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The Liberal government in 1911 was determined to improve the health care of the poor and working class in Britain. The Chancellor of the Exchequer, Lloyd George, introduced a National Insurance Bill before Parliament without consulting the medical profession. The doctors were furious but Horsley, a progressive liberal, was firmly in favour of a national health service and vociferously supported the bill. This led to a series of acrimonious meetings that did not enhance the reputation of the profession and alienated Horsley from his colleagues.

For nearly all of his life Victor Horsley campaigned against the evils of alcohol. This led him into direct conflict with politicians, brewers, publicans and the army. His views are of interest today when the subject of excessive consumption of alcohol is the subject of great public concern.

In 1914 Victor Horsley, 56 years old, pioneer neurosurgeon, politician and ardent supporter of the temperance movement volunteered for active service. After a brief period in France he was posted to the Middle East, initially to Egypt and then to Mesopotamia. There he witnessed the horrors of that campaign. His attempts to alleviate the appalling conditions to which the wounded were subjected took toll of his own health and the official cause of his death in 1916 at Amara was heat stroke.

Previous studies in vitro and in rodent transplantation models have suggested that an analogue of cyclosporin, SDZ-IMM-125, has immunosuppressive properties at least equivalent to that of cyclosporin. As the bioavailability of the drug was considered to be greater than that of cyclosporin, it was hoped that lower doses could be used with the avoidance of nephrotoxicity. Renal allografts were undertaken between beagle dogs from two partially inbred breeding colonies. After transplantation, SDZ-IMM-125 was given orally at a dosage of 5, 7.5, 10 or 20 mg/kg/day, and graft survival compared to that in dogs given cyclosporin 10 mg/kg or in untreated animals. The results showed that SDZ-IMM-125 is immunosuppressive in dogs and prolongs graft survival up to 50 days at a dosage of 20 mg/kg/day. However, at this dose histological changes suggestive of liver toxicity were observed in one dog, and mild anaemia was produced,but there was no evidence of nephrotoxicity. Absorption profiles suggested that the drug is rapidly absorbed and metabolized, and that a more frequent daily dosage may be appropriate. Overall, there appeared to be no significant advantage for the analogue SDZ-IMM-125 over cyclosporin. The transplant model was associated with a high spontaneous renovascular thrombosis rate, particularly after cyclosporin administration, which was prevented by the daily administration of aspirin.

Background: The proto-oncogene bcl-2 encodes a protein that inhibits programmed cell death (apoptosis). The protein is expressed in basal cells in normal human epithelium, but no data are available on the frequency or clinical importance of its expression in carcinoma. We studied bcl-2 expression in patients with non-small-cell lung carcinoma and correlated this phenomenon with survival., Methods: Immunochemical analysis with a monoclonal antibody specific for bcl-2 was used to detect the protein in tumor samples from 122 patients undergoing surgery for squamous-cell carcinoma (80 patients) or adenocarcinoma (42 patients). The possibility that bcl-2 expression correlated with survival was investigated with use of the log-rank test, hazard ratios, and their confidence intervals., Results: We detected bcl-2 protein in 25 percent of squamous-cell carcinomas (20 of 80) and 12 percent of adenocarcinomas (5 of 42). In adjacent normal respiratory epithelium, bcl-2 was expressed only in basal cells. Survival at five years was higher among patients with bcl-2-positive tumors, both in the group as a whole (P < 0.1) and in the group with squamous-cell carcinoma (P < 0.02). Patients 60 years of age or older who had bcl-2-positive tumors had the best prognoses, both in the group as a whole (P < 0.02) and in the group with squamous-cell carcinoma (P < 0.01)., Conclusions: The proto-oncogene bcl-2 is abnormally expressed in some lung carcinomas, and its expression may have prognostic importance.

A group of renal pathologists, nephrologists, and transplant surgeons met in Banff, Canada on August 2-4, 1991 to develop a schema for international standardization of nomenclature and criteria for the histologic diagnosis of renal allograft rejection. Development continued after the meeting and the schema was validated by the circulation of sets of slides for scoring by participant pathologists. In this schema intimal arteritis and tubulitis are the principal lesions indicative of acute rejection. Glomerular, interstitial, tubular, and vascular lesions of acute rejection and "chronic rejection" are defined and scored 0 to 3+, to produce an acute and/or chronic numerical coding for each biopsy. Arteriolar hyalinosis (an indication of cyclosporine toxicity) is also scored. Principal diagnostic categories, which can be used with or without the quantitative coding, are: (1) normal, (2) hyperacute rejection, (3) borderline changes, (4) acute rejection (grade I to III), (5) chronic allograft nephropathy ("chronic rejection") (grade I to III), and (6) other. The goal is to devise a schema in which a given biopsy grading would imply a prognosis for a therapeutic response or long-term function. While the clinical implications must be proven through further studies, the development of a standardized schema is a critical first step. This standardized classification should promote international uniformity in reporting of renal allograft pathology, facilitate the performance of multicenter trials of new therapies in renal transplantation, and ultimately lead to improvement in the management and care of renal transplant recipients.

Sixteen anaesthetized rabbits were subjected to tracheostomy and lung damage produced by the instillation of 4.5 ml/kg hydrochloric acid (pH 1.5) into the trachea. Half of the animals were ventilated with a positive end-expiratory pressure (PEEP) of 3 cmH2O and half with a PEEP of 10 cmH2O for 5 h, the mean airway pressure being kept at 12 cmH2O by adjustment of the end-inspiratory pause time. Pressure-volume curves were recorded every hour. Although the arterial PO2 values and compliance above the inflection point on the pressure-volume curve were greater in the group submitted to 10 cmH2O PEEP, there were no significant differences between the groups in terms of survival and histological findings.

One hundred and eighty-seven operable lung tumours were immunostained with the monoclonal antibody Ki-67 and divided into groups of high, moderate or low proliferation. Patients have been followed clinically for up to 7 years to ascertain whether this immunocytochemical measurement reflected tumour behaviour in terms of survival. The majority of the tumours were squamous cell carcinomas (104 cases) and adenocarcinomas (60 cases). These were divided into three groups of low, intermediate and high growth fraction, in which survival was better for tumours of lower proliferative rate up to approximately 2 years after operation. By 5 years these differences had largely disappeared and all tumours of a particular type showed a similar survival curve. Small cell carcinomas (13 cases) had high Ki-67 labelling indices, with more than 60% of patients deal in the first year, whereas carcinoid tumours (10 cases) had low labelling rates and all but one are still alive. We conclude that measurement of lung tumour growth rate with the monoclonal antibody Ki-67 shows promise as a possible indicator of short-term survival and perhaps as a means of choosing a group of patients with adenocarcinomas and squamous cell carcinomas for post-operative chemotherapy.

A wide variety of disease processes, each requiring different therapy, may give rise to granulomatous and vasculitic pulmonary lesions, making accurate aetiological diagnosis essential. For this, adequate sampling of tissue is necessary, and this usually requires open lung biopsy in order to obtain sufficient material for microbiological, immunocytochemical and ultrastructural as well as histopathological investigation. Many cases diagnosed as lymphomatoid granulomatosis are examples of extranodal lymphoma. It is suggested that this is an inappropriate name and that such cases should be referred to as pulmonary lymphomas and the phenotype specified.

Interleukin 4 (IL-4) receptors were detected by a monoclonal antibody on tumor cells of 10 of 29 squamous cell carcinomas and 6 of 17 adenocarcinomas of the lung. None of the small cell carcinomas or carcinoid tumors stained. Parallel sections stained for epidermal growth factor receptors showed that all but 2 of the IL-4 receptor-positive tumors also expressed epidermal growth factor receptors. Positive labeling for IL-4 receptors was also obtained on nonneoplastic bronchial epithelium and on lymphocytes and macrophages infiltrating the tumor stroma. The role of IL-4 and its receptor in normal human lung is unknown, but the expression of IL-4 receptors on particular subtypes of lung tumors suggests that they may have a role in differentiation or proliferation of squamous and adenocarcinomas.

Spontaneous renal allograft rupture occurring within 14 days of transplantation occurred in 15 patients from 791 consecutive transplants. In each of eight patients treated with azathioprine and prednisolone there was pathological evidence of rejection and only two patients had thrombosis of the renal vein. Of the seven cases occurring in patients treated with triple therapy regimen (low dose cyclosporin, prednisolone and azathioprine), histological evidence of rejection was present in only three cases, but renal vein thrombosis was found in all seven. Spontaneous rupture of a transplanted kidney, a relatively uncommon complication, is more likely to be due to renal vein thrombosis than to rejection in the cyclosporin era.

Diffuse interstitial pulmonary fibrosis is the end result of alveolar damage which may occur as a sudden acute incident or as a slowly developing process. Potentiating factors include release of enzymes and generation of oxygen radicals by granulocytes. Evidence from studies on broncho-alveolar lavage fluid and from immunocytochemistry indicate that an autoimmune process has an important but, as yet, not clearly defined role in initiating the disease. The fibrosis is probably due to proliferation of small clones of fast growing fibroblasts of a specific phenotype. Bronchiolitis obliterans, organizing pneumonia, idiopathic pulmonary fibrosis, usual interstitial pneumonia and desquamative interstitial pneumonia represent different aspects of the same condition. Their varied morphological appearances probably reflect the fact that tissue has been taken at different stages in the development of the disease.

Renal biopsies were taken from 42 patients at seven and 21 days after renal transplantation. Paraffin sections from these specimens were examined immunocytochemically for the presence of platelet microthrombi in glomerular capillaries using the monoclonal antibody Y2/51. Patients were treated by one of four different immunosuppressive regimes, three of which included cyclosporin A, either alone or in combination with steroids and azathioprine. Microthrombi were detected in approximately 30% of biopsies and were much commoner in patients receiving multi-drug therapy. We conclude that, contrary to previous suggestions, glomerular capillary thromboses are not frequent in patients on cyclosporin A alone. They are found mainly in patients on multiple drug therapy, particularly when steroids are included. The detection of microthrombi is unlikely to be of assistance in the earlier detection of cyclosporin toxicity.

The renal biopsy findings in 40 patients with segmental glomerulonephritis are reported. The term is used to describe a condition in which one or more segments of the glomerular tuft is involved by disease when other segments appear unaffected on light microscopy. The word 'focal' is not used as it may be taken to imply that the changes affect some glomeruli but not others and the evidence for this is not convincing. Segmental glomerulonephritis was a relatively common finding in cases of proteinuria with or without the nephrotic syndrome. The severity of the glomerular changes did not correlate with the ultimate prognosis. On the other hand the tubular and interstitial changes, as assessed by a grading procedure and by point counting, were significantly less severe in those patients who showed clinical recovery than in those who did not.

In the period 1968-76, necropsies were carried out on 30 patients who had been treated by long-term intermittent maintenance haemodialysis. Fourteen of these patients developed bilateral cystic disease of the kidney. Clinical, pathological, and radiological investigation of these patients when they first presented did not reveal any evidence of renal cystic change. The main complications of this condition are haemorrhage and tumour formation. Six patients developed renal tumours, and in five cases these were multiple. The histological appearance of these neoplasms gave no indication as to whether they would behave in an aggressive manner. One patient died of metastatic carcinomatosis from a renal primary. The condition of acquired cystic disease of the kidney should be suspected if patients on maintenance haemodialysis suffer from recurrent haematuria or are found to have enlarging kidneys.

The clinical and pathological findings are reviewed in ten cases where renal biopsy showed abnormalities predominantly within the interstitium. In six the nephritis was considered to be drug-induced; in two the aetiology was slightly obscure but the most likely diagnosis was considered to be sarcoidosis. Of the remaining two cases one was chronic pyelonephritis and the other polyarteritis nodosa. The diagnosis and pathogenesis of the renal lesions are discussed and attention is drawn to the importance of distinguishing primary interstitial changes from those found in association with glomerular disease.

Co-expression of intermediate filaments is being increasingly reported for many human tumours including carcinoma of the lung. However, it is unclear whether such findings are unusual or restricted to a group of highly atypical tumours. In the present study the pattern of co-expression of intermediate filaments in 94 human lung tumours has been correlated with light and electron microscopical features which are thought to be atypical for particular tumour types. These same aberrant patterns of intermediate filament co-expression have also been compared with the proliferative rate of these tumours as determined by labelling with the monoclonal antibody Ki67. The results of this study have shown that the aberrant expression of intermediate filaments is not a feature unique to a group of highly unusual tumours but is found throughout the spectrum of lung cancer. The implications of these findings for the use of anti-intermediate filament antibodies in pulmonary pathology are discussed with suggestions for future directions which might be taken in this field.

In an immunocytochemical study of 41 human lung tumours we have shown that Langerhans cells can be reliably identified using the anti-CD1 monoclonal antibody NA1/34. Langerhans cells are present in all the main varieties of human lung tumour although they are infrequent in both small cell carcinoma and carcinoid tumour. There is considerable variation in numbers of Langerhans cells in both adenocarcinomas and squamous cell carcinomas. In this study tumours were divided into those with high numbers of Langerhans cells (greater than 2 per high power field) and those with low numbers (less than 2 per high power field). Analysing these results against patient survival showed a markedly worse survival in those tumours with a high number of Langerhans cells for all the tumours as a single group and for squamous cell carcinoma as a single entity.

Sixty-six lung carcinomas have been examined by light and electron microscopy, as well as by immunocytochemical techniques using a panel of monoclonal antibodies. There was considerable heterogeneity with regard to cell type and in only 18 cases was it possible to classify the tumour as a solely small cell, squamous or adenocarcinoma. In the remaining cases there was evidence of two or three cell types. These findings support the thesis that all lung cancers are derived from a pluripotential basal or reserve cell in the bronchial mucosa which may proliferate along one or more lines of differentiation. This view of the histogenesis of lung cancer would account for the heterogeneous appearance of many tumours and the difficulty experienced in placing them in one of the standard classifications.

Legionnaires' disease was diagnosed in two patients in a transplant unit, both patients having occupied the same postoperative cubicle shortly before onset of their illnesses. Legionella pneumophila was found in water taken from the cubicle shower bath and from other showers in the unit. To eradicate the legionellae, the water supply was treated with chlorine, but this had only a temporary effect.

Fifty-four human lung tumours have been immunostained with a large panel of monoclonal antibodies including reagents against cytokeratins, prekeratins, epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA) and neural antigens. These results have been compared with the histological types of tumour using the current WHO classification scheme. The most striking finding of this study was the considerable overlap of antigenic profile between different histological types of tumour. This suggests that there may be a greater underlying similarity between different histological categories of lung tumour than has hitherto been assumed. Secondly it was evident that immunostaining highlighted areas of different morphology within many tumours emphasizing the heterogeneous differentiation patterns seen in lung cancers. The present study supports the viewpoint that lung tumours arise from a common stem cell and that these neoplasms represent a single tumour with a tendency to differentiate along one or more pathways.

Endometrium and myometrium were collected at hysterectomy from 42 women with measured menstrual blood loss (range 4-840 ml). The specimens, obtained throughout the menstrual cycle, showed no evidence of organic disease on histological examination. The volume fraction occupied by arteries at the myometrial-endometrial junction, and by glandular tissue throughout the endometrium was estimated with a point counting technique. The index of volume-to-surface ratio of endometrial glandular tissue was examined by a combination of point counting and linear intercept methods. No correlation was found between menstrual blood loss and endometrial and myometrial arterial density, endometrial glandular density and volume-to-surface ratio. Consequently, menorrhagia, occurring in the absence of obvious pathology, does not appear to result from an excessive number of arteries of from abnormal glandular distribution.

Morphometry requires, in addition to the accurate counting of points, intersections and transections, meticulous attention to sampling. Methods are described and discussed for ensuring that adequate samples are obtained for a given standard error. For all situations in which stratification is used, the importance of increasing the number of the early strata for reducing the variance is emphasized.

Ninety four pulmonary neoplasms were examined immunocytochemically with two or three different monoclonal antibodies against the intermediate filament proteins cytokeratin, neurofilament, vimentin, and desmin. In normal tissues these have a different and non-overlapping distribution, and it is generally believed that tumours maintain the same pattern of expression as the tissues from which they arise. In this report, however, the coexpression of at least two (and less commonly three or four) different intermediate filaments was seen in 40% (37 of 94) of the cases of lung cancer. These results, especially if confirmed in other common types of human malignancy, have considerable implications for the use of anti-intermediate filament antibodies in diagnostic pathology.

Vesicoureteric reflux was found unexpectedly during routine investigations before renal transplantation in 12 patients with chronic glomerulonephritis and in one with hypertensive nephrosclerosis. They had all received long term hemodialysis treatment for nine to 106 months (mean 47 months) at the time of micturating cystourethrography (MCU). Four of the patients had previously had a normal MCU indicating that reflux developed after onset of end stage renal failure. The cause of reflux is obscure. It was not related directly to defunctioning of the urinary tract as several patients had daily urine volumes in excess of 300 ml. Infection, another potential cause, was uncommon in patients with reflux. Histology of the excised ureters showed abnormality in most cases with loss of the normal mucosal folds and submucosal cellular infiltrate and fibrosis. These changes are also unexplained. In this group of patients nephroureterectomy for reflux in anticipation of renal transplantation was associated with considerable morbidity. A minimal estimate of the incidence of reflux in chronic glomerulonephritis was 11%. We suggest that in this group and in patients with renal diseases other than chronic pyelonephritis reflux alone does not constitute sufficient indication for nephroureterectomy before transplantation to warrant the risks of major surgery.

Lung lavage was performed in 16 anaesthetized rabbits to produce surfactant-deficient lungs. This resulted in alveolar collapse, an arterial PO2 of less than 15 kPa on 100% oxygen and an inflection point on the inspiratory limb of the pressure-volume curve at an airway pressure of 8-10 mm Hg. One group of eight animals was then ventilated with a positive end-expiratory pressure (PEEP) equal to the pressure at the inflection point, whilst the second group of eight was ventilated with a PEEP 5 mm Hg less than the inflection point. Animals in the high PEEP group had a significantly greater arterial PO2 than those in the low PEEP group, but the mean survival time for each group was similar. However, there was a significantly greater incidence of hyaline membranes in the low PEEP group. Various mechanisms to explain these findings are discussed.

The renal biopsy findings in a 76 yr-old woman suffering grom anuria due to acute tubular necrosis are described. The glomeruli were normal on light- and electron microscopy. Immunofluorescent studies failed to reveal any fibrin or immunoglobulins in the glomerular capillaries. Extensive focal areas of necrosis were seen in the tubular epithelium often exposing the lumen of the tubule directly to the tubular basement-membrane. In some areas necrotic cells lay adjacent to normal or near normal cells. The proximity of the necrotic tubular epithelium to the oedematous interstitial tissue and the peritubular capillaries, together with the finding of normal glomeruli is compatible with the theory of back diffusion as a mechanism for the oliguria.

From 1976 to 1982 five patients undergoing haemodialysis at Oxford Renal Unit suffered serious complications from acquired cystic disease of the kidney and two died as a direct result. Clinical features seen were pain, haematuria, palpable renal enlargement, massive haemorrhage, resolution of anaemia, and metastatic malignancy. The clinical histories emphasise the features of a disease that is likely to assume increasing importance in patients undergoing haemodialysis.

The histology of renal allografts was compared in a series of 107 biopsies from patients receiving cyclosporin and 126 biopsies from patients receiving azathioprine and prednisolone. Patients receiving cyclosporin were converted to azathioprine and prednisolone 90 days after transplantation. Biopsies were taken routinely at 7, 21, 90, and 365 days, irrespective of clinical graft function and were examined "blind" by two independent observers. Interstitial haemorrhage was more common in patients treated with azathioprine and prednisolone corresponding with their poorer graft survival. Analysis of glomerular, tubular, vascular, and interstitial changes showed no other important differences between the two groups despite clinical evidence of reversible cyclosporin nephrotoxicity. Quantitation of interstitial fibrosis in 90 day biopsies showed it to be equal in prevalence after treatment with azathioprine and prednisolone and cyclosporin. It was preceded by diffuse interstitial cellular infiltration, a common finding in early biopsies. Diffuse cellular infiltrates were generally associated with higher serum creatinine concentrations and, if persistent, a poorer graft prognosis than focal infiltrates, but they were not always associated with renal dysfunction.

We have used a probe against the adenovirus genome to study cultured epithelial cells specifically infected with various types of adenovirus and Graham 293 cells, which contain few copy numbers of a fraction of the adenovirus genome. We have also examined lung tissue obtained from three cases of acute adenovirus pneumonia, two cases of adenovirus pneumonia that had passed through the acute phase, and nine cases of follicular bronchiectasis. Our purpose was to determine whether the probe was effective in detecting a wide variety of adenovirus types, to determine whether it could detect adenovirus in lung tissue that had been fixed and stored in paraffin blocks for several years, and to test the hypothesis that adenovirus was an important cause of follicular bronchiectasis. The results show that the probe was able to detect adenovirus from Genera B1, B2, C, D, and E with a sensitivity of 5 to 10 copies/cell. The probe also detected adenovirus in 14 of 14 slides from three cases of acute disease, but failed to obtain a positive result in the cases examined after an acute infection or in any of the cases of follicular bronchiectasis. We conclude that the in situ hybridization technique is useful in the investigation of active adenovirus infection of the lung. The failure to show that the virus persisted in the chronic respiratory disease that follows adenovirus infection, or that it was present in cases of follicular bronchiectasis could be due to either a true absence, or to its presence in a latent form that is below the level of sensitivity of this technique.

A panel of seven monoclonal antiepithelial antibodies of different specificities, including anticytokeratin, human milk fat globule membrane, C, and carcinoembryonic antigen (CEA) were used with the alkaline phosphatase-antialkaline phosphatase (APAAP) immunostaining technique to determine their value in the differentiation between benign and malignant mesothelial cells and lung carcinoma in histological preparations. The anticytokeratin antibody reacted strongly with all cases of reactive mesothelium, mesothelioma, and lung carcinoma. Antibodies to human milk fat globule membrane and the Ca antigen stained mesothelioma and carcinoma and 43% of cases of reactive mesothelium. Staining for carcinoembryonic antigen was not detected in reactive mesothelium or mesothelioma, but was present in most of the lung carcinomas. CEA seemed to be the single most useful marker in distinguishing carcinoma from mesothelioma in that a positive reaction for CEA would indicate carcinoma rather than mesothelioma.

The results of immunoperoxidase staining of 33 routinely processed renal biopsies correlated with the results of direct immunofluorescence in 79% of tests performed. Most of the discrepant results were due to positive immunoperoxidase staining, possibly reflecting greater sensitivity of the method. A comparison of two immunoperoxidase methods showed that the indirect method produced less intense staining than the peroxidase-antiperoxidase (PAP) method when equivalent primary antibody titres were used. Lowering the primary antibody titres for the indirect technique resulted in equivalent staining by the two methods. Predigestion by protease VII effectively revealed the antigens under study without causing tissue damage or section loss.