An experimental model of autoimmune pancreatitis in the rat

Autoimmune pancreatitis (AIP), a recently defined disease of unknown etiology, is characterized by inflammatory infiltrates in the pancreas with conspicuous involvement of the ducts. The disease clinically manifests in humans as epigastric pain, weight loss, and jaundice. This report describes the development of a novel animal model of this disease in the rat, which we have termed experimental autoimmune pancreatitis. Adoptive transfer of amylase-specific CD4(+) T cells was able to confer pancreatitis to naive syngeneic recipient animals. No treatments before the adoptive transfer of T cells were necessary for disease to ensue, and the severity of disease was proportional to the number of T cells administered. The pancreatic lesions of rats with experimental autoimmune pancreatitis were characterized histologically as overwhelmingly lymphocytic with occasional plasma cells, neutrophils, and mast cells. Acinar tissue destruction and ductular inflammation were common features, with less frequent involvement of larger ducts. Immunohistochemical analysis revealed the presence of CD4(+) T cells in large numbers as well as CD8(+) T cells, macrophages, and dendritic cells. Expression of MHC I and MHC II also increased at the site of the lesion. Clinically, the disease manifested as either failure to gain weight at a rate concomitant with control animals or as outright weight loss. Thus, administration of activated CD4(+) T cells specific for the pancreatic enzyme amylase can induce pancreatitis in the rat in a manner that is reminiscent of human AIP.     

Expression of fragile X chromosome in human-rodent somatic cell hybrids

The fragile X chromosome, associated with a common form of X-linked mental retardation, is cytologically observed most often as a gap or fragile site near the distal end of the long arm in band Xq28. Expression of this site is variable and dependent upon lowered thymidylate pools. In order to examine the behavior of this fragile site in a foreign genetic background, interspecific somatic cell hybrids were isolated from crosses of hamster cells and lymphoblastoid cells derived from male patients with fragile X-linked mental retardation. Three hybrid cell lines containing the human X chromosome were analyzed. Following induction with 5-fluorodeoxyuridine, all three hybrids expressed the fragile site in approximately 10% of the metaphases examined. Our data indicate that expression of the fragile site in band Xq27 is dependent neither on the integrity of the human genome nor on the expression of human autosomal genes.     

Age-related changes in smooth pursuit initiation

Quantitative analysis of eye movements is a useful tool for examining the behavioural effects of ageing. Although the effect of ageing on saccadic eye movement has been examined in some detail, the effect of ageing on a second class of eye movement, smooth pursuit (SP), has received less attention. We examined the initiation of SP in a group of fifteen healthy older people (mean age 72 years) and compared their performance with that of ten young controls (mean age 21 years). Although their performance was qualitatively similar, pursuit latency was increased in the older group. Investigation of the gap effect on pursuit revealed that, while the gap effect was present in the older group, it seemed to be directionally asymmetrical. When the longer absolute latencies were taken into account, although the gap effect in the two groups was identical for leftward tasks, for rightward tasks it was reduced in the older group, although this did not reach statistical significance. The difference between the old and young groups was driven by some of the older subjects. At the longest gap duration employed (400 ms), while there was a clear gap effect for leftward tasks in these subjects, there was no reduction in latency, or increases in latency, for rightward tasks. This asymmetry was not related to chronological age within the older group. These results suggest an age-related alteration in SP initiation that is more complex than general slowing of information processing in ageing. They may be indicative of additional ageing effects specific to the oculomotor or closely related systems.     

Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses

Five TLRs are thought to play an important role in antiviral immunity, sensing viral products and inducing IFN-alpha/beta and -lambda. Surprisingly, patients with a defect of IRAK-4, a critical kinase downstream from TLRs, are resistant to common viruses. We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. In contrast, IFN-alpha/beta and -lambda were induced normally by TLR-3 and TLR-4 agonists. Moreover, IFN-beta and -lambda were normally induced by TLR-3 agonists and viruses in IRAK-4-deficient fibroblasts. We further show that IFN-alpha/beta and -lambda production in response to 9 of 11 viruses tested was normal or weakly affected in IRAK-4-deficient blood cells. Thus, IRAK-4-deficient patients may control viral infections by TLR-3- and TLR-4-dependent and/or TLR-independent production of IFNs. The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent and paradoxically redundant for protective immunity to most viruses in humans.     

The effect of HIPing on the fatigue and tensile strength of a case, porous-coated Co-Cr-Mo alloy

The process required to sinter porous Co-Cr-Mo alloys results in the formation of substrate porosity through carbide dissolution. Since hot isostatic pressing (HIPing) has been shown to eliminate casting porosity in the Co-Cr-Mo alloy, it is possible that it may be equally effective on pores that are generated from the sintering operation. The effect that HIPing a porous-coated Co-Cr-Mo material has on the fatigue and tensile properties was investigated. Fatigue testing was performed on sintered materials as well as sintered and HIPed materials, both with and without a porous coating. Further, the effect of varying coating thickness on the resulting fatigue strength of sintered and HIPed materials was studied. Light microscopy was performed in order to define the microstructural changes brought about by the various thermal cycles. Scanning electron microscopy was utilized to define the crack initiation process. The fatigue strength of uncoated "as sintered" materials was found to be reduced by 34% relative to the "as cast" condition. The same material that was HIPed revealed a fatigue strength slightly lower than the "as cast" condition. It was found that porous coatings created preferential sites for fatigue crack initiation. However, the presence of the coating did not further reduce the fatigue strength of "as sintered" materials because of the already low strength created by the sintering operation. Materials that were sintered exhibited a lowering in both tensile strength and elongation to failure relative to the "as cast" condition. The HIPing of sintered materials improved both fatigue and tensile properties relative to the "as sintered" condition.     

Mouse homologues of the human AZF candidate gene RBM are expressed in spermatogonia and spermatids, and map to a Y chromosome deletion interval associated with a high incidence of sperm abnormalities

An RNA-binding motif (RBM) gene family has been identified on the human Y chromosome that maps to the same deletion interval as the 'azoospermia factor' (AZF). We have identified the homologous gene family (Rbm) on the mouse Y with a view to investigating the proposal that this gene family plays a role in spermatogenesis. At least 25 and probably >50 copies of Rbm are present on the mouse Y chromosome short arm located between Sry and the centromere. As in the human, a role in spermatogenesis is indicated by a germ cell-specific pattern of expression in the testis, but there are distinct differences in the pattern of expression between the two species. Mice carrying the deletion Yd1, that maps to the proximal Y short arm, are female due to a position effect resulting in non-expression of Sry ; sex-reversing such mice with an Sry transgene produces males with a high incidence of abnormal sperm, making this the third deletion interval on the mouse Y that affects some aspect of spermatogenesis. Most of the copies of Rbm map to this deletion interval, and the Yd1males have markedly reduced Rbm expression, suggesting that RBM deficiency may be responsible for, or contribute to, the abnormal sperm development. In man, deletion of the functional copies of RBM is associated with meiotic arrest rather than sperm anomalies; however, the different effects of deletion are consistent with the differences in expression between the two species.      

Antibodies to maize in patients with Crohn''s disease, ulcerative colitis and coeliac disease.

The incidence of antibodies to maize using an immunofluorescent technique has been found to be 14% in controls, 33% in Crohn's disease, 50% in ulcerative colitis and 44% in coeliac disease. This result indicates that humoral immunity to maize is probably unimportant in the pathogenesis of Crohn's disease. The similar incidence of antibodies in the inflammatory bowel disease and coeliac groups suggests absorption of dietary antigen secondary to an increased mucosal permeability.