Clinical Significance of Spontaneous Pneumomediastinum.

BACKGROUND: Spontaneous pneumomediastinum (SPM) is classified as free air in the mediastinum in the absence of any precipitating cause. It is relatively uncommon, and the clinical significance and risk associated with SPM is not well understood and has not been widely documented in the literature. Our goals were to determine the outcomes of patients who presented with SPM and to determine predictors of severe pathology associated with SPM. METHODS: From 2004 through 2013, a retrospective review was conducted of patients who presented with SPM to our institution. Patient demographics, comorbidities, laboratory tests, and esophageal perforation were recorded. RESULTS: In all, 249 patients were discovered to have SPM on chest radiograph or computed tomography scan. Mean age was 38.7 years (range, 17 to 81). Sixty-one percent of patients (151 of 249) were male. Ten percent of all patients (24 of 249) were ultimately discovered to have esophageal perforation, determined by upper endoscopy, upper gastrointestinal series, or intraoperatively during emergent surgery. Age (p < 0.01), pleural effusion (p < 0.01), and elevated white blood cell count (p < 0.01) were the only significant risk factors for esophageal perforation on multivariate analysis. CONCLUSIONS: Spontaneous pneumomediastinum is usually associated with a benign clinical course. Risk factors for esophageal perforation in these patients include age, elevated white blood cell count, and a pleural effusion. In the absence of abnormal laboratory values or associated radiologic findings, the majority of patients with SPM may be safely observed without the need for further diagnostic testing.

Cellular context-dependent effects of H2ax and p53 deletion on the development of thymic lymphoma.

H2AX and Artemis each cooperate with p53 to suppress lymphoma. Germline H2ax(-/-)p53(-/-) mice die of T-cell receptor-ß(-) (TCR-ß(-)) thymic lymphomas with translocations and other lesions characteristic of human T-cell acute lymphoblastic leukemia. Here, we demonstrate that mice with inactivation of H2ax and p53 in thymocytes die at later ages to TCR-ß(-) or TCR-ß(+) thymic lymphomas containing a similar pattern of translocations as H2ax(-/-)p53(-/-) tumors. Germline Artemis(-/-) p53(-/-) mice die of lymphomas with antigen receptor locus translocations, whereas Artemis(-/-)H2ax(-/-)p53(-/-) mice die at earlier ages from multiple malignancies. We show here that Artemis(-/-) mice with p53 deletion in thymocytes die of TCR-ß(-) tumors containing Tcrα/δ translocations, other clonal translocations, or aneuploidy, as well as Notch1 mutations. Strikingly, Artemis(-/-) mice with H2ax and p53 deletion in thymocytes exhibited a lower rate of mortality from TCR-ß(-) tumors, which harbored significantly elevated levels of genomic instability. Our data reveal that the cellular origin of H2ax and p53 loss impacts the rate of mortality from and developmental stage of thymic lymphomas, and suggest that conditional deletion of tumor suppressor genes may provide more physiologic models for human lymphoid malignancies than germline inactivation.

Assembled DJ beta complexes influence TCR beta chain selection and peripheral V beta repertoire.

TCRbeta chain repertoire of peripheral alphabeta T cells is generated through the stepwise assembly and subsequent selection of TCRbeta V region exons during thymocyte development. To evaluate the influence of a two-step recombination process on Vbeta rearrangement and selection, we generated mice with a preassembled Dbeta1Jbeta1.1 complex on the Jbeta1(omega) allele, an endogenous TCRbeta allele that lacks the Dbeta2-Jbeta2 cluster, creating the Jbeta1(DJbeta) allele. As compared with Jbeta1(omega/omega) mice, both Jbeta1(DJbeta/omega) and Jbeta1(DJbeta/DJbeta) mice exhibited grossly normal thymocyte development and TCRbeta allelic exclusion. In addition, Vbeta rearrangements on Jbeta1(DJbeta) and Jbeta1(omega) alleles were similarly regulated by TCRbeta-mediated feedback regulation. However, in-frame VbetaDJbeta rearrangements were present at a higher level on the Jbeta1(DJbeta) alleles of Jbeta1(DJbeta/omega) alphabeta T cell hybridomas, as compared with on the Jbeta1(omega) alleles. This bias was most likely due to both an increased frequency of Vbeta-to-DJbeta rearrangements on Jbeta1(DJbeta) alleles and a preferential selection of cells with in-frame VbetaDJbeta exons assembled on Jbeta1(DJbeta) alleles during the development of Jbeta1(DJbeta/omega) alphabeta T cells. Consistent with the differential selection of in-frame VbetaDJbeta rearrangements on Jbeta1(DJbeta) alleles, the Vbeta repertoire of alphabeta T cells was significantly altered during alphabeta TCR selection in Jbeta1(DJbeta/omega) and Jbeta1(DJbeta/DJbeta) mice, as compared with in Jbeta1(omega/omega) mice. Our data indicate that the diversity of DJbeta complexes assembled during thymocyte development influences TCRbeta chain selection and peripheral Vbeta repertoire.