Leisure Activities of Individuals With Prader-Willi, Williams, and Down Syndromes

This study extends laboratory-based profiles to participation in leisure activities for persons with three genetic syndromes. Parents of 223 persons with Prader-Willi, Williams, and Down syndromes filled out a newly developed Leisure Activities Questionnaire. Sixteen items loaded onto five distinct factors: social; visual-spatial; visual-strategy; musical; and physical activities. Individuals with Williams syndrome less often participated in visual-spatial activities, those with Prader-Willi syndrome more often performed both visual-spatial and visual-strategy activities, and those with Williams and Down syndromes more often performed musical activities. With increasing chronological ages, all groups increased in their social activities, while those with Williams and Down syndromes decreased in their visual-spatial activities. In both Prader-Willi and Williams syndrome, decreased maladaptive behaviors related to greater amounts of participation in etiology-related activities. Theoretical and practical implications are discussed.     

A complementarity-determining region peptide of an anti-desmosome autoantibody may interact with the desmosomal plaque through molecular mimicry with a cytoplasmic desmoglein 1 sequence

The sera of patients with pemphigus, a group of autoimmune blistering skin diseases, contain autoantibodies directed against components of adhering junctions termed desmosomes. F12, a human monoclonal antibody derived from a pemphigus patient, recognizes an unknown polypeptide of the desmosomal and hemidesmosomal plaques. The third complementarity-determining region of the F12 heavy chain (VH-CDR3) was shown to share a four-amino-acid sequence (GSSG) with the intracellular domains of desmoglein 1 and bullous pemphigoid antigen 2 which interact with components of, respectively, the desmosomal and hemidesmosomal plaques. Computer modeling of F12 showed that the GSSG sequence protudes inside the antigen-combining site and thus might be involved in antigen interactions. The GSSG sequence is essential to F12 function, since a peptide containing the VH-CDR3 inhibited its binding to target antigens while VH-CDR3 peptides with specific modifications of the GSSG sequence did not. These data allow us to hypothesize that certain autoantibodies produced during the course of an autoimmune disease can behave as adhesion molecules, through the molecular mimicry of the motif involved in protein/protein adhesion, and to propose a new self-antigen binding mechanism for some autoantibodies.     

Peripheral clonal deletion of antiviral memory CD8+ T cells

Antiviral cytotoxic memory CD8⁺ T cells adoptively transferred to mice which are persistently infected with lymphocytic choriomeningitis virus WE or DOCILE initially proliferated extensively; they either caused the death of the recipient or, alternatively, disappeared within a few days. Apparently, the complete and coordinated induction and stimulation by widely distributed viral antigen caused these memory T cells to die before virus had been eliminated from the host. Thus memory T cells are as susceptible to peripheral exhaustion/deletion as unprimed T cells. These results indicate possible limitations of exclusively CD8⁺ T cell-mediated adoptive immunotherapy against viral infections or tumors.     

Epidermal T lymphocytes--ontogeny, features and function.

Conclusions The murine epidermis contains a network of Thy-1⁺ dendritic T cells. These T cells arise from early fetal stem cells and differentiate in the fetal or neonatal thymic or epidermal microenvironment. Their lack of expression of CD5, CD4, and CD8 antigens, as well as their virtually exclusive expression of a CD3/TCR V3/V1 complex, distinguishes DETC from the bulk of peripheral T cells.The early appearance of TCR / cells in ontogeny, the lack of expression of CD4 and CD8 antigens, and the relative paucity of and genes compared to and genes, indicates that / T cells provide a phylogenetically primitive, broadly acting, and poorly discriminating immunologic defense system. In this system, recognition of antigen is not restricted by classical MHC class I and class II antigens, but may occur in the context of relatively nonpolymorphic restricting elements, such as Qa [82], Tla [10] or CD1 [62]. This rather primitive immune system provided by DETC may serve to protect the epidermal integrity. Upon recognition of self proteins released following epidermal injury, DETC may become activated and assist in the removal of altered cells. In this limited fashion, the epidermis may be an independently competent immunologic system. However, the fact that the TCR repertoire of DETC does not allow for the recognition of antigenic peptides in conjunction with MHC moieties excludes the possibility that the diverse immune response elicited by topical contact with foreign antigens is mediated by DETC.Whether this statement also applies to the human epidermis cannot be answered at the present time. Let us consider a few plausible concepts concerning derivation and function of human epidermal T cells. First, one could postulate that in early ontogeny, the human epidermis harbors a small, indigenous population of naive T lymphocytes with monomorphic TCR representing an analogue to murine DETC. These cells could function in a manner similar to that proposed for murine DETC. They may even persist into adult life, so far undetected because they would be outnumbered by immigrating polymorphic T cells from peripheral lymphoid organs. Second, it is conceivable that the human epidermis contains an indigenous population of naive T lymphocytes with a polymorphic TCR repertoire representing a phylogenetically advanced analogue to murine DETC. Although equipped with TCR allowing antigen recognition in the context of MHC, their density is probably too low to make them an effective host defense system against the multitude of environmental antigens presented by Langerhans cells. One could rather assume that they proliferate upon recognition of self antigens occurring in a perturbed epidermis. The autoreactivity of these cells may not necessarily be beneficial. Finally, the fact that the entry of circulating HECA-452⁺ memory cells into the skin is dependent upon the injury-induced ELAM-1 expression by endothelial cells of the dermal microvasculature could indicate that all T cells present in adult human epidermis are recruited upon alteration of the skin. Following this reasoning, the human epidermis should not be regarded as a complete, self-sustaining immunologic organ but rather as a homing site for and a target of lymphocytes antigenically sensitized in peripheral lymphoid organs.     

Reflex increases in heart-rate induced by perfusing the hind leg of the rat with solutions containing lactic acid

The hypothesis that metabolic receptors in skeletal muscle influence heart-rate during exercise was tested by means of a perfused preparation of the rat's hind legs. The isolated leg was connected to the body only by nerve and bone and was perfused with tyrode solution. The humoral changes of exercise were simulated by perfusing with modified tyrode solutions in which concentration of K⁺, osmolality, concentrations of lactic acid, and inorganic phosphate were changed to reflect to those occurring during heavy exercise. Only perfusion with a solution enriched with lactic acid elicited a significant increase in heart-rate. The response disappeared when the nerve supply to the leg was cooled or sectioned. 20–60 s after the start of perfusion with solution of high [lactic acid] heart-rate began to increase reaching a maximum ( ± SE = 20.2 ± 8.2,n = 7) after about 2 min. The effect on heart-rate increased when the venous concentration of lactic acid was increased the range from 3 to 10 mmol/l. In further experiments, we tried to separate the effects of pH and lactate. Heart-rate responses were induced only at low pH and at low pH the extent to which heart-rate changed increased with increases in lactate concentration.     

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.     

Quantitative expansion of structural genomic alterations in the spectrum of neuroendocrine lung carcinomas

The pathogenesis and interrelationships of neuroendocrine lung carcinomas are not well understood. Tissue macro-arrays prepared from surgical resection specimens from 35 patients with typical carcinoid (TC), six with atypical carcinoid (AC), 13 with large cell neuroendocrine carcinoma (LCNEC), and 15 with small cell lung carcinoma (SCLC) were investigated by fluorescence in situ hybridization (FISH) and immunohistochemistry. Hybridizations with locus-specific DNA probes demonstrated a high incidence of deletion for the tumour suppressor genes p53 and retinoblastoma (Rb), and for the oncogene cyclin D1, comparable in all carcinoma types. Similarly, an increase of DNA copy number for the Her-2/neu and c-myc oncogenes was noted in all neoplasms. A more detailed quantitative analysis of the results, however, demonstrated increasing numbers of cells harbouring these genomic alterations, from low-grade TC to highly malignant SCLC, with the exception of cyclin D1 deletion. Mutations of the p53 and Rb genes, as assayed by immunohistochemical studies, were observed at high incidence in high-grade carcinomas, compared with a low incidence in the low-grade carcinomas. Conversely, in all carcinoma types, neither membrane-bound Her-2/neu nor nuclear cyclin D1 was detected. It is concluded that structural genomic alterations are frequent in neuroendocrine lung carcinomas and that their occurrence may be underestimated by immunohistochemical studies alone. The quantitative expansion of the Rb, p53, c-myc, and Her-2/neu alterations towards high-grade carcinomas suggests common pathogenetic mechanisms in the spectrum of these neoplasms.