Familial persistent pulmonary hypertension of the newborn resulting from misalignment of the pulmonary vessels (congenital alveolar capillary dysplasia).

Misalignment of the pulmonary veins with congenital alveolar capillary dysplasia, although rare, has been reported as a cause of persistent pulmonary hypertension of the newborn. Reported cases have been mainly sporadic. Familial occurrence has been reported in only three instances. We present affected sibs with this condition. In addition to pulmonary abnormalities, urogenital abnormalities, including ureteric and urethral obstruction, seem to be common. Autosomal recessive inheritance is suggested.     

Structure of an autoimmune T cell receptor complexed with class II peptide-MHC: insights into MHC bias and antigen specificity

T cell receptor crossreactivity with different peptide ligands and biased recognition of MHC are coupled features of antigen recognition that are necessary for the T cell's diverse functional repertoire. In the crystal structure between an autoreactive, EAE T cell clone 172.10 and myelin basic protein (1-11) presented by class II MHC I-Au, recognition of the MHC is dominated by the Vbeta domain of the TCR, which interacts with the MHC alpha chain in a manner suggestive of a germline-encoded TCR/MHC "anchor point." Strikingly, there are few specific contacts between the TCR CDR3 loops and the MBP peptide. We also find that over 1,000,000 different peptides derived from combinatorial libraries can activate 172.10, yet the TCR strongly prefers the native MBP contact residues. We suggest that while TCR scanning of pMHC may be degenerate due to the TCR germline bias for MHC, recognition of structurally distinct agonist peptides is not indicative of TCR promiscuity, but rather highly specific alternative solutions to TCR engagement.     

Characterization of a novel breast carcinoma xenograft and cell line derived from a BRCA1 germ-line mutation carrier

A human tumor xenograft (L56Br-X1) was established from a breast cancer axillary lymph node metastasis of a 53-year-old woman with a BRCA1 germ-line nonsense mutation (1806C>T; Q563X), and a cell line (L56Br-C1) was subsequently derived from the xenograft. The xenograft carries only the mutant BRCA1 allele and expresses mutant BRCA1 mRNA but no BRCA1 protein as determined by immunoprecipitation or Western blotting. The primary tumor, lymph node metastasis, and xenograft were hypodiploid by DNA flow cytometry, whereas the cell line displayed an aneuploidy apparently developed via polyploidization. Cytogenetic analysis, spectral karyotyping, and comparative genomic hybridization of the cell line revealed a highly complex karyotype with numerous unbalanced translocations. The xenograft and cell line had retained a somatic TP53 missense mutation (S215I) originating from the primary tumors, as well as a lack of immunohistochemically detectable expression of steroid hormone receptors, epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER-2), and keratin 8. Global gene expression analysis by cDNA microarrays supported a correlation between the expression profiles of the primary tumor, lymph node metastasis, xenograft, and cell line. We conclude that L56Br-X1 and L56Br-C1 are useful model systems for studies of the pathogenesis and new therapeutic modalities of BRCA1-induced human breast cancer.     

C3d binding to the circumsporozoite protein carboxy-terminus deviates immunity against malaria

The immunogenicity of recombinant protein or anti-viral DNA vaccines can be significantly improved by the addition of tandem copies of the complement fragment C3d. We sought to determine if the efficacy of a circumsporozoite protein (CSP)-based DNA vaccine delivered to mouse skin by gene gun was improved by using this strategy. Instead, we found that C3d suppressed the protective immunity against Plasmodium berghei malaria infection and deviated immunity, most notably by suppressing the induction of antibodies specific for the CSP C-terminal flanking sequence and by suppressing the induction of CSP-specific IL-4-producing spleen cells. We further showed that C3d bound to the C-terminal flanking sequence of the CSP, which may explain the immune deviation observed in CS/C3d chimeric antigen. We have thus identified C3d-mediated epitope masking and shifting of both the humoral and cellular immune responses as a potential novel escape mechanism, which plasmodia may use to divert the induction of protective immunity.     

Analysis of microdissected prostate tissue with ProteinChip arrays--a way to new insights into carcinogenesis and to diagnostic tools

Prostate carcinomas are one of the most common malignancies in western societies. The pathogenesis of this tumor is still poorly understood. These tumors present with two characteristic features: epithelial-mesenchymal interactions, which play a pivotal role for tumor development and most of clinically manifest cancers arise in prostate proper compared to a minority of tumors which develop in the transitional zone. Deciphering the epithelial-mesenchymal cross talk and identification of molecular pecularities of the sub-populations of cells in different zones can therefore help understanding carcinogenesis and development of new, non-invasive tools for the diagnosis and prognosis of prostate carcinomas which has remained a challenge until today. A ProteinChip array technology (SELDI = surface enhanced laser desorption ionization) has been developed recently by Ciphergen Biosystems enabling analysis and profiling of complex protein mixtures from a few cells. This study describes the analysis of approximately 500-1000 freshly obtained prostate cells by SELDI-TOF-MS (surface enhanced laser desorption ionization time-of-flight mass spectrometry). Pure cell populations of stroma, epithelium and tumor cells were selected by laser assisted microdissection. Multiple specific protein patterns were reproducibly detected in the range from 1.5 to 30 kDa in 28 sub-populations of 4 tumorous prostates and 1 control. A specific 4.3 kDa peak was increased in the prostate tumor stroma compared to normal prostate proper and transitional zone stroma and increased in prostate tumor glands compared to normal prostate proper and transitional zone glands. Coupling laser assisted microdissection with SELDI provides tremendous opportunities to identify cell and tumor specific proteins to understand molecular events underlying prostate carcinoma development. It underlines the vast potential of this technology to better understand pathogenesis and identify potential candidates for new specific biomarkers in general which could help to screen for and distinguish disease entities, i.e. between clinically significant and insignificant carcinomas of the prostate.     

Circulating neutrophil CD14 expression and the inverse association of ambient particulate matter on lung function in asthmatic children.

BACKGROUND: Identifying baseline inflammatory biomarkers that predict susceptibility to size-specific particulate matter (PM) independent of gaseous pollutants could help us better identify asthmatic subpopulations at increased risk for the adverse health effects of PM. OBJECTIVE: To evaluate whether the association between lung function and exposure to ambient levels of PM less than 2.5 microm in diameter (PM2.5) (fine) and 10 to 2.5 microm in diameter (PM(10-2.5)) (coarse) in children with persistent asthma differed across baseline measures of inflammation and innate immune activation. METHODS: We performed a panel study on a local population of 16 children with persistent asthma and evaluated daily pulmonary function (percentage of predicted peak expiratory flow and forced expiratory volume in 1 second) while concurrently measuring daily PM2.5 and PM(10-2.5) exposure from a central site in Chapel Hill, North Carolina. The children underwent a baseline medical evaluation that included assessment of several immunoinflammatory biomarkers in peripheral blood. RESULTS: Children without measurable CD14 expression on circulating neutrophils had significantly reduced pulmonary function (forced expiratory volume in 1 second and peak expiratory flow) with each interquartile range (IQR) increase in PM2.5 (IQR = 8.5 microg/m3) and PM(10-2.5) (IQR = 4.1 microg/m3) concentration, unlike children with measurable CD14 expression (P < .001 for interaction). CONCLUSIONS: Asthmatic children with muted surface expression of CD14 on circulating neutrophils may have a decreased capacity to respond to bacterial components of PM.     

N19 polyepitope as a carrier for enhanced immunogenicity and protective efficacy of meningococcal conjugate vaccines

N19, a string of human universal CD4 T-cell epitopes from various pathogen-derived antigens, was shown to exert a stronger carrier effect than CRM197 for the induction of anti-group C Neisseria meningitidis capsular polysaccharide (MenC), after immunization of mice with various dosages of N19-MenC or CRM-MenC conjugate vaccines. After two immunizations, the N19-based construct induced anti-MenC antibody and protective bactericidal antibody titers higher than those induced by three doses of the CRM-MenC conjugate and required lower amounts of conjugate. N19-based conjugates are superior to CRM-based conjugates to induce protective immune responses to MenC conjugates.     

Levels of stem cell factor and interleukin-3 in serum in acute Plasmodium falciparum malaria.

The purpose of the present study was to measure serum concentrations of stem cell factor (SCF) and interleukin-3 (IL-3) in patients with acute Plasmodium falciparum malaria. Serum samples from 15 patients were taken on day of admission and days 7, 14, 21, and 28. Anemia developed in 80% of patients. A transient increase in IL-3 could be observed at the beginning of the disease. It remains controversial whether the measured concentrations of IL-3 and SCF correlate with the grade of anemia. The possibly suppressed IL-3 and SCF production may contribute to the prolonged anemia in P. falciparum malaria, as has been shown for erythropoietin.     

Recognition of viral antigens in 6/94 virus-induced T-cell-mediated cytotoxicity

Distinct events in the virus-stimulated T-cell-mediated cytotoxicity (V-CMC) have been investigated: 1.) The induction of V-CMC is possible by immunizing mice with infectious as well as UV-inactivated virus (parainfluenza type 1 strain 6/94), or with virus-infected cells either compatible or imcompatible with the recipient. 2.) Recognition of viral antigens by the effector cells occurs independently of the H2 environment: Fractionation of effector cells on columns loaded with virus-infected cells eliminates virus-specific cytotoxic cells. Effector cells and cells on the column need not share H-2 antigens. The findings are discussed with regard to the H2 restriction of the virus induced T-cell mediated cytotoxicity.This paper was presented at the Sixteenth Symposium of the European Association Against Virus Diseases in Amsterdam, September 7–9, 1977     

A simple cardiac contractility computer

A single-purpose analogue-computing device is described for the online assessment of the contractile state of the human myocardium from the left ventricular pressure (P_lv) data available during routine cardiac catheterisation. Due attention has been paid to the design of the computer circuits so that they will not process pressure phenomena outside the isovolumic contractile period. Either a \(\left( {\frac{1}{{P_{lv} }}\frac{{dP_{lv} }}{{dt}}} \right)_{max} \) or a plain \(\left( {\frac{{dP_{lv} }}{{dt}}} \right)_{max} \) index is presented on a digitalvoltmeter display, thus obviating the need for any graphical extrapolation or additional computation.