Erythroid cells generated in the absence of specific β1-integrin heterodimers accumulate reactive oxygen species at homeostasis and are unable to mount effective antioxidant defenses

We have previously reported that β1^Δ/Δ mice have a markedly impaired response to hemolytic stress, but the mechanisms of this were unclear. In the present study we explored in detail quantitative, phenotypic and functional aspects of erythropoiesis at homeostasis in a large number of animals for each of 3 murine models with specific β1 heterodimer integrin deficiencies. We found that, at homeostasis, β1-deficient mice have a modest uncompensated anemia with ineffective erythropoiesis and decreased red blood cell survival. Mice lacking only α4 integrins (α4β1/α4β7) do not share this phenotype. There is an increased tendency for reactive oxygen species accumulation in β1^Δ/Δ erythroid cells with decreased anti-oxidant defenses at homeostasis which are exaggerated after stress. Furthermore, expansion of erythroid cells in spleen post-stress is dependent on α5β1, likely through mechanisms activating focal adhesion kinase complexes that are distinct from α4β1-mediated responses. In vivo inhibition of focal adhesion kinase activation partially recapitulates the β1^Δ/Δ stress response. Mice lacking all α4 and β1 integrins (double knockouts) had, at homeostasis, the most severe phenotype with selective impairment of erythroid responses. The fact that integrins participate in mitigating stress in erythroid cells through redox activation of distinct signaling pathways by specific integrin heterodimers is a link that has not been appreciated until now.     

Genetics of carney triad: recurrent losses at chromosome 1 but lack of germline mutations in genes associated with paragangliomas and gastrointestinal stromal tumors

CONTEXT: Carney triad (CT) describes the association of paragangliomas (PGLs) with gastrointestinal stromal tumors (GISTs) and pulmonary chondromas. Inactivating mutations of the mitochondrial complex II succinate dehydrogenase (SDH) enzyme subunits SDHB, SDHC, and SDHD are found in PGLs, gain-of-function mutations of c-kit (KIT), and platelet-derived growth factor receptor A (PDGFRA) in GISTs. OBJECTIVE: Our objective was to investigate the possibility that patients with CT and/or their tumors may harbor mutations of the SDHB, SDHC, SDHD, KIT, and PDGFRA genes and identify any other genetic alterations in CT tumors. DESIGN: Three males and 34 females with CT were studied retrospectively. We sequenced the stated genes and performed comparative genomic hybridization on a total of 41 tumors. RESULTS: No patient had coding sequence mutations of the investigated genes. Comparative genomic hybridization revealed a number of DNA copy number changes: losses dominated among benign lesions, there were an equal number of gains and losses in malignant lesions, and the average number of alterations in malignant tumors was higher compared with benign lesions. The most frequent and greatest contiguous change was 1q12-q21 deletion, a region that harbors the SDHC gene. Another frequent change was loss of 1p. Allelic losses of 1p and 1q were confirmed by fluorescent in situ hybridization and loss-of-heterozygosity studies. CONCLUSIONS: We conclude that CT is not due to SDH-inactivating or KIT- and PDGFRA-activating mutations. GISTs and PGLs in CT are associated with chromosome 1 and other changes that appear to participate in tumor progression and point to their common genetic cause.     

Juvenile mental health histories of adults with anxiety disorders

OBJECTIVE: Information about the psychiatric histories of adults with anxiety disorders was examined to further inform nosology and etiological/ preventive efforts. METHOD: The authors used data from a prospective longitudinal study of a representative birth cohort (N=1,037) from ages 11 to 32 years, making psychiatric diagnoses according to DSM criteria. For adults with anxiety disorders at 32 years, follow-back analyses ascertained first diagnosis of anxiety and other juvenile disorders. RESULTS: Of adults with each type of anxiety disorder, approximately half had been diagnosed with a psychiatric disorder (one-third with an anxiety disorder) by age 15. The juvenile histories of psychiatric problems for adults with different types of anxiety disorders were largely nonspecific, partially reflecting comorbidity at 32 years. Histories of anxiety and depression were most common. There was also specificity. For example, adults with panic disorder did not have histories of juvenile disorders, whereas those with other anxiety disorders did. Adults with posttraumatic stress disorder had histories of conduct disorder, whereas those with other anxiety disorders did not. Adults with specific phobia had histories of juvenile phobias but not other anxiety disorders. CONCLUSIONS: Strong comorbidity between different anxiety disorders and lack of specificity in developmental histories of adults with anxiety disorders supports a hierarchical approach to classification, with a broad class of anxiety disorders having individual disorders within it. The early first diagnosis of psychiatric difficulties in individuals with anxiety disorders suggests the need to target research examining the etiology of anxiety disorders and prevention early in life.     

Body composition in paraplegic men.

To investigate alterations in the body composition of paraplegic men, 31 complete paraplegic men thoracic (T)4-T 12 neurological level of injury, 16 with paraplegia above (high), and 15 below (low) thoracic 7, were compared with 33 able-bodied men. Whole body dual X-ray absorptiometry was used to estimate regional (arms, legs) and total body bone mineral density (g/cm(2)), lean, and fat mass (g).The influence of the neurological level of injury and the duration of paralysis in relation with the above parameters were also investigated. Body mass index, bone mineral density, and lean mass were significantly decreased (p < 0.0005) and fat mass was increased (p < 0.05) in the legs and total body composition in paraplegics. Bone mineral density was significantly lower in high paraplegics' arms compared with low paraplegics (p = 0.028). The correlation of body mass index with fat mass was statistically significant in all paraplegics and controls (r = 0.57, p = 0.001 and r = 0.73, p = 0.0001, respectively) and in low paraplegics (r = 0.72, p = 0.004). Legs' bone mineral density and arms' fat mass were correlated with the duration of paralysis in all paraplegics (r = -0.46, p = 0.009 and r = 0.43, p = 0.020, respectively) and in high paraplegics (r = 0.73, p = 0.001 and r = 0.55, p = 0.042, respectively). Total fat mass was correlated with the duration of paralysis in high paraplegics (r = 0.5, p = 0.05). These results suggest body composition changes in paraplegics.     

Oxidative damage to plasma proteins in patients with chronic alcohol dependence: the effect of smoking

BACKGROUND: Accumulating evidence implicates oxidative stress in ethanol-induced toxicity. Ethanol has been reported to be involved in oxidative damage, mostly in vitro, or in post mortem tissues, while biochemical abnormalities in the blood or serum are scanty or lacking. The aim of the present study was to examine the oxidative status of plasma proteins as markers of oxidative stress in subjects with chronic alcohol dependence (CAD). Since smoking has also been associated with oxidative stress this factor was also considered. PATIENTS AND METHODS: A total of 71 patients with CAD and 61 healthy volunteers of comparable age were included in the study. The protein carbonyl assay was carried out in plasma, as a reliable measure of general oxidative protein damage, in these two groups. RESULTS: Increased plasma protein carbonyls (PCs) were found in patients with CAD as compared with the control group [mean values (nmollmg protein): 4.73+/-1.46 and 3.62+/-0.91 respectively, p<0.000001]. Within the control group, smokers had higher PCs than the non-smokers, however this difference was of marginal significance [mean values (nmol/mg protein): 3.93+/-1.32 and 3.47+/-0.63, respectively]. The CAD group had significantly increased PCs compared with both the smoker and the non-smoker subgroups of the controls (p<0.001 and p<0.0001, respectively). Duration of alcohol consumption, daily alcohol intake, smoke load, folic acid and vitamin B12 levels did not correlate significantly with PC levels. CONCLUSION: The above results support the evidence for systemic oxidative stress in CAD, which must be attributed mainly to alcohol consumption, while smoking may act synergistically.     

Very late antigen-4 function of myeloblasts correlates with improved overall survival for patients with acute myeloid leukemia

Adhesion of acute myeloid leukemia (AML) blasts in the bone marrow microenvironment confers protection from chemotherapy-induced apoptosis. One mechanism for retention of blasts within the bone marrow is adhesion via very late antigen-4 (VLA-4), the alpha(4)beta(1) integrin heterodimer that binds to its main ligands, fibronectin, and vascular cell adhesion molecule-1 (VCAM-1). To examine the relationship of functional expression of VLA-4 to prognosis in AML, we studied marrow samples from 175 adult AML patients who underwent induction chemotherapy with anthracycline and cytarabine on Southwest Oncology Group trials. The studies included flow cytometry and functional in vitro assays for ligand binding and maximal beta(1) activation. VLA-4 expression varied widely, with mean expression 60.6% for alpha(4), and was not significantly associated with response to chemotherapy, relapse-free, or overall survival (OS). However, increased binding of soluble VCAM-1 via VLA-4 was significantly associated with longer OS, corrected for age (P = .033). Estimated 5-year OS was 31% (95% confidence interval, 14%-48%) in 30 patients with soluble VCAM-1 binding greater than or equal to 40%, compared with 10% (confidence interval, 3%-17%) in 72 patients with lower binding. Adhesion and migratory properties of AML blasts thus appear to influence chemosensitivity and therefore may be therapeutic targets.     

Links between parenting and extra-familial relationships: Nature or nurture?

The current paper examined associations between parenting and both peer group characteristics and friendship quality within a genetically sensitive design. Participants were aged 12-19 years (approximately equal numbers of males and females), including 424 sibling pairs and 1185 twin pairs, of whom 328 were MZ, 311 were DZ same-sex, 463 were DZ opposite-sex and 83 were of unknown zygosity. The adolescents provided self-report questionnaire measures of parental discipline, friendship quality, and peer group characteristics. All three relationship measures were moderately to substantially heritable. The novel and provocative finding, that adolescents' genetic propensities are largely responsible for the overlap seen between parental discipline strategies and friendship quality, is discussed in terms of its implications for socialization theory and understanding of adolescent relationships.