Age-related differences in novelty and target processing among cognitively high performing adults

Previous research on age-related changes in ERP components in response to novel and target stimuli has not carefully controlled for differences in level of cognitive status between age groups, which may have contributed to the common findings of increased P3 latency, decreased P3 amplitude, and altered P3 scalp distribution. Here, cognitively high-performing (top third based on published norms) old, middle-aged, and young adults matched for IQ, education, and gender participated in a novelty oddball paradigm. There were no age-associated differences in P3 latency. Older adults had a larger, more anteriorly distributed P3 amplitude to all stimulus types, even repetitive standards, suggesting they may rely on increased resources and effortful frontal activity to successfully process any kind of visual stimulus. However, after controlling for this non-specific age-related processing difference, the amplitude and scalp distribution of the P3 component to novel and target stimuli were comparable across age groups, indicating that for cognitively high functioning elders there may be no age-related differences specific to the processing of novel and target events as indexed by the P3 component.     

A-raf oncogene localizes on mouse X chromosome to region some 10–17 centimorgans proximal to hypoxanthine phosphoribosyltransferase gene

The localization of the A-rafcellular oncogene on the mouse X chromosome has been determined using Xbal-restricted DNAs prepared from progeny of an interspecies backcross between the B6.CBA.R1 and the Spe/Pas mouse strains. This localization to the proximal part of the mouse X chromosome has been confirmed by the use of somatic cell hybrids, carrying partially deleted X chromosomes and suggests that the A-raf oncogene localizes to a region lying some 10–17 centimorgans proximal to the hypoxanthine phosphoribosyltransferase (Hprt) gene between the locus DXPas4and the locus DXPas7defined by the cross-reacting human X chromosome-specific probe DXS32 (M2C). This localization on the mouse X chromosome is compatible with the presence of the A-rafoncogene on the short arm of the human X chromosome between the centromere and Xp21.     

Exosomes bearing HLA-DR1 molecules need dendritic cells to efficiently stimulate specific T cells

Exosomes are small vesicles (60-100 nm) secreted by various cell types upon the fusion of endosomal compartments with the plasma membrane. Exosomes from antigen-presenting cells (APC), such as B lymphocytes and dendritic cells (DC), bear MHC class II molecules. In addition, the injection of DC-derived exosomes was reported to elicit potent T cell responses in vivo. Here, we analyzed the activation of specific T cells by MHC class II-bearing exosomes in vitro. The rat mast cell line, RBL-2H3, was engineered to express human class II molecules uniformly loaded with an antigenic peptide [HLA-DR1-hemagglutinin (HA)]. These cells secreted exosomes bearing DR1 class II molecules upon stimulation by a calcium ionophore or IgE receptor cross-linking. Exosomes bearing DR1-HA(306-318) complexes activated HA/DR1-specific T cells only weakly, whereas the cross-linking of such exosomes to latex beads increased stimulation of specific T cells. By contrast, the incubation of free exosomes with DC resulted in the highly efficient stimulation of specific T cells. Thus, exosomes bearing MHC class II complexes must be taken up by professional APC for efficient T cell activation.     

Regional Administration of Recombinant Tumour Necrosis Factor-α in Cancer, with Special Reference to Melanoma

Recombinant tumour necrosis factor-alpha (rTNFalpha) possesses the unique property of activating and selectively destroying the tumour-associated microvasculature. Systemic application of rTNFalpha has shown that the maximum tolerated dose (MTD) is 10 times lower than the efficient dose in animals. The main toxicity corresponds to the systemic inflammatory response syndrome (SIRS), with a decrease of vascular resistance and hypotension. We found that it is possible to administer rTNFalpha at 10 times the MTD in an isolated limb perfusion system, using a heart-lung machine, for advanced melanoma and sarcoma of the limbs. Our results, using the combination of high dose rTNFalpha, interferon-gamma and melphalan (TIM), produced an overall objective response rate of 100% in 2 successive studies on melanoma, with 90% and 78% complete response, respectively. In sarcoma, there was an overall response rate of 64%, with 36% complete response. Angiographic and immunohistological studies demonstrated selective and early damage of the tumour-associated microvasculature, preceded by upregulation of adhesion molecules and intratumoural leak of von Willebrand factor. Tumour invasion by platelets and, in some cases, by polymorphonuclear cells, appeared within hours after the application of rTNFalpha, long before the lysis of the tumour. Systemic changes after rTNFalpha treatment included the production of soluble TNFalpha receptors and of interleukin-6. A typical acute phase reaction was observed within 3 days, with increase of C-reactive protein parallelled by an increase of tenascin-C. A selective effect on intratumoural endothelial cells seems to be involved in the mechanism of the impressive antitumour effect of rTNFalpha, but the role of acute phase protein production is not fully understood. In selected cases of melanoma, specific cytotoxic T lymphocytes were increased after perfusion.     

The response of NG2-expressing oligodendrocyte progenitors to demyelination in MOG-EAE and MS

Remyelination of primary demyelinated lesions is a common feature of experimental models of multiple sclerosis (MS) and is also suggested to be the normal response to demyelination during the early stages of MS itself. Many lines of evidence have shown that remyelination is preceded by the division of endogenous oligodendrocyte precursor cells (OPCs) in the lesion and its borders. It is suggested that this rapid response of OPCs to repopulate the lesion site and their subsequent differentiation into new oligodendrocytes is the key to the rapid remyelination. Antibodies to the NG2 chondroitin sulphate proteoglycan have proved exceedingly useful in following and quantitating the response of endogenous OPCs to demyelination. Here we review the literature on the response of NG2-expressing OPCs to demyelination and provide some new evidence on their response to the chronic inflammatory demyelinating environment seen in recombinant myelin oligodendrocyte glycoprotein (MOG) induced experimental allergic encephalomyelitis (EAE) in the DA rat. NG2-expressing OPCs responded to the inflammatory demyelination in this model by becoming reactive and increasing in number in a very focal manner. Evidence of NG2⁺OPCs in lesioned areas beginning to express the oligodendrocyte marker CNP was also seen. The response of OPCs appeared to occur following successive relapses but did not always lead to remyelination, with areas of chronic demyelination observed in the spinal cord. The presence of OPCs in the adult human CNS is clearly of vital importance for repair in multiple sclerosis (MS). As in rat tissue, the antibody labels an evenly distributed cell population present in both white and grey matter, distinct from HLA-DR⁺microglia. NG2⁺cells are sparsely distributed in the centre of chronic MS lesions. These cells apparently survive demyelination and exhibit a multi-processed or bipolar morphology in the very hypocellular environment of the lesion.     

A locus for Bowen-Conradi syndrome maps to chromosome region 12p13.3

Bowen-Conradi syndrome (BCS) is a lethal autosomal recessive disorder with an estimated incidence of 1 in 355 live births in the Hutterite population. A few cases have been reported in other populations. Here, we report the results of a genome-wide scan and fine mapping of the BCS locus in Hutterite families. By linkage and haplotype analysis the BCS locus was mapped to a 3.5 cM segment (1.9 Mbp) in chromosome region 12p13.3 bounded by F8VWF and D12S397. When genealogical relationships among the families were taken into account in the linkage analysis, the evidence for linkage was stronger and the number of potentially linked regions was reduced to one. Under the assumption that all the Hutterite patients were identical by descent for a disease-causing mutation, haplotype analysis was used to infer likely historical recombinants and thereby narrow the candidate region to a chromosomal segment shared in common by all the affected children. This study also demonstrates that BCS and cerebro-oculo-facial-skeletal syndrome (COFS) are genetically distinct.