[Reminiscences on the occasion of the Whipple's disease centenary: a summary paper]. / Reminiscence k stoletému výrocí objevu Whippleovy nemoci: souborný referát.

The disease referred to eponymically as Whipple's disease (WD) in medical literature was thoroughly described by the American physician and pathologist George Hoyot Whipple (1878-1976) in 1907 and given a temporary denomination of "intestinal lipodystrophy". According to literature, WD is rare, but its precise incidence has not yet been established. Familial incidence of the disease is acknowledged, and its immunogenetic pathogenesis is assumed. The incidence ofWD is prevailingly observed in middle-aged men (mean age 55), exceptionally at child age - the ratio being 3 to 6 for men and women, respectively. 1. Clinical diagnosis is based on symptoms in the GIT region and, in rare cases, on extraintestinal symptoms. Clinical symptomatology includes: abdominal pain with persistent diarrhoea (steatorrhoea), symptoms typical of malabsorption connected with weight loss, fevers, polyarthritic symptoms, swollen lymph nodes and, in part of patients, skin hyperpigmentation. Anaemia and hypoalbuminaemia (reduced IgA) are typically detected in laboratory tests. Rarer extraintestinal symptoms of the disease are of a diverse nature: cardiac lesions, cerebral lesions, ocular symptoms, conspicuous or even tumour-like enlargement of lymph nodes, lesions of the hemopoietic system. The clinical course ofWD is of progressive or remittent nature and the disease is fatal without treatment. Long-term therapy with antibiotics, especially a combination oftetracyclines (doxycyclin) and corticoids (dexametazone), or chloramphenicol in case of cerebral lesion, have a significantly positive effect on the course and prognosis of WD. From the point of view of pathology, WD is a multisystem infectious disease (Tropheryma whipplei) primarily affecting the GIT (39, 47, 52, 103) or different extraintestinal locations. Due to the known diversity of clinical symptoms, no clinical-diagnostic standard has been established for WD. Differential diagnosis includes different multisystem diseases, primarily malignant lymphomas (especially Hodgkin's disease). From the pathogenetic point of view, we can either assume the effect of a particular cytokine (or TNFalpha) activating macrophage phagocytosis or, if its production is normal, a disorder or defect of the respective receptor in the macrophage cellular membrane. The identification of "Whipple's bacteria" - Tropheryma whipplei - gen. nov. et sp. nov. was made possible by modern molecular biology research methodologies. Its cultivation allows both for the acquisition of the specific antibody and of detailed knowledge of its genoma (PCR, 16S rRNA sequencing).

Apoptosis-related proteins, BCL-2, BAX, FAS, FAS-L and PCNA in liver biopsies of patients with chronic hepatitis B virus infection.

While the elimination of hepatitis B virus (HBV) is a common phenomenon at the end of the acute phase of disease, the persistence of HBV is characteristic for chronic hepatitis (CHB). Recent evidence indicates that the elimination of HBV is achieved by FAS/FAS-L induced apoptosis of infected hepatocytes. The aim of this study was to test the hypothesis that HBV persistence in the hepatocytes of CHB patients is due to the delayed onset of apoptosis caused by altered FAS/FAS-L interactions between lymphocytes and hepatocytes. The expression of FAS, FAS-L, BAX, BCL-2, ICE and PCNA in the liver biopsies of 55 patients (14 HBsAg positive, 20 patients with alcoholic hepatopathy, 21 patients with other hepatopathies) was tested by immunohistochemistry. Apoptosis of hepatocytes was evaluated by morphological as well as by TUNEL method. The results were correlated with a grading/staging score and analysed statistically using a one way analysis of variance and the Duncan test. Significantly highernumbers of BAX positive hepatocytes were observed in HBsAg positive patients when compared to control groups. Similarly, both BAX and FAS positive lymphocytes were more frequent in HBsAg positive patients. FAS-L positive lymphocytes and hepatocytes were numerous in all patient groups. Increased numbers of BAX positive hepatocytes in CHB may reflect the increased readiness of these cells to undergo apoptosis. However, the increased numbers of both BAX and FAS positive lymphocytes in CHB suggest that these cells may be particularly sensitive to FAS-L mediated apoptosis potentially resulting in lowered viability of these lymphocytes. This may explain, at least in part, the defective removal of virus-infected cells in chronic hepatitis. However, we cannot rule out the possibility that survival of hepatocytes during CHB may be due to other mechanisms such as defects in apoptosis activation triggered by CD40, defects involving DNase and/or other caspases downstream in the apoptotic cascade within these cells, or to defects in CTL function.

[Can we foresee the end of the alphabet in viral hepatitis?]. / Lze dohlédnout konce abecedy u virových hepatitid?

There is a number of viruses which may cause acute or chronic liver damage. Only some of them belong into the group of hepatotropic viruses and only the latter are the cause of acute or chronic viral hepatitis. So far we know seven hepatotropic viruses. The virus of hepatitis A (HAV), virus of hepatitis B (HBV), virus of hepatitis C (HCV), virus of hepatitis D (HDV), virus of hepatitis E (HEV), virus of hepatitis G (HGV) and Transfusion-Transmitted-Virus (TTV). For HAV and HEV orofaecal transmission is typical, the others are transmitted by the parenteral route. All cause acute hepatitis. Only HAV and HEV infections develop into the chronic stage. The decisive finding for the dynamic development of the problem of viral hepatitis was the discovery of the Australian antigen (Au antigen) by B. Blumberg in 1965. The discovery made it possible to recognize viral hepatitis B and by the application of new biotechnologies the genes of other viruses were detected. Some of them were not visualized so far. A great advance was alpha interferon and lamivudine treatment in patients with chronic hepatitis B and alpha interferon treatment along with ribavirine in chronic hepatitis C.

[Characteristics of still unknown hepatotropic viruses and a clinical picture of the disease]. / Charakteristika dosud známých hepatotropních viru a klinický obraz onemocnení.

So far seven hepatotropic viruses were identified. They are described by letters A,B,C,D,E, G and TTV. The virus of hepatitis F is so far speculative. Virus of hepatitis A and E are transmitted by the orofaecal route and cause only acute hepatitis. The remaining hepatotropic viruses are transmitted by the parenteral route and have a longer incubation period than viruses A and E. The infection with the virus of hepatitis B develops into the chronic stage in about 10% and that of virus C in 50-90%. At least one third of chronic carriers of the virus of hepatitis B or C develop within 10-20 years liver cirrhosis or hepatocellular carcinoma. The objective of therapeutic regimes is eradication of the viruses or at least arrest or retarding of the activity of the disease. Corticoids are not used. The basis of therapeutic regimes is interferon alpha or lamivudine in hepatitis B and interferon alpha with ribavirine in hepatitis C. There is a permanent therapeutic response only in cca 40-50%. Active immunisation is possible against virus of hepatitis A and B. The virus of hepatitis D is a false virus, i.e. a so-called virold, and the cause is a super- or co-infection with the virus of hepatitis B. In this country it is practically not encountered, similarly as the virus of hepatitis E. The assembled findings on virus of hepatitis G are not applied so far very much in practice.

[Hodgkin's disease with epithelioid granulomatous reaction]. / Hodgkinova nemoc s epiteloidne granulomatózní reakcí.

Hodgkin's disease with a conspicuous presence of epithelioid-histiocytic elements was described as a particular subvariant of mixed type Hodgkin's disease. The authors presented four new cases. An additional increase of Langerhan's and interdigitating cells was observed in two cases, sarcoidosis-like granulomas with epithelioid and big multinucleated cells in the third. This female died and granulomas were found in several other organs. A prognostic relevance of this conspicuous reaction has not been clear for the time being. The mentioned patient deceased one year after the diagnosis had been settled, other three patients have been clinically well surviving 2-5 years.

High dose chlorambucil versus Binet's modified cyclophosphamide, doxorubicin, vincristine, and prednisone regimen in the treatment of patients with advanced B-cell chronic lymphocytic leukemia. Results of an international multicenter randomized trial. International Society for Chemo-Immunotherapy, Vienna.

BACKGROUND: In recent years, much attention has been paid to the possible efficacy of intensive chemotherapy in the treatment of advanced, progressive B-cell chronic lymphocytic leukemia (CLL) patients. For this reason, the International Society for Chemo-Immunotherapy, Chronic Lymphocytic Leukemia Cooperative Group, has begun a randomized multicenter trial comparing Binet's modified cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen with continuous high dose chlorambucil (HD-CLB). METHODS: During the period January 1987 to May 1993, 228 previously untreated CLL patients from 7 cooperative institutions were randomized to this trial. Advanced and/or progressive disease was defined by high Total Tumor Mass (TTM) score (> 9), and/or short doubling time (DT) (< 12 months), and/or bone marrow failure. The response to therapy was defined by reduction of the initial TTM score. The end points of the trial were response rate, survival, and toxicity. RESULTS: HD-CLB resulted in a higher response rate than CHOP in evaluable cases, with 89.5% overall responses (complete response+partial response) versus 75%, respectively (P < 0.001). At the time of an analysis performed in July 1995 (after a median follow-up period of 37 months), overall survival was also longer in the HD-CLB treatment arm (median survival, 68 months) than in the CHOP treatment arm (median survival, 47 months) (P < 0.005). Toxicity was acceptable and comparable in the two treatment arms. CONCLUSIONS: The current study showed that HD-CLB is an effective and well-tolerated therapeutic option for patients with advanced and/or progressive CLL. Therefore, the authors recommend its wider use, possibly in comparison with and/ or in combination with new therapeutic agents, such as purine analogues.

[Malignant lymphoma with epithelioid cells]. / Maligní lymfomy s epiteloidními bunkami.

Authors studied a group of 6 cases of malignant lymphomas with epithelioid cells. Their additional common features were a variegated cell population, big admixture of T lymphocytes and rare elements reminding of Reed-Sternberg cells. The seventh case serving as a standard was Hodgkin's disease with a high content of epithelioid cells. According to phenotyping the group consisted of 3 peripheral T cell lymphomas of the type of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) and single cases of centroblastic ML, T-rich B-cell lymphoma and Hodgkin's disease. The latter diagnosis was settled after revision of a T-rich B-cell lymphoma. Some large cells were CD 20 and CD 30 positive. The classification was proved by autopsy. Authors tried to be more precise when classifying ML but they may be inapparent transitions among single types (e.g. between peripheral type of T cell lymphoma AILD type and AILD or between T-rich B-cell lymphoma and Hodgkin's disease with lymphocytic predominance). The patients were followed for a relatively short period. Four of them died in several months after diagnostic excision, two showed a conspicuous generalization at autopsy. The presence of epithelioid cells in ML may not be connected with a more moderate behaviour and better prognosis.

The level of neopterin in blood serum as one of the possible prognostic markers of Crohn's disease activity.

Neopterine is considered to be one of the markers of immunity system activity. An increased level of this pteridine derivate is determined in blood or urine in infections, transplant rejections, and in other conditions accompanied by changes in the immunity system. Monitoring its level in various body liquids can be important when assessing the immunity system condition, nevertheless, its non-specificity causes difficulties when interpreting the results. Up to now, very few papers have been published dealing with the determination of neopterine levels in patients with IBD. We studied a group of 25 patients who are monitored in a longterm manner at our clinic suffering from Crohn's disease. During 1993 and 1994, we were determining their levels of neopterine in blood together with other parameters. It was a group of patients chosen at random in different stages of disease, and we were interested in the correlation of the height of neopterine level with the activity of Crohn's disease. We proved statistically unimportant correlation between the height of neopterine level in blood serum and Crohn's disease activity. The question is discussed whether the examination of this marker be useful when monitoring Crohn's disease activities.

C-ANCA and p-ANCA in patients with Crohn's disease.

In 32 patients suffering from various stages of activity of Crohn's disease, c-ANCA and p-ANCA in serum were examined. Altogether, 54 blood samples were examined. In 21 patients of 32, i.e. 65.6%, at least in one examination of c-ANCA in serum the value was higher than 9 units (positive finding). In 10 patients of 32, i.e. 32.2%, at least in one examination of p-ANCA in serum the value was higher than 9 units (positive finding). In the case of high activity of Crohn's disease, c-ANCA in serum were higher than 9 units (positive finding) in 69.6% examinations, in case of low activity, values of c-ANCA in serum were higher than 9 units (positive finding) only in 9.5% examinations. p-ANCA in serum were, when the activity was high, positive in 46.1% examinations, while when the activity of Crohn's disease was low, p-ANCA were positive in 9.5%. The question of specificity of findings is discussed.

Fulminant hepatitis caused by a hepatitis B virus infection in the patients with haematologic malignancies. Report of 5 cases.

We describe 5 cases of fulminant hepatitis caused by the HBV infection in patients with haematological diseases, mostly malignancies (ALL, lymphoma, aplastic anemia, AML) following intensive chemotherapy. Infection was confirmed by serological examination (HBsAg positivity) and by electron microscopy (viral particles). After termination of chemotherapy fulminant hepatitis developed with hepatic failure and very high levels of AST and ALT. Autopsy revealed massive necrosis without signs of regeneration. We suggest that immunosuppressive therapy increases the risk of severe infection of hepatocytes with HBV and subsequent withdrawal of chemotherapy causes "immunological rebound" leading to massive necrosis.

Immunohistochemical study of the expression of BCL-2, PCNA and P53 proteins in the patients with hepatitis B. The pilot study.

In HBV related hepatitis it is generally accepted that the liver injury is mediated by an immune response to the virus, since HBV is not directly cytopathic. The first step in cytotoxic T lymphocyte mediated immune reaction in HBV infected mice is the induction of apoptosis. The role of BCL-2, p53 and PCNA (as the main regulators of cell cycle homeostasis) in this process has not been studied. The aim of this pilot study is to estimate immunohistochemically the expression of the BCL-2, p53 and PCNA in a group of HBV infected patients at various stages of the disease. Formalin fixed, paraffin embedded liver biopsies from 5 patients with HBsAG positivity in their serum were used for immunohistochemical study of the expression of BCL-2, PCNA (PC10) and P53 (DO1clone). As the chromogen we used both the DAB and AEC. The results were co-related with the 3 liver biopsies as controls. In the hepatocytes of the all cases (including controls) we did not found any positivity of BCL-2, p53 and PCNA. However the majority of the lymphocytes present in the liver of some cases of HBV infected patients were strongly BCL-2 positive. This preliminary results of very small group of patients could indicate that hepatocytes in the HBV infection are in the quiescent stage as in the controls and that the cell cycle regulation during infection could be controlled by other genes such as bax, bcl-Xs, FAS etc., but further studies are required.

[New findings on the classification, diagnosis and therapy of primary gastrointestinal lymphomas]. / Nové poznatky o klasifikaci, diagnostice a terapii primárních gastrointestinálních lymfomu.

Based on available recent data from the literature the authors review recent findings pertaining to the etiopathogenesis, immunology, clinical manifestations and treatment of primary gastrointestinal lymphomas. From the pathogenetic aspect in particular the close association with infections and immune disorders in various portions of the gastrointestinal tract is important. In their review the authors draw attention to new aspects of the histological and immunological classification of these tumors, in particular as far as definition of lymphomas of the MALT-system is concerned. They evaluate also data from their own group of 83 patients with regard to the incidence and site of the disease. In the conclusion they draw attention to the importance of some new therapeutic approaches, incl. antibacterial treatment.

[Anti-HCV positivity in blood donors]. / Pozitivita anti-HCV u dárcu krve.

At the blood transfusion department of the Faculty Hospital in Olomouc in 1992 and 1993 18,293 blood donors were examined and in 70, i.e. 0.38% anti-HCV positivity was found. All positive subjects were subjected to clinical, laboratory and sonographic examination and are checked regularly at the Second Medical Clinic. In none of the patients liver biopsy was performed so far. The clinical, laboratory and sonographic findings provide evidence of liver damage in 15, i.e. 21.4%. In two of them, i.e. in 2.8%, the findings support the diagnosis of chronic active hepatitis; this will be verified by biopsy. The authors consider dispensarization of anti-HCV positive subjects useful. In all examination of RNA HCV however must be made.

Granulomatous vasculitis of Churg-Strauss type in a patient with diabetes insipidus.

The CHSS was first described as an allergic granulomatosis and angiitis. This syndrome is characterized by pulmonary and systemic vasculitis, extravascular granulomas and eosinophilia which occur in patients with bronchial asthma and allergy. The CHSS in limited form may be present in an isolated organ or tissue. Despite increased awareness by clinicians, recognition of the condition can be difficult. It should be mentioned that CHSS may be a life-threatening disorder, especially via cardiac failure. Hence, an early diagnosis and treatment of this syndrome is very important, including the application of corticoids that favorably affect the course of the disease.

Axillary venous thrombosis (Paget-Schroetter syndrome): possible therapy by low-molecular weight heparin.

The authors report on a patient with spontaneous thrombosis of the right axillary vein (Paget-Schroetter syndrome). The treatment with low-molecular weight heparin was successful and no complications were observed.

[Asymptomatic HBs antigenemia in pregnant women]. / Asymptomatická HBs antigenémie u gravidních zen.

The authors have dispensarized for more than ten years HBsAg carriers at the Second Medical Clinic of the Olomouc Faculty Hospital when antigenaemia was detected during blood donorship. Since 1990 the authors dispensarize also women where HBs antigenaemia was revealed during pregnancy. In the presented paper the authors analyze this group of women. In 1990-1991 the authors examined blood samples for HBsAg from 12,042 symptom-free pregnant women. HBsAg positivity was proved in 34 women (0.28%). Eleven women (32.3%) are regularly followed up since delivery. The authors know nothing about the fate of 10 women (29.4%), as they did not respond to repeated invitations to the surgery. It must be however mentioned that 6 of them are Vietnamese and probably left Czechoslovakia. Four women (11.7%) did not attend the clinic for examination but the authors know that they were delivered of their babies elsewhere. In the remainder, i.e. 8 women the delivery was normal, usually in term. The neonates were passively as well as actively immunized at the appropriate dates. Their umbilical blood (if collected) was HBsAg positive, while the venous blood was in all instances negative. All 20 women who attended examination were throughly examined (ultrasound, HBeAg, HBeAb etc.) and the clinical picture is that of a "healthy" HBsAg carrier (not verified by histological examination).

Immunohistochemical determination of some tumour markers (blood group antigens A, B, H, T-antigen, CEA) in colonic and rectal tissue after endoscopic polypectomy.

The expression of blood group antigens A, B, H, T-antigen and CEA was determined in tissue samples of polyps of the rectosigmoideum removed by endoscopic polypectomy. On average 39 months later, during colonoscopic examination bioptic samples were removed at the site of previous polypectomy and the expression of the same tumour markers as previously was determined. In contrast to literary data, the cellular expression of blood group antigens was demonstrated only in one case out of seven adenomas of the rectosigmoideum. On the other hand, cellular expression of blood group antigen B was found in 6 cases at the site of previous polypectomy and in 6 cases, this antigen was incompatible. Interpretation of these results is difficult at this time.

Secondary Hodgkin's disease in polymyositis and type 1 diabetes mellitus after a long-term immunosuppressive treatment.

Immunological disorders can play an important role in the etiopathogenesis of malignant lymphogranuloma. The authors demonstrate a patient with autoimmune polymorbidity (polymyositis and type 1 diabetes mellitus) which underwent a long-term immunosuppressive and cytostatic therapy. After 7 years of that treatment, Hodgkin's disease of mixed cellularity type developed. The clinical findings of the case are described and the clinical particularities along with possible mutual links among these diseases are stressed.

Bleeding to the adrenal gland as a terminal manifestation of acute leukaemia.

The authors refer about an unusual localization of haemorrhage to the adrenal glands, observed in two patients with acute leukaemia similar to the picture of Waterhouse-Friderichsen's syndrome. This complication causing serious and dramatic effects should be taken into differential diagnostic consideration. Literature data and own results are given in order to review the general characteristics of bleeding in acute leukaemia.