in both schizophrenia and right hemisphere lesions due to stroke, dementia, and traumatic brain injury. In the latter conditions, anosognosia is thought to arise from unilateral hemispheric dysfunction or interhemispheric disequilibrium, which provides an anatomical model for exploring illness unawareness in other neuropsychiatric disorders, such as schizophrenia. Methods: Both voxel‐based morphometry using Diffeomorphic Anatomical Registration through Exponentiated Lie Algebra (DARTEL) and a deformation‐based morphology analysis of hemispheric asymmetry were performed on 52 treated schizophrenia subjects, exploring the relationship between illness awareness and gray matter volume. Analyses included age, gender, and total intracranial volume as covariates. Results: Hemispheric asymmetry analyses revealed illness unawareness was significantly associated with right < left hemisphere volumes in the anteroinferior temporal lobe (t = 4.83, P = 0.051) using DARTEL, and the dorsolateral prefrontal cortex (t = 5.80, P = 0.003) and parietal lobe (t = 4.3, P = 0.050) using the deformation‐based approach. Trend level associations were identified in the right medial prefrontal cortex (t = 4.49, P = 0.127) using DARTEL. Lack of illness awareness was also strongly associated with reduced total white matter volume (r = 0.401, P < 0.01) and illness severity (r = 0.559, P < 0.01). Conclusion: These results suggest a relationship between anosognosia and hemispheric asymmetry in schizophrenia, supporting previous volume‐based MRI studies in schizophrenia that found a relationship between illness unawareness and reduced right hemisphere gray matter volume. Functional imaging studies are required to examine the neural mechanisms contributing to these structural observations. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

Disruptions in white matter microstructure associated with impaired visual associative memory in schizophrenia-spectrum illness

European Archives of Psychiatry and Clinical Neuroscience - Episodic memory ability relies on hippocampal-prefrontal connectivity. However, few studies have examined relationships between memory...