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(2004). Primary carcinoid tumours of the ovary. Journal of Obstetrics and Gynaecology: Vol. 24, No. 1, pp. 99-101.

When immunological tolerance breaks down, autoimmune destruction of insulin-producing beta cells in the pancreas can cause insulin-dependent diabetes mellitus. We previously showed that transgenic nonobese diabetic (NOD) mice expressing IL-4 in the pancreas (NOD-IL-4 mice) were protected from insulitis and diabetes. Here we have characterized the avoidance of pathological autoimmunity in these mice. The absence of disease did not result from a lack of T cell priming, because T cells responding to dominant islet Ags were present. These islet Ag-specific T cells displayed a Th2 phenotype, indicating that Th2 responses could account for the observed tolerance. Interestingly, islet Ag-specific Th1 T cells were present and found to be functional, because neutralization of the Th2 effector cytokines IL-4 and IL-10 resulted in diabetes. Histological examination revealed that NOD-IL-4 splenocytes inhibited diabetogenic T cells in cotransfer experiments by limiting insulitis and delaying diabetes. Neutralization of IL-4 in this system abrogated the ability of NOD-IL-4 splenocytes to delay the onset of diabetes. These results indicate that IL-4 expressed in the islets does not prevent the generation of pathogenic islet responses but induces islet Ag-specific Th2 T cells that block the action of diabetogenic T cells in the pancreas.

The role of the cytokine, interleukin (IL)-4, in allograft rejection and protection is not clear. We have previously shown that IL-4 transgenically expressed in a pancreas allograft does not protect the allograft from rejection. Here, we analyze the effect of the transgenically expressed IL-4 on the cytokine profile of the allograft-specific immune response.C57BL/6SCID mice were infused with small numbers of spleen cells from C57BL/6 donors. The former received pancreas grafts from 1- to 2-day-old BALB/c donors which did or did not transgenically express IL-4 in the graft. Three weeks after the cell infusion, the spleens were removed and the splenocytes were restimulated in vitro with BALB/c APC, and third party BALB.K APC. IL-2 and IL-4 levels in the culture supernatants were measured.The presence of a pancreatic allograft induced an increase in the levels of both IL-2 and IL-4 in culture supernatants from splenocytes of mice receiving grafts compared with mice not receiving grafts. The presence of IL-4 transgenically expressed in the pancreas allograft had no effect on the in vitro cytokine profile.from these results we conclude that the failure of transgenically expressed IL-4 to protect the allograft was not associated with up-regulation of a graft antigen-specific IL-4 response.

The 4th year of the Avon breast screening programme comprises two distinct groups: those called for screening for the first time (prevalent group) and those who were initially screened 3 years earlier (incident group). The cancer detection rate, stage of disease and rate of interval cancers in these patients have been compared. For the prevalent groups of year 1 and year 4 there was no statistically significant difference in the cancer detection rate, proportion of small tumours or node positivity. For the prevalent and incident groups of year 4, there was no statistically significant difference in the cancer detection rate or proportion of small tumours. There were significantly fewer node-positive tumours in the incident group (5/45 vs 8/23; P < 0.05). Fifty-six interval cancers presented in the 3-year period between years 1 and 4 of screening; 28 (50%) after 24 months. The screening programme may result in tumours being detected at an earlier stage, but this may be offset by the high rate of interval cancers. This suggests that the time between screens may need to be reduced to 2 years.

We have reproducibly induced specific tolerance to multiple minor histocompatibility antigens with nondepleting anti-CD4 and -CD8 monoclonal antibodies. The tolerance induced is effective for the lifetime of the host. We have tested this therapy in a number of mouse strain combinations to further understand the mechanisms.Various mouse strains were grafted with allogeneic tail skin with and without nondepleting CD4- and CD8-specific monoclonal antibody therapy. The grafts were monitored daily for signs of rejection.Whereas the CBA/Ca (H2k) strain can be made tolerant to skin grafts that are mismatched at multiple minor histocompatibility antigens indefinitely, using the same protocol, long-term survival of similarly mismatched grafts on the HW80 (B6 congenic for BALB H1) mouse strain is limited to around 8 weeks. Interestingly, the B10.BR strain, which is also of the H2k haplotype, is also not readily tolerized. In addition, an F1 between the CBA/Ca and the resistant B10.BR strains is B10.BR-like in its susceptibility to tolerance induction. Susceptibility to such antibody-dependent tolerance induction is not related to immunogenicity because grafts mismatched at only a single minor antigen also do not reproducibly survive beyond 8 weeks when grafted onto HW80 mice in the presence of the antibody therapy.The data strongly suggest that the B6/B10 genetic background confers a level of resistance to CD4- and CD8-specific monoclonal antibody-dependent tolerance induction.

Tissue slices (500 to 1000 microns thick) of archival formalin-fixed, paraffin-embedded breast tissue were immunostained by a cytokeratin antibody (MNF116) using a streptavidin-biotin complex procedure. The technique requires prolonged exposure of tissue slices to the reagents. Use of the detergent Triton X-100 facilitated penetration of high molecular weight reagents through the tissue slices. Fifty of 58 slices 500 microns thick (86%) showed good to excellent immunostaining, and 13 of 20 slices 1000 microns thick (65%) showed similar staining. Omission of the primary antibody eliminated any immunostaining. Comparison with corresponding Haematoxylin staining of the thick slices (the conventional procedure for such breast tissue slices) showed that thick-slice cytokeratin immunostaining markedly improved visualization of the epithelial structure in normal lobules and invasive carcinomas. Although the immunohistochemical technique takes 33 days for completion, the quality of the epithelial images outweighs this disadvantage.

There is controversy as to the value of the radiological or pathological estimation of surgical clearance of microcalcifying breast lesions. An important part of this issue has been addressed by coordinated three-dimensional radiographic and histological examination of a prospective consecutive series of 40 benign and malignant mammographically detected lesions in surgical breast biopsy specimens containing microcalcifications, including 20 cases of ductal carcinoma in situ. They were radiographed from four viewpoints by means of rotation in a radiolucent tetrahedral container. The planes of histological examination were then chosen to correspond to the radiographic view showing the minimum separation of the edge of the specimen and the outermost microcalcification. There was a close correlation (Spearman ranked) between the least tetrahedral radiographic distance and the corresponding histological distance separating the surgical margin of excision. There were, however, incompatible Wilcoxon signed ranking orders when comparing the least tetrahedral distance or the histological distance with all four single radiographic views, including the conventional specimen radiographic view. Two-dimensional specimen mammography and standardized histological examination are suboptimal and may thus have contributed to confusion as to the value of determining adequate surgical excision of ductal carcinoma in situ of the breast. Although labour-intensive, use of four-view radiography and choice of the appropriate plane of histological examination give a better correlation of the radiographic estimates of surgical clearance with histology than single-view specimen radiography and arbitrary histological sectioning.

A 780 nm stage-scanned confocal transmission microscope using compact disk (CD) player optics has been constructed and used to study test objects (including scattering effects) and breast tissue specimens (25-1500 micrometer thick). Confocal alignment in transmission is achieved using the CD optical mechanism moving coils to scan the objective lens until intensity peaks; the specimen is present but motionless. Intensity variation as a 3D function of mis- alignment of the two foci may allow estimation of optic deterioration caused by the specimen; appropriate confocal apertures and sample spacings can then be selected. Experimental measurements have been supplemented by 2D Monte-Carlo modeling of photon transport for a scattering- limited confocal transmission system. Modeling has characterized: transmission as a function of focal depth in a slab; contrast produced by a range of embedded spherical target radii; and optical mis-alignment. Poor dye perfusion within thick stained specimens results in little visible internal structure. This may be improved using partially phase dependent imaging (approximately equal to split- detector), sensitive to specimen refractive index variations.© (1997) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

European statesmen of the second half of the seventeenth century conducted their relationships with one another in an ever-changing and uncertain environment. The ‘turning points’ and ‘trends’ so often identified by modern historians were often difficult or impossible to detect at the time. Rumours based on inadequate or obsolete information could alter perceptions of other states’ actions; unexpected births, marriages, deaths or political upheavals could transform a state’s attitudes towards the European scene, or other states’ attitudes towards it. In these circumstances, it was difficult for any state or monarch to construct a long-term foreign policy based on fixed principles. These considerations affected Restoration Britain to a particularly marked extent. The Restoration itself, so rapid and unexpected from the viewpoints of almost all the courts of Europe, seemed to be further proof of the chronic political instability which had blighted the British kingdoms since 1640, and it immediately raised the question of the nature of the foreign policy which the new regime might pursue. The record of successive governments since the 1620s seemed to offer few clues. Over those four decades, British involvement in European politics had alternated between essentially isolationist (intentionally so in the 1630s, enforced in the 1640s) and erratically interventionist — disastrously so in the 1620s under James I and the Duke of Buckingham, but with dramatic effect in the 1650s, when the governments of the Commonwealth and Protectorate had aggressively deployed naval and land forces in a manner which both scared and impressed many European governments.

The induction of tolerance in a primed immune system would be valuable therapeutically, but has been difficult to achieve. Mice primed to multiple minor histoincompatible antigens (minors) are able to rapidly reject secondary grafts using either their CD4+ or CD8+ T-cell subpopulations. Short courses of treatment with nonlytic anti-CD4 and anti-CD8 antibodies targeted at both T-cell subsets can induce long-term peripheral T-cell tolerance in primed mice. We examine the mechanisms by which peripheral tolerance is maintained, and show that tolerant mice harbor CD4+ T cells capable of specifically suppressing rejection mediated by either subset of primed T cells. Remarkably, elimination of CD4+ T cells from tolerant mice resulted in graft rejection, suggesting that graft-reactive CD8+ T cells had not been eliminated, but had been under continuous regulation by "tolerant" CD4+ T cells. This result demonstrates that it may be possible to establish therapeutic operational tolerance without permanently inactivating all antigen-reactive cells.

An encounter of the mature immune system with Ag usually leads to an immune response. If Ag is administered with CD4- and CD8-specific mAbs, the outcome of the response can be tolerance. This form of tolerance is peripheral, Ag specific, and maintained lifelong, and is associated with the suppression of nontolerant cells by CD4 cells of the tolerant host. Here we demonstrate that the degree of suppression is dependent on the number of suppressor cells. A neutralizing anti-IL-4 Ab was partially able to inhibit suppression, indicating a role for IL-4 in the regulation of Th1 rejection responses.

Allogeneic tissues transplanted to mice treated with CD4- and CD8-specific Abs are often accepted indefinitely due to the induction of immunologic tolerance. When transplantation tolerance was induced to grafts mismatched at multiple minor histocompatibility loci, Ag specificity was inferred because third party grafts, mismatched at the MHC, were rejected normally. However, some "third party" grafts were either accepted, or rejected more slowly. Tolerant mice possess CD4+ cells, which suppress rejection by T cells reacting to the same grafts. Therefore, we hypothesized that tolerated third party grafts might share Ags with the original tolerizing graft, and that these Ags are a target for such suppression. To test this idea, we tolerized mice to a set of minor Ags (B10 minors) and challenged them with third party grafts that carried those minors, as well as an additional strong transplantation Ag, the class I MHC molecule, H-2Kb. This class I molecule acts as a good target for rejection in both naive mice and in mice tolerized to B10 minors. However, when this third party class I molecule is provided "linked" to those B10 minors on an F1 graft, rejection was significantly impaired. The data suggest that suppression within tolerant animals operates locally (perhaps on the same APC) via linked recognition. In addition, our preliminary findings suggest that suppression via linked recognition can also lead to tolerance to the third party Ag.

Collagenous spherulosis is characterised histologically by the accumulation of hyaline globules containing basement membrane components. Originally described in the breast, it has also been found in skin and salivary gland neoplasms. In the breast it has hitherto always been associated with benign disease and reports have asserted that this is invariably the case, cautioning against the diagnosis of malignancy when the condition is seen. We present here five cases with similar appearances to collagenous spherulosis in routine histology and immunohistochemistry, and ultrastructural studies in one of them, in which the condition was not associated with simple benign breast disease. Two of the cases were associated with invasive carcinomas of unusual histological types, one with intracystic papillary carcinoma, one with comedo ductal carcinoma-in-situ and one with atypical ductal hyperplasia. We suggest that appearances similar to collagenous spherulosis can be associated, either through being formed by a lesion or by collision, with malignancy and warn that on encountering the lesions the pathologist must not assume, as suggested in previous accounts, that it denotes a benign process. This is an important observation since collagenous spherulosis is likely to be encountered more frequently in the range of lesions biopsied in national breast screening programs.

The aim of the scheme was to determine consistency of histopathological reporting in the United Kingdom National Breast Screening Programme. This external quality assessment scheme involved 51 sets of 12 slides which were circulated to 186-251 pathologists at intervals of 6 months for 3 years. Participants recorded their diagnoses on standard reporting forms, which were submitted to the U.K. National Cancer Screening Evaluation Unit for analysis. A high level of consistency was achieved in diagnosing major categories of breast disease including invasive carcinoma and the important borderline lesions, radial scar and ductal carcinoma in situ (DCIS), the latter exceeding a national target set prior to the onset of the scheme. Atypical hyperplasia (AH) was reported with much less consistency although, where it was the majority opinion, over 86% of diagnoses were of benign disorders and only 14% were of DCIS. Inconsistency was encountered in subtyping and measuring DCIS, the former apparently due to current uncertainties about classification and the latter to poor circumscription, variation in size in different sections and merging with zones of AH. Reporting prognostic features of invasive carcinomas was variable. Measurement of size was achieved with adequate consistency except in a small number of very poorly circumscribed tumours. Grading and subtyping were inconsistent although the latter was not specifically tested and will be the subject of future study. Members of the National Coordinating Group achieved greater uniformity than the remainder of the participants in all diagnostic categories, but both groups experienced similar types of problem. Our findings suggest that participation in the scheme improves diagnostic consistency. In conclusion, consistency in diagnosing invasive carcinoma and radial scar is excellent, and good in DCIS, but improvements are desirable in diagnosing atypical hyperplasia, classifying DCIS and reporting certain prognostic features of invasive tumours. Such improvements will require further research, the development of improved diagnostic criteria and the dissemination of clearer guidelines.

In the first year of screening in Avon, 93 malignant lesions were detected of which one-half were impalpable. Of the impalpable lesions, one-half were in situ or showed areas of microinvasion only. One-fifth of the malignant lesions were invasive tumours of special histological type which are known to carry a good prognosis even when not detected by screening. One-quarter of the lesions had clinical or pathological features which would be expected to confer a poor prognosis. Only 16 invasive ductal carcinomas measuring 1 cm or less in diameter were detected--a small proportion of the total number of malignant lesions. Although these early figures suggest that the effect of screening on mortality from breast cancer may be small, continued high-quality screening and careful detailed analysis are essential to determine the effect of screening on the mortality from breast cancer and the effect on the population as a whole.

Traditionally India ink has been used to mark surgical resection margins, more recently with acetone to aid drying. Alternative methods have been suggested in recent months, including solutions of alcian blue, and Tippex. These methods use one colour only and Tippex is radiodense. Artists' pigments have been used, but their radiodensity makes them unsuitable for the detailed mammograms of the sliced screened specimens. An alternative method was specifically designed for impalpable breast lesions. It is based on coloured gelatins that are painted on to the biopsy specimen before dissection. The markers are radiolucent, quick to set, and do not penetrate the connective tissue. They can be applied to both fresh and fixed tissues, and the cost is about 0.05 pounds a specimen. The system is also suitable for marking other large specimens.

The different types of surgical breast specimens encountered by the pathologist are described. The macroscopic examination and blocking procedure are reviewed, including some recommendations based on the personal experience of the two authors.

At the Rutherford Appleton Laboratory near Oxford a synchrotron provides 750 MeV protons to generate neutrons by spallation and fast fission at a uranium target. The protons are pulsed at 50 Hz so that neutron energies can be determined by ‘Time-of-flight’ along the many neutron beams. A μ/u test beam of reasonable duty cycle is obtained off a target, inside the accelerator, vibrating at 50 Hz into protons having incorrect orbits to be extracted. Pulsed neutrinos from the uranium target are investigated with a large liquid scintillator detector — KARMEN. Finally a thin transmission target in the extracted proton beam provides surface/cloud muons.

Alternative titles for this paper could be ‘What the Newspapers Say’ or ‘Has Cold Fusion always been Hot — the Importance and Dangers of Tritium’. It is based on an April article in Nature1 updated to July.

A method called "backprocessing", for subgross examination of sections, ranging between 50 microns and 1 mm in thickness using a dissecting microscope was developed. It requires either archival or current diagnostic breast tissue. In this study tissue is assumed to have been already embedded in paraffin wax for immediate diagnostic purposes. The advantages of backprocessing include the ability to select valuable or rare diagnostic tissue from archival histopathological material, and the preservation of histological structure should further examination at 5 microns thickness be required at a later date.

A panel of peroxidase-conjugated lectins was used to stain frozen sections of human foetal, neonatal, infant and adult aortae. Two main distinctive staining patterns were observed at the light microscope level, depending on the lectin employed. Lectins from Concanavalin A, Triticum vulgaris, Arachis hypogaea and Glycine max resulted in staining of the surfaces of aortic elastic lamellae and the interlamellar areas. With lectins from Dolichos biflorus and Bandeiraea simplicifolia staining was seen predominantly in the interlamellar areas. The findings indicate the presence of several different glycoconjugates at various sites within the aorta. In addition, there were alterations in the lectin binding affinities of the aortae that were dependent upon age. The findings are interpreted as indicating sequential changes in the composition of glycoprotein or proteoglycan moieties in the development of the human aorta.

Antibodies to alpha-elastin peptides, amyloid P component, lysozyme and plasma protease inhibitors have been used in an immunoperoxidase method to stain elastic fibres in frozen sections of human breast tissues. A loss of immunoreactivity seen in formalin-fixed, paraffin-embedded sections was reversed by a preliminary proteolysis. Differences in the tinctorial dye and immunohistochemical staining patterns following proteolysis by a variety of enzymes suggests a selective unmasking or removal of elastic fibre components and thus the presence of separate binding sites for individual antibodies and tinctorial dyes. Antibody blocking experiments and double immunoenzymatic labelling support the existence of several different epitopes within elastic fibres.

A distinctive lymphadenopathy in nine cats, four of which were of the Longhair breed, was characterized by capillary vasoproliferation and lymphoid atrophy. It occurred in the cervical or inguinal regions. The animals were, apart from local manifestations, healthy at the time and remained so subsequently. In the absence of any clinical or morphological evidence for viral, neoplastic or developmental aetiologies, we postulate an ischaemic pathogenesis for the lesions which may be related to human "vascular transformation of lymph node sinuses". The lesions appear to be by no means a rare cause of non-neoplastic lymphadenopathy in domestic cats, since they constituted over 5 per cent of surgical biopsies of cat lymph nodes seen in the past 5 years. The lesions merit wider recognition and investigation.