Differentiation of interstistial cells and stromal proteins in the secondary septum of early postnatal rat: Effect of maternal chronic exposure to whole cigarette smoke

The intention of this investigation was to ascertain the effect of maternal exposure to cigarette smoke on the early postnatal morphogenesis of pulmonary interstitum in offspring. Female rats were chronically exposed to whole cigraette smoke. Offspring of these and control animals were sacrificed at postnatal day 15, and their tissues were prepared for quantitative and qualitative analyses. Results indicate a diminished quantitative representaion of parenchymal tissue (P <0.01) and a slower pace of secondary septal growth (P <0.07) in the experimental lung. Furthermore, a greater cellular volume density (P <0.0002) was ascertained for the experimental septal inerstitium. There was proportionately less of elastin substances (P < 0.009), collagen together with basal laminae (P < 0.0008), and nonfibrillar, amorphous matrix (P < 0.02) in the experimental extracellular stroma. Fribrillar collagen and nonfibrillar matrix were represented quantitatively 6.3 times more in the experimental extracellular interstitum than elastin, whereas that ratio for the control tissue was only 4.2. Most experimental interstitial cells (80%) contained numerous lipid globules, which, in contrast, were only occasionally present in control cells (7.3%). Experimental cells, consequently, possessed a larger cross-sectional diameter and a smaller nucleus-to-cytoplasm volume ratio than control cells. These divergent developmental patterns are possibly suggestive of a delayed differentiation of interstitial cells and a modified production to degradation balance of stromal proteins in offspring of animals chronically exposed to whole cigarette smoke.     

High frequency of MYC gene amplification is a common feature of radiation‐induced sarcomas. Further results from EORTC STBSG TL 01/01

Irradiation is a major causative factor among the small subgroup of sarcomas with a known etiology. The prognosis of radiation‐induced sarcomas (RIS) is significantly worse than that of their spontaneous counterparts. The most frequent histological subtypes include undifferentiated pleomorphic sarcomas, angiosarcomas, and leiomyosarcomas. A high frequency of MYC amplifications in radiation‐induced angiosarcomas, but not in primary angiosarcomas, has recently been described. To investigate whether MYC amplifications are also frequent in RIS other than angiosarcomas, we analyzed the MYC amplification status of 83 RIS and 192 sporadic sarcomas by fluorescence in situ hybridization. We found significantly higher numbers of MYC amplifications in RIS than in sporadic sarcomas (P < 0.0001), especially in angiosarcomas, undifferentiated pleomorphic sarcomas, and leiomyosarcomas. Angiosarcomas were special in that MYC amplifications were particularly frequent and always high level, while other RIS showed low‐level amplifications. We conclude that MYC amplifications are a frequent feature of RIS as a group and may contribute to the biology of these tumors. © 2012 Wiley Periodicals, Inc.     

Differential presentation of endogenous and exogenous hepatitis B surface antigens influences priming of CD8+ T cells in an epitope‐specific manner

Little is known about whether presentation of endogenous and exogenous hepatitis B virus (HBV) surface antigens on APCs targeted by vaccination and/or virus‐harboring hepatocytes influences de novo priming of CD8⁺ T cells. We showed that surface antigen‐expressing transfectants exclusively display a K^b/S190 epitope, whereas cells pulsed with recombinant surface particles (rSPs) exclusively present a K^b/S208 epitope to CD8⁺ T cells. The differential presentation of these epitopes largely reflects the selective, but not exclusive, priming of K^b/S190‐ and K^b/S208‐specific T cells in C57BL/6 mice by endogenous/DNA‐ or exogenous/protein‐based vaccines, respectively. Silencing the K^b/S190 epitope (K^b/S190_V194F) in antigen‐expressing vectors rescued the presentation of the K^b/S208 epitope in stable transfectants and significantly enhanced priming of K^b/S208‐specific T cells in C57BL/6 mice. A K^b/S190‐mediated immunodominance operating in surface antigen‐expressing cells, but not in rSP‐pulsed cells, led to an efficient suppression in the presentation of the K^b/S208 epitope and a consequent decrease in the priming of K^b/S208‐specific T cells. This K^b/S190‐mediated immunodominance also operated in 1.4HBV‐S^mut transgenic (tg) hepatocytes selectively expressing endogenous surface antigens and allowed priming of K^b/S208‐ but not K^b/S190‐specific T cells in 1.4HBV‐S^mut tg mice. However, IFN‐γ⁺ K^b/S208‐specific T cells could not inhibit HBV replication in the liver of 1.4HBV‐S^mut tg mice. These results have practical implications for the design of T‐cell‐stimulating therapeutic vaccines.     

Living organ donation practices in Europe – results from an online survey

In Europe, living organ donation (LOD) is increasingly accepted as a valuable solution to overcome the organ shortage. However, considerable differences exist between European countries regarding frequency, practices and acceptance of donor–recipient relations. As a response, the Coordination Action project ‘Living Organ Donation in Europe’ ( www.eulod.eu ), funded by the Seventh Framework Programme of the European Commission, was initiated. Transplant professionals from 331 European kidney and liver transplant centres were invited to complete an online survey on living kidney donation (LKD) and living liver donation (LLD). In total, 113 kidney transplant centres from 40 countries and 39 liver transplant centres from 24 countries responded. 96.5% and 71.8% performed LKD and LLD respectively. The content of the medical screening of donors was similar, but criteria for donor acceptance varied. Few absolute contraindications for donation existed. The reimbursement policies diverged and the majority of the donors did not get reimbursed for their income loss during recovery. Large discrepancies were found between geographical European regions (the Eastern, the Mediterranean and the North‐Western). As a result of this survey we suggest several recommendations to improve quality and safety of LOD in Europe.     

The Early Recognition Inventory ERIraos detects at risk mental states of psychosis with high sensitivity

The identification of patients carrying an increased risk of psychosis is one of the most important demands in schizophrenia research. Currently used diagnostic instruments mainly focus on either attenuated psychotic symptoms and brief limited intermittent psychotic symptoms or solely cognitive basic symptoms. The “Early Recognition Inventory based on IRAOS” (ERIraos) has been developed as a comprehensive assessment of both symptom groups within one scale. We compared the results obtained by ERIraos with an international standard instrument, the “Comprehensive Assessment of At Risk Mental States” (CAARMS) and applied both scales in a sample of 121 outpatients positively tested on a screening checklist for at risk mental states (ARMS). Subsamples were classified as first episode of psychosis, late ARMS with prevalent attenuated psychotic symptoms and/or brief limited intermittent psychotic symptoms, earlier stages of ARMS presenting cognitive basic symptoms as well as a vulnerability group, also differing regarding mean age and psychosocial functioning. Our results point to a higher sensitivity of ERIraos compared to scales that mainly focus on attenuated psychotic symptoms and brief limited intermittent psychotic symptoms. A detailed assessment of cognitive basic symptoms seems to be important in early detection, might be an important focus for therapeutic interventions in ARMS patients and might sustain attempts to alleviate cognitive dysfunction in schizophrenia.     

The diabetogenic, insulin-specific CD8 T cell response primed in the experimental autoimmune diabetes model in RIP-B7.1 mice

Type 1 diabetes mellitus can result from the specific destruction of pancreatic beta cells by autoreactive T cells. As shown here, experimental autoimmune diabetes (EAD) is efficiently induced in RIP-B7.1 mice by preproinsulin (ppins)-encoding DNA vaccines. EAD develops in RIP-B7.1 mice within 3-4 wk after a single immunization with ppins-encoding plasmid DNA. RIP-B7.1 mice develop insulitis, insulin deficiency and hyperglycemia after vaccination with plasmids encoding murine ppins-I or murine ppins-II or human hu-ppins. EAD induction critically depends on CD8 T cells and is independent of CD4 T cells. To be diabetogenic, ppins-specific CD8 T cells had to express IFN-gamma. Neither expression of perforin nor signaling through the type I IFN receptor is an essential component of this pathogenic CD8 T cell phenotype. Using plasmids encoding truncated ppins variants, we show that EAD is only induced by DNA vaccines encoding the insulin A-chain. Diabetogenic CD8 T cells specifically recognize the Kb-restricted A12-21 epitope of the insulin A-chain. The RIP-B7.1 model hence represents an attractive model for the characterization of cellular and molecular events involved in the CD8 T cell-mediated immune pathogenesis of diabetes.