A tale of two sisters.

Hereditary haemochromatosis is the most common inherited disorder in white populations, whereas non-alcoholic steatohepatitis (NASH) is becoming the most common reason for referral for investigation of abnormal liver function tests (LFTs). This report describes two sisters, from similar environments, who were referred to the clinic after being found to be C282Y homozygotes and to have abnormal LFTs. One sister had developed features of haemochromatosis and the other had developed NASH. These cases illustrate the potential non-penetrance of HFE gene mutations and the need to investigate abnormal LFTs fully, even when there is a positive genetic test at the outset.

Minimal change nephropathy in the west of Scotland: a review of sixty-four patients.

Sixty-four patients with a histological diagnosis of minimal change nephropathy have been followed for a median of 110 months. Patients transferred from paediatric units (11%) had a worse prognosis in that all became frequent relapsers. Patients who relapsed within three months or who went on to become frequent relapsers had a higher 24 hour urine protein excretion at presentation than patients who did not relapse. After fifteen months of remission relapse was rare; 97% of those who relapsed did so within 36 months. Patients who have been off steroids and proteinuria free for 36 months might therefore be considered cured.

Glomerular basement membrane thinning in adults: clinicopathological correlations of a new diagnostic approach.

We have studied glomerular basal laminar thickness in biopsy material, using a simple technique involving 16 selected measurements per case. Twenty-nine biopsied cases of adult glomerular haematuria were examined together with 'diseased' controls represented by a variety of glomerulopathies including minimal-change disease and IgA nephropathy. 'Normal' control populations were provided by 13 patients with acute-onset renal failure of non-glomerular origin and nine patients undergoing nephrectomy. Analysis of groups determined by the presence or absence of haematuria, the degree of proteinuria and presence or absence of a diagnostically characteristic immunofluorescence pattern showed that the nine patients with haematuria and proteinuria of less than 200 mg/24 h represented a distinct subpopulation with a mean membrane thickness of 225 nm compared to the control mean of 343 nm (P less than 0.0001). All members of this subpopulation had mean values below an arbitrary cut-off value of 270 nm. Within other specific disease categories, sporadic cases had mean membrane thicknesses below this critical value, indicative of an overlap of pathologies. On short-term follow-up there is no evidence that the 'pure' thin-membrane population are subject to any deterioration in renal function. It is of further interest that eight of nine thin-membrane 'syndrome' cases were O Rh positive. This finding may provide a starting point for investigation of a specific genetic defect.

Immunoalkaline phosphatase technique applied to paraffin wax embedded tissues in diagnostic renal pathology.

An indirect immunoalkaline phosphatase (IAP) technique was used to evaluate the glomerular deposition of immunoglobulins, C3, C1q and fibrinogen. In 80 renal biopsy specimens the results obtained using this technique were compared with those obtained by direct immunofluorescence to see if it could be used as a viable alternative. The IAP technique was straightforward to perform, it yielded quick results, and was highly reproducible, provided that a standardised short fixation period of two and a half hours was used. For the detection of immunoglobulin deposits, the IAP results correlated well with those of immunofluorescence. Despite poorer performance in identifying complement components and fibrinogen it could, within certain limits, provide an adequate diagnostic alternative to immunofluorescence. Each technique gave false negative results, those of immunofluorescence being related to its failure to identify mesangial deposition of IgA in two cases where its distribution seemed to be focal, and those of IAP to a failure to detect linear deposition of IgG in all three cases of anti-glomerular basement membrane disease.

The effect of repeated hemoperfusion over charcoal in the conscious rat on liver pathophysiology.

An investigation has been made into the effects of repeated charcoal hemoperfusion in the rat on liver pathophysiology. Animals underwent hemoperfusion over Norit RBX1 charcoal using a technique which allowed perfusion in the unrestrained and conscious state, thus minimizing any possible effects from stress and eliminating the necessity of repeated anesthesia. Controls consisted of animals subjected to perfusion through empty columns and animals cannulated only. Liver weight, function, and histology were recorded at various times following hemoperfusion and control procedures. The results show that repeated charcoal hemoperfusion is well tolerated in the rat and can be performed safely with no deleterious effects on liver tissue.

The classification of ultrastructural topography in the context of an ultrastructural diagnostic service.

Ultrastructural diagnosis relies on the recognition of specific organelles and the identification of various subcellular features and relationships. As E.M. case loads increase, the recall and comparison of particular cases becomes increasingly difficult. A system of classification is proposed, in a format compatible with SNOP and SNOMED, which permits the precise coding of subcellular details. Such a system could assist in the classification of disease, the storage and analysis of data and the retrieval and study of case material on an inter-departmental basis.

The ultrastructure of some gastrointestinal lesions in experimental animals and man.

This has been a brief and necessarily selective review, covering only a few of the numerous experimental and diagnostic uses of electron microscopy in the field of gastroenterology. The roles of experimentalist and diagnostician have emerged in a kind of counterpoint. We have identified the contrasting themes of the controllable laboratory experiment and the uncontrollable experiment of disease; of the three-dimensional image of the surface scanning technique and the two-dimensional world of the thin section. There is harmony, also, in our common concern for morphology and our shared interest in any structural change. Altered morphology, whether in tissue architecture or cellular organisation, may offer a key to the better understanding of altered function. In the future, both the experimental and the diagnostic electron microscopist will come to rely more on correlative procedures, such as the re-processing of specimens for a second look with a different technique. Functional dividends are promised to the morphologist by advances in detector technology and associated techniques such as analytical microscopy. It remains to be seen whether medical benefits will accrue, in terms of a more precise diagnosis or a more effective prognosis in individual cases of human gastrointestinal disease.

SEM in service pathology: a review of its potential role.

New medical technology evolves through distinct phases. Initial technical proving is followed by a phase of detailed data recording, often with no detailed attempt to fill any specific service requirements. Next an attempt is made to establish correlations with other techniques and results, with a view to defining any unique attributes of the technology in particular fields. Detailed service-related applications are then worked out, but the final adoption of new instrumentation into clinical practice depends not only on the success of its technical performance, but also on its cost-effectiveness. This paper reviews studies of clinically-derived material from the viewpoint of a U.K. diagnostic pathologist. Detailed comparisons are drawn between the evolution of SEM on the one hand and of LM and CTEM on the other. An attempt is made to identify areas of practice in which SEM might make the greatest impact in the foreseeable future. It is proposed that paraffin-embedded tissue in pathology back files may provide a valuable source of investigative material for diagnostic SEM.

Serum protein changes associated with alpha1-antitrypsin deficiency.

Using a radial immunodiffusion technique, the concentrations of eight serum proteins have been measured in sera from 60 chest clinic patients previously shown to have abnormally low alpha1-antitrypsin levels, and in 60 age and sex matched control sera. Of the proteins, only alpha2-macroglobulin showed a highly significant increase in the alpha1-antitrypsin deficient group. The findings confirm a previously reported association between alpha1-antitrypsin deficiency and increased alpha2-macroglobulin, and lend support to the suggestion that the rise in alpha2-macroglobulin is a specific compensatory response.

Non-organ specific autoantibodies in malignant diseases.

A significant increase in non-organ specific autoantibodies is demonstrated in13 per cent of the sera from 202 patients with histologically proven malignancies, as compared with only 4 per cent of sera from 214 age and sex matched control patients. It appears that the incidence of autoantibodies is related to the histological type of the tumour but not to the presence or absence of tumour dissenmination. While the control group shows the expected increase in both incidence and titre of autoantibodies with increasing age, the malignant patients show no such pattern i.e. in cancer patients autoantibodies occur with equal frequency and at similar titres regardless of age. The absence of an age related increase in incidence and titre of non organ specific autoantibodies does not appear to have been reported previously. Our findings lend support to the hypothesis that cancer is associated with a breakdown of immunological surveillance, not only in old but also in young cancer patients. Thus the findings of non organ specific autoantibodies, especially to smooth muscle antigen, in an apparently healthy adult could be considered evidence of such a breakdown, carrying with it an increased risk of neoplasia.

The effects of portacaval shunting and portacaval transposition on serun IgG levels in the rat.

In rats subjected to end-to-side portacaval shunt and to portacaval transposition, serum IgG levels rose progressively by approximately 100% over a 5-week period. During the same period, sham-operated control animals showed only the increase expected with age. Rats with a portacaval shunt showed a greater fall in body weight and liver weight than did those with a portacaval transposition, and also showed a greater fall in levels of liver-synthesized proteins. Serum enzyme levels were markedly elevated during the first 48 hr after portacaval shunting, whereas after portacaval transposition the elevation was very small. Over the following 5 weeks enzyme elevation continued to be margiallly greater in the portacavallly shunted animals. Because IgG levels rose to a similar degree in both groups of animals, the prsent results support the hypothesis that hypergammaglobulinemia is due to the shunting of antigen-rich portal blood past the reticuloendothelial cells of the liver, and the hepatocellular damage does not play a major role in this process. The etiology of hypergammaglobulinemia in chronic liver disease in man may be similar.

Action of staphylococcal epidermolytic toxin on mouse skin: an electron microscopic study.

The ultrastructure of the skin of 3-day-old mice challenged with small doses of highly purified staphylococcal epidermolytic toxin was examined at various time intervals. Up to 130 min few changes were evident, but at this time wide gaps developed between cells in the horizontal planes of the stratum granulosum, and "bubbles" normally present in the intracellular spece were no longer apparent. Splitting of the desmosomes occurred after the development of distended intercellular spaces. After 20 hr, that is, in the "healing" phase, the appearance suggested that normal maturation of keratinocytes was altered. Also at this time a degree of cell separation was still apparent in the outermost actively maturing layer of the stratum granulosum. The proteinase inhibitor Trasylol was tested for its effect on the toxin when administered up to 45 min after challenge.