The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells.

The three DNA methyltransferase (DNMT)-inhibiting cytosine nucleoside analogues, azacitidine, decitabine and zebularine, which are currently studied as nonintensive therapy for myelodysplastic syndromes and acute myeloid leukemia (AML), differ in structure and metabolism, suggesting that they may have differential molecular activity. We investigated cellular and molecular effects of the three substances relative to cytarabine in Kasumi-1 AML blasts. Under in vitro conditions mimicking those used in clinical trials, the DNMT inhibitors inhibited proliferation and triggered apoptosis but did not induce myeloid differentiation. The DNMT inhibitors showed no interference with cell-cycle progression whereas cytarabine treatment resulted in an S-phase arrest. Quantitative methylation analysis of hypermethylated gene promoters and of genome-wide LINE1 fragments using bisulfite sequencing and MassARRAY suggested that the hypomethylating potency of decitabine was stronger than that of azacitidine; zebularine showed no hypomethylating activity. In a comparative gene expression analysis, we found that the effects of each DNMT inhibitor on gene transcription were surprisingly different, involving several genes relevant to leukemogenesis. In addition, the gene methylation and expression analyses suggested that the effects of DNMT-inhibiting cytosine nucleoside analogues on the cellular transcriptome may, in part, be unrelated to direct promoter DNA hypomethylation, as previously shown by others.

Helicobacter pylori eradication in the treatment and differential diagnosis of giant folds in the corpus and fundus of the stomach.

In an earlier study, we were able to show that giant fold gastritis is probably a special form of Helicobacter pylori-associated gastritis. Proof of this contention, however--namely regression of the giant folds following eradication of the organism--in a large number of patients was not then possible. To rectify this, Helicobacter pylori (HP) eradication treatment with omeprazole and amoxicillin was applied to 47 patients with HP gastritis and giant folds (5 patients with giant folds localized in the anterior or posterior wall, 42 patients with generalised giant folds within the corpus and fundus). The results of treatment were investigated by endoscopy and histology at the earliest 4 weeks after termination of treatment. In 40 of the 47 patients (85.1%), HP eradication treatment was successful. In 7 patients in whom treatment was unsuccessful, follow-up examinations revealed no changes in the endoscopic or histological findings. In 2 out of 3 patients in whom the endoscopic findings were unchanged despite successful HP eradication, biopsy material revealed the cause of the giant folds to be a signet ring cell carcinoma; in the remaining patient the cause of giant fold persistence was unclear. In 36 patients, the endoscopic--findings normalised completely, while in one patient there was obvious regression of the giant folds. We conclude from this study that giant fold gastritis is indeed a special form of HP gastritis, and that eradicating the organism in patients with gastric giant folds may help to distinguish between inflammatory, hyperplastic and tumorous giant folds.

[Partial portal vein and mesenteric vein thrombosis in familial protein S deficiency]. / Partielle Pfortader- und Mesenterialvenenthrombose bei familiärem Protein-S-Mangel.

Protein S, a vitamin-K dependent glycoprotein is a cofactor of protein-C system, which acts as an inhibitor of the plasmatic coagulation. Protein-S congenital deficiency results in recurrent venous thromboses, atypical locations in portal and mesenteric veins are possible. In our patient the partial thrombosis of the portal vein was diagnosed by computed tomography and angiography. Small bowel ischaemia due to mesenteric vein thrombosis required segmental resection. Post-operatively the patient was heparinized and later phenprocoumon was applied to a long-term therapy.

Giant fold gastritis--a special form of Helicobacter pylori associated gastritis.

We investigated the question as to how frequently Helicobacter pylori gastritis is present in cases of endoscopically detected giant folds of the corpus and fundic mucosa, and whether this gastritis differs from Helicobacter pylori associated gastritis with no giant folds. Biopsy material obtained from 138 patients with giant folds (sex ratio: 1.0 men: 105 women; average age 61.0 years) was evaluated histologically and compared with that obtained from 1,196 patients with H. pylori associated gastritis without giant folds (1.1 men: 1.0 women; average age 51.9 years). Among the patients with giant folds, H. pylori colonisation of the gastric mucosa was found in 88.4% of the cases. The degree of H. pylori colonisation determines the degree and activity of the gastritis in the antrum and corpus (p < 0.001). A comparison of the degree of colonisation with H. pylori, the degree of gastritis and the activity of the gastritis in patients with giant folds and in H. pylori gastritis without giant folds revealed no statistically significant differences within the antrum. In contrast, in the case of the corpus, a comparison between the two groups showed that H. pylori colonisation, degree of gastritis, and activity of gastritis were statistically significantly more pronounced in patients with giant folds than in patients with H. pylori gastritis but no giant folds (p < 0.0001). A comparative analysis showed that giant fold formation in the fundus and corpus of the stomach may be a consequence of severe high-grade active H. pylori gastritis, that is, a special and rare form of reaction to the colonisation of the gastric mucosa with Helicobacter pylori.(ABSTRACT TRUNCATED AT 250 WORDS)

The long-term prognosis of the primary glomerulonephritides. A morphological and clinical analysis of 1747 cases.

Long-term studies of all types of primary glomerulonephritis (GN) taking into consideration the major morphological and clinical findings revealed the following: 1) Endocapillary GN, post-streptococcal type has a very good prognosis when only glomerulitis is present. The prognosis is significantly worse if either interstitial inflammation with fibrosis or nephrotic syndrome (NS) is present at the time of the biopsy. 2) The prognosis of the various types of mesangioproliferative GN (IgA nephritis, non-IgA nephritis, and immunohistologically negative GN) is very good if there is only glomerulitis. The prognosis is worse for all three types when the renal cortical interstitium exhibits inflammation with fibrosis at the time of the biopsy, and is worst of all when both interstitial fibrosis (IF) and the signs of acute renal failure (ARF) are present. Of this group, the type in which there are negative immunohistological findings exhibits the best prognosis. No difference in prognosis is found between IgA nephritis and non-IgA nephritis. 3) Minimal changes GN with NS has a very good prognosis when the interstitium is not involved. The presence of interstitial inflammation and fibrosis worsens the prognosis significantly. 4) Focal sclerosing GN has a much poorer prognosis than minimal changes GN with NS, even when there is glomerulitis only (5- and 10-year renal survival rates (RSRs) of 90% and 67%, respectively). If interstitial inflammation and fibrosis are present, the prognosis is significantly worse (5- and 10-year RSRs of 84% and 55%, respectively). The prognosis is worst when both ARF and IF are present at the time of the biopsy (5- and 10-year RSRs of 56% and 46%, respectively). From the clinical side, the prognosis is significantly worse if, at the time of the biopsy, NS is present or the serum creatinine concentration is elevated to more than 1.3 mg%. 5) Chronic membranous GN has a better prognosis than focal sclerosing GN if glomerulitis only is present (5-year RSR, 88%; 10-year RSR, 77%). If the renal cortical interstitium is also involved (in the form of IF), the prognosis is significantly worse (5-year RSR, 65%; 10-year RSR, 38%). The prognosis in this disease, too, is worst when both ARF and IF are present at the time of the biopsy (5-year RSR, 38%; 10-year RSR, 25%). 6) Membranoproliferative GN has a worse prognosis than any of the types of GN so far mentioned (5-year RSR, 51%; 10-year RSR, 32%).(ABSTRACT TRUNCATED AT 400 WORDS)

[Acute cor pulmonale as a sequela of tumor embolism]. / Akutes Cor pulmonale als Folge einer Tumorembolie.

It is reported on a 22-year-old female patient with a chondroplastic osteosarcoma in the sacrum in whom in the course of her disease a massive embolism due to a tumour developed under the clinical picture of an acute pulmonary embolism. The clinical tentative diagnosis of a massive pulmonary embolism was confirmed by means of lung perfusion scintigram and pulmonary angiography. All efforts for a rapid recanalisation of the left pulmonary trunk by means of mechanical alteration, use of balloon catheter and subsequent thrombolysis were without success. Pathologo-anatomically a recurred tumorous thrombus embolism with an extensive pulmonary infarction in the left inferior lobe of the lung was found. The incidence as well as diagnostic viewpoints of embolisms due to tumour are discussed.

The pathogenesis of chronic renal failure in diabetic nephropathy. Investigation of 488 cases of diabetic glomerulosclerosis.

Investigation of renal biopsy specimens from 488 patients with diabetic glomerulosclerosis (DGS) of varying severity revealed the following: 1) The severity of DGS increases with the duration of the diabetes. 2) As the severity of DGS increases, it is complicated with increasing frequency by exudative changes, which correspond in detail to hyperperfusion lesions described in the literature. 3) As the severity of DGS increases, the severity of arteriolosclerosis and the incidence of nephrotic syndrome increase significantly. 4) The 5- and 10-year renal survival rates are highest for those diabetic patients in whom the tubules and renal cortical interstitium are of normal appearance. These survival rates are diminished if any of the following are present at the time of biopsy: a) interstitial fibrosis; b) hyperperfusion lesions; c) nephrotic syndrome; d) elevation of the serum creatinine concentration to more than 1.3 mg%. 5) No significant correlation was found between renal survival rate and age, sex, or type of diabetes. 6) The inflammation of the renal interstitium seen in diabetes does not differ from that seen in chronic glomerulonephritis. Monocytes, macrophages, T lymphocytes, fibroblasts and fibrocytes play the major role in this inflammation. This inflammatory process is considered to represent not pyelonephritis, but rather an auto-immune process. In other words, it is proposed that the diabetic kidney fails not only as a result of non-specific glomerular lesions (hyperperfusion lesions) but also because of non-specific tubulointerstitial changes, whereas diabetic glomerulosclerosis alone does not lead to chronic renal failure.

The consequences of tubulo-interstitial changes for renal function in glomerulopathies. A morphometric and cytological analysis.

Morphometric investigation of the structures of the cortex in kidneys exhibiting various types of glomerulopathy revealed the following: 1. In various types of glomerulonephritis, diabetic glomerulosclerosis, and glomerular amyloidosis there are significant correlations between the severity of fibrosis of the renal cortical interstitium and tubular atrophy resulting from chronic interstitial inflammation, and the serum creatinine concentration, creatinine clearance, inulin clearance and PAH clearance. 2. As illustrated with the example of membranoproliferative glomerulonephritis type I, if glomerulopathy alone is present, there is no elevation of the serum creatinine concentration, even if the glomerular inflammatory changes are severe; neither are severe renal amyloidosis that is confined to the glomeruli and severe isolated diabetic glomerulosclerosis associated with elevation of the serum creatinine concentration. 3. There is a significant negative correlation between the severity of interstitial fibrosis resulting from chronic inflammation and the total number and cross-sectional area of the intertubular capillaries; i.e., the total cross-sectional area and number of capillaries per unit area decrease as the fibrosis of the cortical interstitium increases. 4. Cases of glomerulonephritis in which there is accompanying fibrosis of the renal cortical interstitium have a significantly worse long-term prognosis than those in which there is only severe glomerulitis. 5. Obliteration of the post-glomerular capillaries leads to an increase in the cross-sectional area of the glomerular capillary convolution, the morphological equivalent of an increase in intraglomerular pressure. 6. The cause of the disease of the renal cortical interstitium that may accompany the various types of glomerulonephritis is not known. It is considered possible, as a working hypothesis, that this inflammation represents a T-cell stimulated autoimmune process in which fibroblast proliferation occurs, leading to an increase in numbers of fibrocytes in the renal cortical interstitium and thus to increased production of collagen.

IgA nephritis: on the importance of morphological and clinical parameters in the long-term prognosis of 239 patients.

This study is concerned with the correlation between tubulointerstitial changes (interstitial fibrosis, acute renal failure, and interstitial fibrosis with acute renal failure), glomerular changes (focal and segmental lesions, hyperperfusion lesions), vascular changes, clinical data at the time of biopsy (serum creatinine concentration, creatinine clearance, hematuria, proteinuria, and hypertension) and first symptoms (hematuria, proteinuria and hypertension) and the kidney survival rate in 239 patients with IgA nephritis without nephrotic syndrome. The morphological and clinical parameters were subjected to multivariate analysis in order to examine their significance with regard to the prognosis. The interstitial fibrosis was proven to be the most important morphological parameter, and the most important clinical parameters were the serum creatinine concentration and the creatinine clearance.

Long-term prognosis of chronic idiopathic membranous glomerulonephritis. An analysis of 334 cases with particular regard to tubulo-interstitial changes.

A retrospective long-term study (average follow-up time 5.2 years) of 334 patients with idiopathic membranous glomerulonephritis (MGN) was carried out with the following results: 1) MGN was found to have a relatively good prognosis when all cases were considered together: 5-year kidney survival rate (KSR) -88%, and 10-year KSR -77%. 2) Univariate survivorship analysis showed the following morphological and clinical parameters to be associated with an increased risk of terminal renal insufficiency or death from renal disease: a) tubulo-interstitial changes; b) glomerular stage III as opposed to stages I and II; c) elevation of serum creatinine concentration at the time of the biopsy; d) arterial hypertension at the time of the biopsy. 3) Multivariate analysis showed that only tubulo-interstitial changes (interstitial fibrosis and/or acute renal failure) found at the time of the biopsy and their clinical correlate, serum creatinine concentration, were significant and therefore of definite prognostic importance. 4) Unsystematic therapy with steroids and/or cytostatic agents does not improve the long-term prognosis of MGN. 5) The cause of disease in the tubulo-interstitial system in MGN is discussed. Interstitial fibrosis is considered to develop possibly as a consequence of unresorbed interstitial edema which can develop during an episode of acute renal failure. Coexisting T-cell-mediated disease in the region of the intertubular capillaries is also considered as a possible factor in the development of interstitial fibrosis.