T cell response of I-Aq mice to self type II collagen: meshing of the binding motif of the I-Aq molecule with repetitive sequences results in autoreactivity to multiple epitopes

Type II collagen (CII) is of immunological interest because of its repetitive structure and properties as an autoantigen. The mouse gene has recently been cloned, thus enabling T cell-defined epitopes to be identified. Multiple novel epitopes on mouse CII are here detected in the autoreactive T cell response. The major response is directed to an epitope with residues 707-721 located on the CB10 fragment. Some 25 other epitopes are also recognized, including the autologous homologue of the 256-270 epitope which dominates in the response to foreign collagen. The cells reactive with mouse collagen peptides were of Th1 type, as judged by release of IFN-gamma. No significant reactivity was detected to mouse CII peptides during ongoing disease. Alignment of the mouse epitopes revealed a sequence motif with characteristic side chains at residues P1, P4 and P7, and to a lesser extent at P5, within a nonamer core sequence. Binding of these epitopes was simulated in a computer model of the I-Aq molecule, where peptides with anchor residues at P1, P4 and P7 were indeed found to fit the binding groove best. The spacing of pockets and the fine structure of the binding surface of the I-Aq molecule meshes with the repetitive structure of the collagen (X-Y-Gly), thus providing a likely explanation for the occurrence of multiple epitopes. Comparison with human DR binding motifs showed that the I-Aq motif resembles most closely that of the DR4 subtypes which predispose for rheumatoid arthritis.      

Survey of the attitudes of British physicians to pacing.

OBJECTIVES--To assess how the opinions of cardiologists, physicians, and general practitioners on the indications for permanent pacing compare with published guidelines, and to determine whether resources, pacing experience, and position influence referral practices. DESIGN--Anonymous postal survey by questionnaire from St Bartholomew's Hospital, London and the King's Fund Institute, London. The questionnaire established the respondent's position, resources, and previous pacing experience. Eleven clinical and electrocardiographic situations were described and respondents were asked to decide on whether pacing was indicated. The responses received were compared with the guidelines provided by the 1984 American College of Cardiology/American Heart Association task force. PARTICIPANTS--The 630 members of the British Cardiac Society, 1370 randomly selected general physicians, and 2000 general practitioners. RESULTS--Patients with symptoms were more likely to be referred for pacing than symptom free patients regardless of underlying aetiology. In relatively symptom free patients the frequency with which pacing was recommended was low, even when it was unequivocally indicated on prognostic grounds. Failure to recommend pacing was unrelated to diagnostic facilities or referral difficulties. Respondents with pacing experience were more likely to recommend pacing. CONCLUSIONS--The physicians surveyed had a conservative approach towards recommending pacing. Most physicians were influenced predominantly by symptoms and the prognostic indications for pacing were not well appreciated.     

The value of technetium-99M renography for the detection of renal artery stenosis in patients with aortic and lower limb vascular disease.

The results of technetium renography were compared with arteriography to determine whether this is a satisfactory screening test for renal artery stenosis (RAS). Sixty-three patients were studied before aortic surgery. All were investigated by aortography and isotope renography. These tests were assessed blind and all arteriograms were graded by a single independent radiologist. Renal artery stenosis was detected by arteriography in 34 (54%) patients. Twenty-three (37%) had mild (less than 50%) stenosis, seven (11%) had moderate (50-80%) stenosis and four (6%) had severe (greater than 80%) stenosis. Of these 34 patients, only 6 (18%) were correctly diagnosed by isotope renography. None of the four with severe stenosis were identified. Isotope renography resulted in six true positives, six false positives, 23 true negatives and 28 false negatives. It was concluded that isotope renography did not fulfil the criteria for a screening test for the detection of RAS and appeared to be of no value in those patients undergoing aortic surgery in whom arteriography was not indicated.     

The mouse Mid1 gene: implications for the pathogenesis of Opitz syndrome and the evolution of the mammalian pseudoautosomal region

We have recently reported isolation of the gene responsible for X- linked Opitz G/BBB syndrome, a defect of midline development. MID1 is located on the distal short arm of the human X chromosome (Xp22. 3) and encodes a novel member of the B box family of zinc finger proteins. We have now cloned the murine homolog of MID1 and performed preliminary expression studies during development. Mid1 expression in undifferentiated cells in the central nervous, gastrointestinal and urogenital systems suggests that abnormal cell proliferation may underlie the defect in midline development characteristic of Opitz syndrome. We have also found that Mid1 is located within the mouse pseudoautosomal region (PAR) in Mus musculus , while it seems to be X- specific in Mus spretus. Therefore, Mid1 is likely to be a recent acquisition of the M. musculus PAR. Genetic and FISH analyses also demonstrated a high frequency of unequal crossovers in the murine PAR, creating spontaneous deletion/duplication events involving Mid1. These data provide evidence for the first time that genetic instability of the PAR may affect functionally important genes. In addition, we show that MID1 is the first example of a gene subject to X-inactivation in man while escaping it in mouse. These data contribute to a better understanding of the molecular content and evolution of the rodent PAR.      

p53 immunoreactivity in hepatocellular adenoma, focal nodular hyperplasia, cirrhosis and hepatocellular carcinoma

The prolonged half-life of mutant p53 makes feasible its immunocytochemical detection. In order to assess the pathogenetic role of mutant p53 in regenerative and neoplastc liver disease we studied its immunohistochemical expression in cases of hepatic cirrhosis, hepatocellular carcinoma (HCC), cirrhosis with areas of HCC, hepatocellular adenoma and focal nodular hyperplasia. The study included needle and wedge biopsies of 50 cirrhotic livers, 59 HCCs (36 of them with associated cirrhosis), six adenomas and two focal nodular hyperplasias. Sixty-five HCC fineneedle cytology specimens were also included in the study. There was no immunohistochemical evidence of mutant p53 expression in any of the cases of cirrhotic liver (except for one instance associated with HCC) adenoma or focal nodular hyperplasia. In contrast p53 was detected in 8.5% of HCC cases in the biopsy series and 24% of HCC cases in the fine needle aspiration series. In addition, mutant p53 expression in HCC was positively correlated with tumour grade. According to grade, the distribution of p53 positive immunoreactivity among HCCs was as follows: Grade I-II, 0% of cases in the biopsy series and 9% in the fine needle aspirates; Grade III, 18% in the biopsy series and 55% in the fine needle aspirates; and Grade IV, 40% in the biopsy series. Therefore, mutant p53 expression does not seem to be associated with benign liver lesions but seems to correlate with the progression of HCC through various grades of increasing malignancy.     

Effect of metal ions on diphtheria toxin production.

The effect of several metal ions on the production of diphtheria toxin was tested. By using the gel immunodiffusion system for detecting toxin, a wide range of metal ion concentrations was conveniently surveyed. Five divalent cations, Fe2+, Cu2+, Co2+, Ni2+, and Mn2+ inhibited toxin production within a range of concentrations that did not inhibit growth of the producing strain. Growth and toxin production were inhibited at identical concentrations by both Cd2+ and Zn2+, whereas Al3+ and Sr2+ affected neither growth nor toxin production over the range of concentrations tested. The data showed that Fe2+ was the most effective inhibitor on an equivalence basis, followed by Cu2+, Co2+, and Ni2+ in descending order. All eight strains of Corynebacterium diphtheriae chosen from diverse ecological origins responded similarly to all metals at similar concentrations. A mutant strain which produces toxin at Fe2+ concentrations 500 times greater than are inhibitory for the parent strain had simultaneously acquired resistance to inhibitory concentrations of Cu2+, Co2+, Ni2+, and Mn2+. This suggests that there is at least one common point in the activity of all these metal ions, and that toxin may respond broadly to changes in metal ion concentrations in the environment.     

电离辐射对放射工作者职业健康的影响

目的 分析放射工作者外周血象、淋巴细胞微核及染色体畸变情况,为放射工作者职业防护和健康监测提供依据。方法 对2015年、2017年和2019年连续3次接受健康检查的127名放射工作者进行淋巴细胞微核、染色体及血象分析,将其设为放射组。另外选取133名无射线接触史的医务人员设为对照组;结果 放射组中淋巴细胞微核率和染色体畸变率高于对照组,白细胞和血小板计数低于对照组,均具有统计学意义（P < 0.05）。127名放射工作者外周血白细胞总数随着接触电离辐射时间的增长逐渐降低,染色体畸变率逐渐增加,均具有统计学意义（P < 0.05）。损害工龄大于20年的放射工作者染色体畸变率高于低工龄组,不同损害工龄之间比较无统计学意义（P > 0.05）。核医学与介入治疗工种染色体畸变率高于其他工种,具有统计学意义（P < 0.05）。结论 长时间接触低剂量电离辐射可使放射工作者白细胞总数降低和淋巴细胞染色体畸变率增加,应加强放射工作者防护措施以备降低电离辐射损伤程度,特别要加强核医学和介入治疗放射工作人员的职业防护。     

Myocardial dysfunction in the elderly: A form of cardiomyopathy?

Abstracts

Myocardial dysfunction in the elderly: A form of cardiomyopathy?     

Normal development of refractive state and ocular component dimensions in the marmoset (Callithrix jacchus).

Refractive state and ocular dimensions were studied longitudinally in nine normal marmosets. Animals were anaesthetised and examined (with some exceptions) at 4, 6, 7, 8, 10, 15, 24 and 39 weeks of age. Cycloplegic retinoscopy showed that hyperopia early in life rapidly diminished. Refraction corrected for the artefact of retinoscopy stabilised by 8 weeks of age, but at a slightly myopic value, rather than at emmetropia. The ocular components continued to change throughout the period studied. Corneal radius, measured by photokeratometry, increased slightly during development. Anterior segment depth and vitreous chamber depth (VCD), measured by A-scan ultrasonography, increased throughout development while lens thickness initially increased and then decreased. Data from the eyes of these normal animals were compared with that from the contralateral eyes of animals which received short periods of monocular deprivation early in life (Troilo, D., & Judge S.J. (1993). Ocular development and visual deprivation myopia in the common marmoset (Callithrix jacchus jacchus). Vision Research, 33, 1311-24); eyes which viewed through no lens or a plano lens (Graham, B. & Judge, S.J. (1999)). The effects of spectacle wear in infancy on eye growth and refractive error in the marmoset (Callithrix jacchus). Vision Research, 39, 189-206), and eyes of normal animals in another colony. There were no significant differences between the first two groups and the normal animals in our colony while age-matched animals from the other colony were slightly but significantly less myopic than our animals.     

The effects of spectacle wear in infancy on eye growth and refractive error in the marmoset (Callithrix jacchus).

We made a comprehensive study, involving observations on 45 marmosets, of the effects on ocular growth and refraction of wearing spectacles from the ages of 4-8 weeks. This period was within the period early in life when the eye grows rapidly and refraction changes from hyperopia to its adult value of modest myopia. In one series of experiments we studied the effect of lenses of powers -8, -4, +4 and +8D fitted monocularly. In another series of experiments we studied the effect of lenses of equal and opposite powers fitted binocularly, with the two eyes alternately occluded, so as to give an incentive to use both eyes, and in particular to accommodate, for at least part of each day, through the negative lens. The vitreous chamber of eyes that wore negative lenses of -4D or -8D, combined with alternate occlusion, elongated more rapidly than that of the fellow eye (negative lens eye-positive lens eye, 0.21 +/- 0.03 mm (S.E.M.), P < 0.01 and 0.25 +/- 0.06 mm, P < 0.05, respectively) and became relatively more myopic (2.8 +/- 0.26D, P < 0.01 and 2.4 +/- 0.61D, P < 0.05 respectively). Eyes that wore -4D lenses monocularly elongated more rapidly and became myopic than fellow eyes. Eyes that wore +4D or +8D lenses were less strongly affected: animals that wore +8D lenses monocularly (without alternate occlusion) developed a slight relative hyperopia (0.99 +/- 0.21D, P < 0.01), with the more hyperopic eyes also slightly shorter (0.09 +/- 0.05 mm) than their fellow eyes, but eyes wearing +4D lenses were not significantly different from their fellow eyes. Animals that wore -8D lenses monocularly (without alternate occlusion) developed a slight relative hyperopia after three weeks of lens-wear (0.85 +/- 0.26D, P < 0.05). These were the only eyes that responded in a non-compensatory direction to the optical challenge of spectacle wear, and we interpret this effect as one due to visual deprivation. After the removal of lenses, the degree of anisometropia slowly diminished in those groups of animals in which it had been induced, but in the three groups in which the largest effects had been produced by lens-wear the overall mean anisometropia (0.68 +/- 0.24D, P < 0.01) and vitreous chamber depth (VCD) discrepancy (0.09 +/- 0.03 mm, P < 0.01) were still significant at the end of the experiments, when the animals were 273 days old. The reduction of anisometropia in these groups was associated with an increase in the rate of elongation of the vitreous chamber in the eyes that had previously grown normally i.e. the less myopic eyes grew more rapidly than their fellow eyes: in the seven weeks following lens-wear these eyes became more myopic and longer than normal eyes (refraction P < 0.001; VCD P < 0.001). Control experiments showed that occlusion of one eye for 50% of the day had no effect on eye growth and refraction, and therefore that alternate occlusion itself had no effect.