Predominance of Th1-type T cells in synovial fluid of patients with Yersinia-induced reactive arthritis.

The pathogenetic mechanisms underlying the development of reactive arthritis and the functional capacities of synovial T cells specific for Yersinia enterocolitica are still unclear. In this study we have determined the cytokine secretion patterns of 24 CD4+ synovial fluid (SF)-derived T cell clones from 2 patients with Yersinia-induced reactive arthritis, 16 clones specific for different Yersinia antigens and 8 clones as controls. The clones specific for Yersinia antigens predominantly belong to the T helper cell 1 (Th1) subset with production of interferon (IFN)-gamma and interleukin (IL)-2, but no IL-4, whereas SF T cells not reactive with Yersinia antigens produce IL-2, IL-4 and IFN-gamma and thus belonged to the Th0 subset. Moreover, short-term T cell lines established from SF and peripheral blood showed the same pattern. To further analyze the functional relevance of these data we investigated the influence of IFN-gamma and IL-4 on the intracellular killing of Yersinia in a human glioblastoma cell line. Our data show that the Th1 cytokine IFN-gamma promotes intracellular killing of Yersinia, whereas this effect is antagonized by the Th2 cytokine IL-4. Furthermore, the Th2 cytokine IL-10 inhibited the antigen-specific proliferative response and IFN-gamma and IL-2 production by the Th1 cells. These results provide insight into the antibacterial mechanisms at work in reactive arthritis after infection with Yersinia enterocolitica and, for the first time, reveal the cross-regulatory properties of cytokines derived from Th1 and Th2 cells in a human immune response to bacterial antigens.     

Early recognition of newborn goat kids by their mother: II. Auditory recognition and evidence of an individual acoustic signature in the neonate

The vocal recognition of newborn kids by their mother at 2 days postpartum and the possible existence of interindividual differences in the voice structure of newborn kids were investigated in two separate studies. The ability of goats to discriminate between the bleats of their own versus an alien kid was tested at 2 days postpartum in mothers being prevented access to visual and olfactory cues from the young. Goats spent significantly more time on the side of the enclosure from which their own kid was bleating, looked in its direction for longer, and responded more frequently to the bleats of their own than to those of the alien kid (p < 0.05). In the second study, the sonograms of 13 kids, studied from Days 1 to 5, showed significant interindividual differences for the five variables taken into account and on each of the 5 days (duration of bleat, fundamental frequency, peak frequency, and numbers of segments and of harmonics). The potential for individual coding ranged between 1.1 and 4.1, indicating that for some variables variations between individuals were greater than intraindividual variations. Furthermore, when considering the five parameters together, the discriminating scores showed an average of 95% in the 78 combinations of any 2 kids for any given day. Finally, some significant intraindividual differences also were found between days, suggesting ontogenic changes in the characteristics of the kid's voice in early life. Therefore, mother goats are likely to recognize the vocalizations of their 48-hr-old kids, as they show sufficient interindividual variability to allow the existence of individual vocal signatures, even though some of the characteristics of the bleats change rapidly over time.     

Undifferentiated embryonal sarcoma of the liver in an adult: a case report

Undifferentiated embryonal sarcoma of the liver is rare. It is usually observed in children and adolescents. We report one case of embryonal sarcoma of the liver arising in patient without any antecedent. The only symptom was right scapular pain. The liver scan showed a multicystic lesion suspicious for infectious origin or a tumor. Serologies for ecchinococcus, schistosomiasis and brucellosis were negative. The treatment was a right hepatectomy. On gross examination, the tumor was unencapsulated, multicystic and contained large areas of necrosis admixed with gelatinous areas. Microscopically, there were epithelioid and spindle tumor cells in a myxo?d stroma. Lipoblastic-like or rhabdomyoblastic-like, giant cells and PAS positive hyaline globules in the cell cytoplasm were present. The tumor cells expressed vimentin, cytokeratin (KL1), alpha-1-antitrypsin and smooth muscle actin. This observation shows that embryonal sarcoma of the liver may develop in adult patients and should be taken into consideration in any differential diagnosis of cystic hepatic tumor.     

Endometrial and colorectal tumors from patients with hereditary nonpolyposis colon cancer display different patterns of microsatellite instability

The colorectum and uterine endometrium are the two most commonly affected organs in hereditary nonpolyposis colon cancer (HNPCC), but the genetic basis of organ selection is poorly understood. As tumorigenesis in HNPCC is driven by deficient DNA mismatch repair (MMR), we compared its typical consequence, instability at microsatellite sequences, in colorectal and endometrial cancers from patients with identical predisposing mutations in the MMR genes MLH1 or MSH2. Analysis of non-coding (BAT25, BAT26, and BAT40) and coding mononucleotide repeats (MSH6, MSH3, MLH3, BAX, IGF2R, TGF beta RII, and PTEN), as well as MLH1- and MSH2-linked dinucleotide repeats (D3S1611 and CA7) revealed significant differences, both quantitative and qualitative, between the two tumor types. Whereas colorectal cancers displayed a predominant pattern consisting of instability at the BAT loci (in 89% of tumors), TGF beta RII (73%), dinucleotide repeats (70%), MSH3 (43%), and BAX (30%), no such single pattern was discernible in endometrial cancers. Instead, the pattern was more heterogeneous and involved a lower proportion of unstable markers per tumor (mean 0.27 for endometrial cancers versus 0.45 for colorectal cancers, P < 0.001) and shorter allelic shifts for BAT markers (average 5.1 bp for unstable endometrial cancers versus 9.3 bp for colorectal cancers, P < 0.001). Among the individual putative "target" loci, PTEN instability was associated with endometrial cancers and TGF beta RII instability with colon cancers. The different instability profiles in endometrial and colorectal cancers despite identical genetic predisposition underlines organ-specific differences that may be important determinants of the HNPCC tumor spectrum.     

Hair cells in the inner ear of the pirouette and shaker 2 mutant mice

The shaker 2 (sh2) and pirouette (pi) mouse mutants display severe inner ear dysfunction that involves both auditory and vestibular manifestation. Pathology of the stereocilia of hair cells has been found in both mutants. This study was designed to further our knowledge of the pathological characteristics of the inner ear sensory epithelia in both the sh2 and pi strains. Measurements of auditory brainstem responses indicated that both mutants were profoundly deaf. The morphological assays were specifically designed to characterize a pathological actin bundle that is found in both the inner hair cells and the vestibular hair cells in all five vestibular organs in these two mutants. Using light microscope analysis of phalloidin-stained specimens, these actin bundles could first be detected on postnatal day 3. As the cochleae matured, each inner hair cell and type I vestibular hair cell contained a bundle that spans from the region of the cuticular plate to the basal end of the cell, then extends along with cytoplasm and membrane, towards the basement membrane. Abnormal contact with the basement membrane was found in vestibular hair cells. Based on the shape of the cellular extension and the actin bundle that supports it, we propose to name these extensions cytocauds. The data suggest that the cytocauds in type I vestibular hair cells and inner hair cells are associated with a failure to differentiate and detach from the basement membrane.     

Jumping translocations in multiple myeloma

Jumping translocations (JT) have been defined as nonreciprocal translocations involving a same donor chromosome arm or chromosome segment onto two or more recipient chromosomes in different cell lines in the same patient, leading to a mosaic karyotype. This definition has been expanded to also include extra copies of a same donor segment on different recipient chromosomes in a single clone. Six patients with multiple myeloma and JT involving chromosome arm 1q were identified among 37 patients presenting with chromosome 1 abnormalities. All six patients had an advanced disease and a short survival. The literature review allowed us to identify 24 additional patients with JT. Chromosomes 16 and 19 were the recipients in 11 (45.8%) and 6 (25%) of these 24 patients, respectively. Breakpoints on the recipient chromosomes were pericentromeric in 46.2% and telomeric in 40.4% of the breakpoints recorded. Since telomeres are made of (TTAGGG)n tandem DNA repeats that are also found in the pericentromeric heterochromatic regions (interstital telomeric sequences), it is presumed that jumping translocations arise through illegimate recombination between telomere repeat sequences and interstitial telomeric sequences.     

Highly immunogenic and protective recombinant vaccine candidate expressed in transgenic plants

Vaccine development has been hampered by difficulties in developing new and safe adjuvants, so alternative technologies that offer new avenues forward are urgently needed. The goal of this study was to express a monoclonal recombinant immune complex in a transgenic plant. A recombinant protein consisting of a tetanus toxin C fragment-specific monoclonal antibody fused with the tetanus toxin C fragment was designed and expressed. Immune complex formation occurred between individual fusion proteins to form immune complex-like aggregates that bound C1q and FcgammaRIIa receptor and could be targeted to antigen-presenting cells. Unlike antigen alone, the recombinant immune fusion complexes were highly immunogenic in mice and did not require coadministration of an adjuvant (when injected subcutaneously). Indeed, these complexes elicited antibody titers that were more than 10,000 times higher than those observed in animals immunized with the antigen alone. Furthermore, animals immunized with only 1 mug of recombinant immune complex without adjuvant were fully protected against lethal challenge. This the first report on the use of a genetic fusion between antigen and antibody to ensure an optimal expression ratio between the two moieties and to obtain fully functional recombinant immune complexes as a new vaccine model.     

Six novel heterozygous MLH1, MSH2, and MSH6 and one homozygous MLH1 germline mutations in hereditary nonpolyposis colorectal cancer

Most hereditary nonpolyposis colorectal cancer (HNPCC) cases are caused by germline mutations of mismatch repair (MMR) genes (i.e., MLH1, MSH2, or MSH6). Here we describe six novel mutations in patients referred for genetic assessment. All of these mutations lead to premature translation termination. Five single base pair deletions lead to frameshift (MLH1: g.38-39insCCCA, g.1971del.T; MSH2: g.163del.C, g.746del.A; MSH6: g.3320del.A) and one nonsense mutation in MSH2 g.1030C>T leads to a stop codon: p.Q344X. In one patient, the previously described MLH1 nonsense mutation g.806C>G was found in a homozygous state. In this patient, the familial histories of both the mother and father suggested HNPCC syndrome. This patient developed colon cancer at 22 years of age, suggesting a more aggressive phenotype. The results of our study provide further insight into the mutational spectrum of MMR genes in HNPCC families.     

Expression and folding of an antibody fragment selected in vivo for high expression levels in Escherichia coli cytoplasm

In this review, we summarize some of our results on folding and directed evolution of an antibody fragment in Escherichia coli cytoplasm. We will also discuss some attempts to construct other antibodies active in this cellular compartment.