CD8+ T cells contribute to macrophage accumulation and airspace enlargement following repeated irritant exposure

BACKGROUND: Persistent macrophage accumulation and alveolar enlargement are hallmark features of chronic obstructive pulmonary disease (COPD). A role for CD8(+) lymphocytes in the development of COPD is suggested based on observations that this T cell subset is increased in the airways and parenchyma of smokers that develop COPD with airflow limitation. In this study, we utilize a mouse model of COPD to examine the contributions of CD8(+) T cells in the persistent macrophage accumulation and airspace enlargement resulting from chronic irritant exposure. METHODS: We analyzed pulmonary inflammation and alveolar destruction in wild-type and Cd8-deficient mice chronically exposed to acrolein, a potent respiratory tract irritant. We further examined cytokine mRNA expression levels by RNase protection assay, matrix metalloproteinase (MMP) activity by gelatin zymography, and epithelial cell apoptosis by active caspase3 immunohistochemistry in wild-type and Cd8-deficient mice exposed chronically to acrolein. RESULTS: These studies demonstrate that CD8(+) T cells are important mediators of macrophage accumulation in the lung and the progressive airspace enlargement in response to chronic acrolein exposures. The expression of several inflammatory cytokines (IP-10, IFN-gamma, IL-12, RANTES, and MCP-1), MMP2 and MMP9 gelatinase activity, and caspase3 immunoreactivity in pulmonary epithelial cells were attenuated in the Cd8-deficient mice compared to wild-type. CONCLUSIONS: These results indicate that CD8(+) T cells actively contribute to macrophage accumulation and the development of irritant-induced airspace enlargement.     

A single amino acid in the second transmembrane domain of GABA rho receptors regulates channel conductance

GABAC receptors, expressed predominately in vertebrate retina, are thought to be formed mainly by GABA rho subunits, each of which exhibits distinct physiological and pharmacological properties. In this study, the receptors formed by perch GABA rho subunits were expressed in HEK cells, and their single channel conductances were determined using noise analysis techniques. The receptors formed by the perch rho1A subunit gate a channel with a conductance of 0.2 pS, whereas the receptors formed by GABA rho2 subunits exhibit much higher channel conductances, i.e., 3.2 and 3.5 pS for perch rho2A and rho2B receptors, respectively. A comparison of the amino acid sequences of the channel-forming TMII regions of the various subunits suggested that a single amino acid at position 2' was a potential site for the large differential in conductance. We found that switching the serine residue at that site in the GABA rho2 subunit to the proline residue present in the rho1 subunit reduced the channel conductance to a level similar to that of the wild type rho1 receptor. Conversely, mutating proline to serine in the amino acid sequence of the rho1 receptor significantly increased its unitary conductance. These results indicate that a single amino acid in the TMII region plays an important role in determining the single channel conductance of the GABAC receptors.     

Validity of retrospective measures of early maltreatment and depressive episodes using the Childhood Experience of Care and Abuse (CECA) instrument -- A life-course study of adult chronic depression - 2

BACKGROUND: A previous paper, using data collected retrospectively from sister pairs, reported substantial associations of adult depressive episodes lasting at least 12 months with childhood maltreatment [Brown, G.W., Craig, T.K.J., Harris, T.O. Handley, R.V. & Harvey, A.L. 2007a-this issue. Development of a retrospective interview measure of parental maltreatment using the Childhood Experience of Care & Abuse (CECA) instrument - a life-course study of adult chronic depression - 1. J. Affect. Disord. doi:10.1016/j.jad.2007.05.022]. Risk was far less when depressive episodes of any duration were considered. This paper considers how much scientific weight can be placed on these findings in the light of doubt often expressed about retrospective collection of childhood and adult data. METHODS: The retrospectively gathered material was obtained from adult sister pairs within 5 years of age, comprising a high-risk series (n = 118) where the first sister was selected as likely to have experienced childhood abuse or neglect, and a comparison series (n = 80) where she was selected at random. Current age ranged between early 20s and 50s. Data was collected by semi-structured interviews, using investigator-based ratings covering a wide range of parental behaviour and childhood behaviour. RESULTS: A series of analyses failed to reveal evidence of significant bias in the collection of material about adult depression or parental maltreatment. There was, however, some evidence of under reporting. LIMITATIONS: Conclusions from such analyses can only be judged in terms of degree of plausibility. CONCLUSIONS: Nothing emerged to suggest the presence of significant bias in the aetiological findings of our earlier paper. There is evidence of some underreporting of both early adverse experience and adult depressive episodes, but this is unlikely to threaten the conclusions drawn about the link of parental maltreatment with adult chronic depressive episodes.     

p53 pathway gene single nucleotide polymorphisms and chronic lymphocytic leukemia

The p53 pathway plays a critical role in chronic lymphocytic leukemia (CLL). The association between the single-nucleotide polymorphism (SNPs) within the p53 gene (R72P) and its downstream target/regulators, BAX (G125A) and MDM2 (SNP309), and clinical parameters/prognostic markers was investigated in 83 CLL patients. Although the p53 R72P SNPs and MDM2 SNP309 did not associate with any of the parameters studied, the BAX G125A SNPs was associated with a more advanced Binet stage at diagnosis, supporting a potential role for this variant in CLL disease progression. In reporter assays, however, the BAX 5' untranslated region G125A SNPs surprisingly caused a 1.8-fold increase in basal promoter activity and did not alter the ability of p53 to trans-activate the promoter. Further studies are required to understand the role of SNPs in the p53 pathway in CLL.     

Loss of Bim results in abnormal accumulation of mature CD4-CD8-CD44-CD25- thymocytes

The process of thymopoiesis is tightly regulated by a series of selection events which ensure that only functional T-lymphocytes directed against foreign antigens are exported into the periphery. The adaptive immune response largely depends on the regulation of thymocyte development, and thymocytes which fail selection in the thymus are removed by apoptosis. However, the roles of specific apoptotic proteins in early T-lymphocyte development are poorly understood. Here, we report a novel function for Bim in thymocyte development. There is an accumulation of thymocytes in Bim(-/-) mice that lack expression of CD4, CD8, CD44, and CD25 but express CD3 and TCRbeta. Further, the CD4(-)CD8(-)CD25(-)CD44(-)CD3(+)TCRbeta(+) thymocytes are smaller and do not proliferate. These data suggest that these thymocytes are mature DN thymocytes that may have down-regulated the expression of CD4 and CD8. The DN thymocyte phenotype in Bim(-/-) mice is unaffected by the additional loss of Bak or Bax and is similar to the thymic phenotype in mice lacking both Bak and Bax. These data demonstrate that Bim functions to ensure the proper homeostasis of mature thymocytes during selection and thymic export.     

Comparison of nanoindentation measurements between osteogenesis imperfecta Type III and Type IV and between different anatomic locations (femur/tibia versus iliac crest)

Nanoindentation was used to compare the intrinsic mechanical properties of bone tissue (iliac crest biopsy) from children with type III and type IV osteogenesis imperfecta (OI). Young's modulus and hardness values were not significantly different between the two clinical severity groups on either cortical or trabecular measurement. In comparing the ratio of modulus over hardness (E/H) between OI type III and IV. The type III bone showed a marginally significant decrease for cortical bone and significant decrease for trabecular bone, which indicated that the OI type III bone was more brittle than OI type IV bone at the tissue level. In addition, nanoindentation measurements of the bone tissue harvested at femur/tibia from the same patients were compared with the results from the iliac crest biopsy. Young's modulus and hardness values were not significantly different between the two anatomic locations in either cortical or trabecular measurements. The ratio of E/H was not significantly different between the two groups. Results indicate that intrinsic modulus, hardness, and indentation deformation pattern (E/H) of OI bone tissues are not significantly different at long bone (midshaft of femur/tibia) and iliac crest. We observed that age (1.9 to 13.2 years) did not influence OI bone tissue intrinsic mechanical properties.     

ERN varies with degree of psychopathy in an emotion discrimination task

It is hypothesized that anterior cingulate cortex (ACC) function may be disrupted in psychopathy. Since ACC is considered the generator of the error-related negativity (ERN), we expected the ERN to be sensitive to the degree of psychopathy among violent offenders. EEG was collected while offenders and controls responded to a standard letter flanker task and to a face flanker task that required discrimination between angry and fearful expressions. Offenders were as accurate as controls on the letter flanker task but made more errors in emotion discrimination on the face flanker task. ERNs elicited by letter flanker errors did not differ across groups but were markedly reduced in the offenders in the face flanker condition. These effects were related to the degree of psychopathy within the offender group. Source modelling of the ERN also indicated an atypical response for psychopaths when error monitoring required the discrimination of affectively based information.