The inability of thyroid allografts to induce self-tolerance of organ-specific antigens in foetal lambs.

Foetal lambs in the eighth week of gestation were submitted to thyroidectomy followed by the immediate implantation of a thyroid allograft from a donor of similar age. Excised thyroid glands were transplanted to nude mice and maintained there for approximately 2 months, after which they were re-implanted in the original donor. Some foetuses also received second allografts of thyroid tissue from the original donors at this time. Several weeks later, foetuses were killed to permit histological examination of the original thyroid allografts and of subsequent autografts and allografts. Examination revealed heavy lymphocytic infiltration, interpreted as autoimmune thyroiditis, in reimplanted autografts. Thyroid allografts which had been transferred in the eighth week occasionally showed limited areas of lymphocytic infiltration but their most notable feature was a highly abnormal follicular morphology. Whilst these primary allografts had not been rejected, second thyroid allografts from the same donors were all rapidly destroyed. The failure of foetal lambs which had experienced thyroidectomy and receipt of a thyroid allograft to acquire self-tolerance to thyroid tissue was attributed to the inadequacy of thyroid-specific antigens to achieve this when presented exclusively on allogeneic thyroid cells.     

High-resolution analysis of genomic alterations and human papillomavirus integration in anal intraepithelial neoplasia

Anal intraepithelial neoplasia (AIN) is the likely precursor to anal cancer. AIN is associated with human papillomavirus (HPV) infection, and HPV-associated genomic instability may play an important role in the progression of squamous intraepithelial neoplasia to cancer. Microarray-based comparative genome hybridization (aCGH) was performed on DNA from AIN specimens to determine the host genomic alterations and their correlation with HPV DNA integration or rearrangement. Of 27 high-grade AIN specimens tested by CGH, 8 (30%) showed regional DNA copy number abnormalities (CNAs). Five additional cases previously identified by chromosome CGH to carry CNAs were reanalyzed by aCGH and pooled with the 8 new cases for analysis. The most common regions of gain were on chromosome arms 1p, 1q, 3q, 8p, and 20q. The most common regions of loss were on chromosome arms 2q, 7q, 11p, 11q, and 15q. HPV16 DNA integration or rearrangement correlated with CNAs in host cell DNA (P = 0.007). Although aCGH can resolve amplicons at the 1- to 2-megabase (Mb) regional resolution, the most common alteration on chromosome 3 could only be resolved to a 75-Mb region from 3q21 to qtel. Our data suggest that there may be several oncogenes in this region that are coactivated to contribute to progression to high-grade AIN.     

The relative contributions of immune system and target organ to variation in susceptibility of rats to experimental allergic thyroiditis

Previous investigations of the cellular basis of genetic susceptibility to experimental allergic thyroiditis (EAT) in semi-allogeneic mice bearing thyroid grafts from resistant, parental strain donors have indicated that these grafts remain relatively resistant to EAT when this is induced in the susceptible bearer. It was concluded that genetic control of susceptibility to EAT is expressed in both the immune system and the thyroid gland. Our experiments in which thyroid grafts were transferred to fully allogeneic, but immunologically tolerant, recipient rats indicate that thyroid tissue from an EAT-resistant strain of rat becomes entirely susceptible when transplanted into a susceptible host. The differing susceptibility of thyroid grafts in semi-allogeneic and tolerant allogeneic hosts may result from restrictions on interaction between host lymphocytes and the graft in the former situation. The present findings call into serious doubt the proposition that genetically determined resistance to EAT is mediated, to any extent, at the level of the target organ.     

Repair of cartilaginous fractures during chick limb development.

The embryonic chick wing has been used extensively in experimental analyses of the mechanisms involved in limb development. This study employs the embryonic wing in an examination of the possible origin of congenital pseudoarthrosis, a poorly understood limb disorder. To this end, chick radii were fractured in the middiaphysis prior to the onset of osteogenesis (6.5-7 days of incubation). The subsequent development of the fractured elements was examined using both whole mount preparations and histology. Callus cartilage did not form around any of the fractures. Nonetheless, the majority (29 of 33 specimens) of fractures united during primary osteogenesis (within 24-36 h of the operation), with bone formation occurring both across the fracture site and also over the cut ends of the cartilage. In addition, bones that exhibited a configuration similar to that described as giving rise to a type II congenital pseudoarthrotic condition were obtained. Typically, these bones showed an "hourglass" constriction midshaft and anterior bowing. These results suggest that the embryonic chick limb may serve as a useful experimental model system for the investigation of this congenital limb disorder.     

Median nerve compression in Proteus syndrome

Proteus syndrome is a multi–organ disorder, a prime feature of which is localized gigantism, usually clinically obvious. Symptoms secondary to hypertrophy of nerves has not been previously recognized as a part of the syndrome. Accepted: 16 May 1997     

TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons

Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-α/β induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-β protein, and thereby also controls constitutive mRNA levels for IFN-stimulated genes (ISGs) in fibroblasts. Tlr3^–/– mouse embryonic fibroblasts also have lower basal ISG levels. Moreover, human TLR3 controls basal levels of IFN-β secretion and ISG mRNA in induced pluripotent stem cell–derived cortical neurons. Consistently, TLR3-deficient human fibroblasts and cortical neurons are vulnerable not only to both VSV and HSV-1, but also to several other families of viruses. The mechanism by which TLR3 restricts viral growth in human fibroblasts and cortical neurons in vitro and, by inference, by which the human CNS prevents infection by HSV-1 in vivo, is therefore based on the control of early viral infection by basal IFN-β immunity.     

Role of the ATP-binding cassette transporter Abcg2 in the phenotype and function of cardiac side population cells

Recently, the side population (SP) phenotype has been introduced as a reliable marker to identify subpopulations of cells with stem/progenitor cell properties in various tissues. We and others have identified SP cells from postmitotic tissues, including adult myocardium, in which they have been suggested to contribute to cellular regeneration following injury. SP cells are identified and characterized by a unique efflux of Hoechst 33342 dye. Abcg2 belongs to the ATP-binding cassette (ABC) transporter superfamily and constitutes the molecular basis for the dye efflux, hence the SP phenotype, in hematopoietic stem cells. Although Abcg2 is also expressed in cardiac SP (cSP) cells, its role in regulating the SP phenotype and function of cSP cells is unknown. Herein, we demonstrate that regulation of the SP phenotype in cSP cells occurs in a dynamic, age-dependent fashion, with Abcg2 as the molecular determinant of the cSP phenotype in the neonatal heart and another ABC transporter, Mdr1, as the main contributor to the SP phenotype in the adult heart. Using loss- and gain-of-function experiments, we find that Abcg2 tightly regulates cell fate and function. Adult cSP cells isolated from mice with genetic ablation of Abcg2 exhibit blunted proliferation capacity and augmented cell death. Conversely, overexpression of Abcg2 is sufficient to enhance cell proliferation, although with a limitation of cardiomyogenic differentiation. In summary, for the first time, we reveal a functional role for Abcg2 in modulating the proliferation, differentiation, and survival of adult cSP cells that goes beyond its distinct role in Hoechst dye efflux.     

Investigating the ‘placebo personality’ outside the pain paradigm

Aim

To identify personality traits related to placebo responding outside the context of pain.

Methods

Sixty three healthy volunteers completed the study. Personality traits were measured online one week prior to a laboratory session in which two psychosocial stress tests were administered. Prior to the second test, the placebo group received an intranasal spray of ‘serotonin’ (placebo) with the suggestion that it would enhance recovery. Subjective stress, heart rate and heart rate variability were measured. Self reported and physiological responses to the placebo suggestion were assessed against personality variables.

Results

Placebo effects were demonstrated in both self reported and physiological stress metrics. Lower optimism and less empathic concern predicted greater perceived benefits from the placebo treatment; and lower drive, fun, and sensation seeking were related to a greater physiological response to the manipulation. Multivariate analyses revealed lower optimism and behavioural drive to be predictive of responding to the placebo manipulation.

Conclusion

Findings are in contrast with prior work in pain paradigms which found higher levels of the same traits to be related to greater placebo analgesic responses. A cluster of traits characterised by behavioural drive, extraversion, optimism and novelty or fun seeking appears to be germane to placebo responsiveness, but contextual stimuli may generate different patterns of responding. A new conceptualisation of placebo responsiveness may be useful. Rather than a ‘placebo personality’ it may be that responsiveness is better typified by a two faceted transactional model, in which different personality facets respond to different contextual contingencies.