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M Sachs

Publications and source records attributed to M Sachs.

At least 19 recordsLinked to original sources
PubMed1992

A functional domain in the heavy chain of scatter factor/hepatocyte growth factor binds the c-Met receptor and induces cell dissociation but not mitogenesis.

We recently found that scatter factor (SF), a cell motility factor with a multimodular structure, is identical to hepatocyte growth factor (HGF), a potent mitogen of various cell types. SF/HGF is the ligand of the c-Met receptor tyrosine kinase. Here we used transient expression of naturally occurring and in vitro mutagenized cDNAs of SF/HGF to delineate the protein domains necessary for biological activity and binding to the c-Met receptor. (i) A single-chain SF/HGF resulting from the destruction of the protease cleavage site between heavy and light chain (Arg-494--> Gln) was largely inactive, indicating that proteolytic cleavage is essential for acquisition of the biologically active conformation. (ii) A SF/HGF splice variant encoding a protein with a 5-amino acid deletion in the first kringle domain was as highly active as the wild-type molecule. (iii) The separately expressed light chain (with serine protease homology) was inactive in all assays tested. (iv) The separate heavy chain as well as a naturally occurring splice variant consisting of the N terminus and the first two kringle domains bound the c-Met receptor, stimulated tyrosine auto-phosphorylation, and induced scattering of epithelial cells but not mitogenesis. These data indicate that a functional domain in the N terminus/first two kringle regions of SF/HGF is sufficient for binding to the Met receptor and that this leads to the activation of the downstream signal cascade involved in the motility response. However, the complete SF/HGF protein seems to be required for mitogenic activity.

Amino Acid Sequence↗
PubMed1992

Detection of human immunodeficiency virus type 1 provirus in mononuclear cells by in situ polymerase chain reaction.

BACKGROUND: Studies of human immunodeficiency virus type 1 (HIV-1) infection have attempted to quantitate the viral load correlate it with the degree of immune deficiency. In one study, only about 1 in 10,000 peripheral-blood mononuclear cells (PBMC) expressed HIV-1, but in other studies, at least 1 in 100 CD4-positive cells was infected and harbored the HIV-1 provirus. METHODS: We developed a new, highly sensitive in situ polymerase-chain-reaction (PCR) method that amplifies selected genetic regions within intact single cells. We used this technique to determine the proportion of PBMC carrying HIV-1 provirus in infected patients in different stages of disease. RESULTS: None of the PBMC from 11 HIV-1--seronegative patients were found to be positive for HIV-1 provirus by the in situ PCR method. In 56 patients infected with HIV-1, the percentage of PBMC with HIV-1 ranged from 0.1 percent to 13.5 percent. The mean percentage of infected mononuclear cells was greater in 13 patients with persistent generalized adenopathy (mean, 6.6 percent) and 19 with the acquired immunodeficiency syndrome (Stages IV-A to IV-C) (4.6 percent) than in 19 patients with asymptomatic HIV-1 infection (0.9 percent) (P less than 0.001). However, in five patients with Kaposi's sarcoma (Stage IV-D), an average of only 1.6 percent of mononuclear cells were infected. CONCLUSIONS: In HIV-1 infection, the proportion of PBMC that are infected appears to be at least 10 times higher than previously described. It is likely that most infected cells contain HIV-1 provirus in a latent or defective form that was not detected in some earlier studies.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Extracellular proteolytic cleavage by urokinase is required for activation of hepatocyte growth factor/scatter factor.

The extracellular protease urokinase is known to be crucially involved in morphogenesis, tissue repair and tumor invasion by mediating matrix degradation and cell migration. Hepatocyte growth factor/scatter factor (HGF/SF) is a secretory product of stromal fibroblasts, sharing structural motifs with enzymes of the blood clotting cascade, including a zymogen cleavage site. HGF/SF promotes motility, invasion and growth of epithelial and endothelial cells. Here we show that HGF/SF is secreted as a single-chain biologically inactive precursor (pro-HGF/SF), mostly found in a matrix-associated form. Maturation of the precursor into the active alpha beta heterodimer takes place in the extracellular environment and results from a serum-dependent proteolytic cleavage. In vitro, pro-HGF/SF was cleaved at a single site by nanomolar concentrations of pure urokinase, generating the active mature HGF/SF heterodimer. This cleavage was prevented by specific urokinase inhibitors, such as plasminogen activator inhibitor type-1 and protease nexin-1, and by antibodies directed against the urokinase catalytic domain. Addition of these inhibitors to HGF/SF responsive cells prevented activation of the HGF/SF precursor. These data show that urokinase acts as a pro-HGF/SF convertase, and suggest that some of the growth and invasive cellular responses mediated by this enzyme may involve activation of HGF/SF.

Animals↗
PubMed1992

[Metabolic changes in a patient in the early phase of acute pancreatitis].

The present paper reports on the perioperative metabolic changes in a 70-year-old female patient in whom an acute (oedematous) pancreatitis occurred during the transduodenal excision of a villous adenoma of the duodenal papilla. Since blood was taken for metabolic investigations before, during and after surgery, data on the changes in the intermediary metabolism during the early phase of acute pancreatitis in humans was recorded. Raised activity of the pancreatic enzymes amylase and lipase was demonstrable just minutes after extirpation of the papillary tumour after intraoperative cholangiography had been performed via a choledochotomy. This showed occlusion of the duodenal papilla as well as imaging the pancreatic duct. The reflux of bile into the pancreatic duct is considered to be one of the causative factors of acute pancreatitis (Opie-syndrome). The following metabolic changes were registered at surgery and on the first day thereafter: reduction in the serum concentration of cholesterol ester, the triglycerides and the phospholipids by 30 to 50% of the preoperative values respectively, as well as lactacidaemia (up to 60 mg/dl). At the same time, the serum bilirubin concentration and the concentrations of the amino acids alanine and glutamate in the serum were temporarily raised. The question is, whether these metabolic changes were a direct consequence of the activity of the pancreatic enzymes of amino acid and lipid metabolism that were released into the blood, or whether reduced synthesis by the liver (lipoproteins, lecithin: cholesterol-acyl-transferase) was responsible for these changes.

Acute Disease↗
PubMed1991

[Metabolic changes in patients with hereditary fructose intolerance. A contribution to the topic of fructose administration for parenteral feeding].

The literature contains a number of reports of death following the intravenous administration of fructose in patients with hereditary fructose intolerance (HFI). The aim of the present study was, therefore, to investigate the metabolic changes occurring during intravenous administration of fructose to patients with HFI, with the aim of identifying metabolic parameters that would permit the early diagnosis of HFI. Also, the deaths reported in the literature were analyzed. In three of our own patients with fruit intolerance known since childhood, and in volunteers with normal metabolism, a one-hour intravenous fructose tolerance test (1.7 g fructose/min) was performed. An analysis was done using the usual enzymatic and chemical methods: blood glucose, fructose, lactic acid, serum uric acid, ammonia, free fatty acids, inorganic phosphate, and serum amino acids (ion exchange chromatography). During fructose infusion, the following metabolic changes were detected: hypoglycemia (20 to 60 mg/dl), increase in blood fructose levels (up to 350 mg/dl), hypophosphatemia (2 to 3 mg/dl), hyperlacticacidemia (up to 60 mg/dl), elevation of plasma ammonia levels (up to 120 mg/dl), increased serum glutamate, and a decrease in serum glutamine, as also hyperuricemia (up to 10 mg/dl). On termination of the fructose infusion, these changes were completely reversible. Analysis of the deaths reported in the literature revealed a known intolerance to fruit or sweets, and that no regular metabolic studies were apparently performed. Although HFI is rare, use should be made of the known advantages of sugar substitutes in post-aggression metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

The role of E-cadherin and scatter factor in tumor invasion and cell motility.

The acquisition of invasive properties by transformed epithelial cells constitutes an essential step in the progression of carcinomas. We have defined 2 types of interferences leading to enhanced motility and invasiveness of epithelial cells: (i) disturbances of intercellular adhesion, and (ii) treatment with "scatter factor", a secretory protein of mesenchymal cells. Invasive properties (invasion of collagen gels or embryonal heart tissue) are acquired by epithelial cells in vitro when intercellular adhesion is inhibited by antibodies that are specific for the cell-cell adhesion molecule E-cadherin. Furthermore, we found that differentiated human carcinoma cell lines are noninvasive and express E-cadherin, whereas dedifferentiated carcinoma lines are invasive and have lost E-cadherin expression. Invasiveness of these latter cells could be prevented by transfection with E-cadherin cDNA and was again induced by treatment of the transfected cells with anti-E-cadherin antibodies. A correlation between the degree of tumor differentiation and the amount of E-cadherin expression was also visualized on frozen sections of ovarian carcinomas, lobular breast carcinomas, and squamous carcinomas of head and neck. Thus, loss of E-cadherin appears to be a critical step in the establishment of an invasive, i.e. fully malignant phenotype. Scatter factor, which is also capable of dissociating epithelial cell colonies in vitro, was isolated from conditional medium of human fibroblasts; it is a 92,000 mol.wt glycoprotein, which is proteolytically cleaved into 62,000 and 34/32,000 mol.wt subunits. The purified glycoprotein induces invasion of MDCK cells into collagen matrices, and induces or enhances the invasive properties of various human carcinoma cell lines. Sequencing of tryptic peptides of scatter factor revealed strong similarity with hepatocyte growth factor. Furthermore, both factors exhibit identical activities, i.e. scatter factor stimulates DNA synthesis of primary hepatocytes and hepatocyte growth factor dissociates and increases the motility of various epithelial cells. Thus scatter factor and hepatocyte growth factor represent identical or closely similar proteins.

Amino Acid Sequence↗
PubMed1991

[Synchronous development of benign cholangiomas and a cholangiocarcinoma in the liver of a patient 43 years after thorotrast administration].

This is a report on a 59-year-old patient in whom the synchronous occurrence of benign cholangiomas and a cholangiocarcinoma was observed in the liver 43 years after single intraarterial application of thorotrast. Despite a half-life of over 130 years (alpha radiation), X-ray contrast media containing thorium (colloidal thorium dioxide) were used up to the 1950's in X-ray diagnosis, particularly for angiographies. Thorotrast is mainly stored in the liver, in the spleen and in epigastric lymph nodes and can therefore be easily detected radiologically in a survey radiograph of the abdomen. International studies have shown that thorotrast patients have an up to 100 times greater risk of contracting hepatic malignancies compared to control collectives. Among the causes of death of thorotrast carriers in the (old) Federal Republic of Germany, 15% are attributed to primary hepatic tumours (cholangiocarcinomas, malignant haemangioendotheliomas, hepatic cell carcinomas). In the patient presented here, a cystic mass approximately 2 cm in diameter was detected in the right lobe of the liver during computed tomography of the epigastric region conducted as part of the German Thorotrast Study at the German Cancer Research Centre in Heidelberg, as well as in sonography. Intraoperatively, this finding corresponded to a cystic cholangioma. By chance, a cholangiocarcinoma approximately 1 cm in size and several benign cholangiofibromas were also found in the left lobe of the liver. All of the tumours were excised in toto by atypical segment resection. As shown by this case report, thorotrast-induced hepatic tumours are still to be expected, even 40 years after thorotrast was removed from the market.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma, Bile Duct↗
PubMed1991

Steroid profiles of brown adipose tissue.

In brown adipose tissue of alp-marmot (Marmota marmota), badger (Meles meles) and Wistar rats steroids of C21- and C19-type are identified and quantified. The detection of 3 alpha-hydroxy-5 alpha-pregnan-20-one, 3 alpha-hydroxy-5 beta-pregnan-20-one, 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one, 3 alpha,21-dihydroxy-5 beta-pregnan-20-one and 3 beta,21-dihydroxy-5 alpha-pregnan-20-one is of special interest since sleep-inducing properties have been described with these steroids.

Adipose Tissue, Brown↗
PubMed1991

E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells.

The ability of carcinomas to invade and to metastasize largely depends on the degree of epithelial differentiation within the tumors, i.e., poorly differentiated being more invasive than well-differentiated carcinomas. Here we confirmed this correlation by examining various human cell lines derived from bladder, breast, lung, and pancreas carcinomas. We found that carcinoma cell lines with an epithelioid phenotype were noninvasive and expressed the epithelium-specific cell-cell adhesion molecule E-cadherin (also known as Arc-1, uvomorulin, and cell-CAM 120/80), as visualized by immunofluorescence microscopy and by Western and Northern blotting, whereas carcinoma cell lines with a fibroblastoid phenotype were invasive and had lost E-cadherin expression. Invasiveness of these latter cells could be prevented by transfection with E-cadherin cDNA and was again induced by treatment of the transfected cells with anti-E-cadherin mAbs. These findings indicate that the selective loss of E-cadherin expression can generate dedifferentiation and invasiveness of human carcinoma cells, and they suggest further that E-cadherin acts as an invasion suppressor.

Antibodies, Monoclonal↗
PubMed1991

[Pancreatogenic pleuritis and pancreatico-pleural fistula: pathogenesis, diagnosis and therapy].

Two patients with alcohol-induced chronic pancreatitis are presented, who developed a massive pleural effusion characterized by an extremely high amylase content. We report our diagnostic observations and therapeutic experiences in non-operative and surgical management. A review on the pertinent literature is given. Acute pancreatitis frequently (10-20%) occurs in conjunction with small left-sided pleural effusions. These effusions usually undergo spontaneous regression. Their genesis is explained by vascular transdiaphragmatic inflammatory involvement of the pleural space. In patients with alcohol-induced chronic pancreatitis pleural effusion is, however, a rare event. The activity of the pancreas-specific enzymes (amylase, lipase) are extremely high. The most likely underlying pathogenetic mechanism is transdiaphragmatic lymphatic transfer of pancreatic secretions to the subpleural space. A rare cause is the formation of a pancreatico-pleural fistula. The use of endoscopic retrograde pancreatography (ERP) can reveal the site of pancreatic fistulas to the pleural cavity.

Alcoholism↗
PubMed1990

[The metabolism of panthenol in patients with postoperative intestinal atony].

The aim of this study was the examination of the metabolism and mechanism of action of D-pantothenyl alcohol in patients with postoperative intestinal atony. Seven metabolically healthy patients were examined on the 4th day following colorectal surgery, before bowel activity had started. Increased urinary excretion of the vitamin pantothenic acid was noted following the intravenous application of 2 gm of D-pantothenyl alcohol. Ten to 30% of the administered dose D-pantothenyl alcohol is excreted in the urine as pantothenic acid within 24 h. Simultaneously, the urinary excretion of beta-alanine, a pantothenic acid component, is increased. D-pantothenyl alcohol was metabolized to pantothenic acid in all the patients examined. Pantothenic acid is a component of coenzyme A, a key substance in the intermediary pathway of metabolism. Coenzyme A plays a role in the synthesis of acetylcholine from choline (a co-enzyme of cholinacetylase). Peristalsis induced by D-pantothenyl alcohol may be due to the increased synthesis of coenzyme A and acetylcholine in the autonomic nerve plexus of the intestinal tract.

Gastrointestinal Motility↗
PubMed1990

Results of surgical treatment for atherosclerotic renovascular occlusive disease.

In this study we retrospectively examined the results of surgery for atherosclerotic renal artery lesions and analysed the factors that may affect postoperative blood pressure response, changes in renal function and late mortality. A total of 326 patients were operated on over a 15 year period and were followed up for periods from 4 to 165 months (mean follow-up time: 37.2 months). An extra renal vascular area was also involved in 91.4% of cases and in 187 (57.3%) a significant involvement of both renal arteries was found and simultaneously treated. Combined revascularisation of other arteries was performed in 50.3% of patients. The indications for surgery were the treatment of extreme hypertension in 243 patients (74.5%), the improvement of renal function in 45 with renal insufficiency, and preservation of the kidney in 38 (11.7%). The preferred method of reconstruction was transaortic endarterectomy (236 cases, i.e. 72.4%) and postoperative angiography demonstrated a normal patent renal artery in 319 of 338 studied renal arteries (94.4%). There were no deaths in the early postoperative period after isolated renal artery reconstruction. Of the 164 patients with simultaneous renal and aortic reconstruction however 14 died during the early postoperative phase. The overall early mortality was thus 4.3% (14 out of 326 patients) and correlated significantly with the extent of the atherosclerotic disease, the age of the patients, the operative technique used and the different intra- and postoperative management during the two different periods of our experience (1974-1980 v. 1981-1989).(ABSTRACT TRUNCATED AT 250 WORDS)

Arteriosclerosis↗
PubMed1989

[Metabolic changes and infusion therapy in ileus].

The aim of the investigation was to determine the changes in intermediary metabolism that occur in cases of ileus, and to develop a concept for parenteral perioperative nutrition on a pathophysiological basis. Seventeen metabolically healthy patients, suffering from mechanical ileus, have been evaluated. Besides the nonspecific metabolic changes characteristic of the postaggressive metabolism (abnormalities in peripheral glucose utilization, gluconeogenesis, lipolysis, proteolysis) we were able to demonstrate elevated serum levels of albumin, lactate and arachidonic acid preoperatively in these patients. The plasma histamine levels lay within normal limits. In the immediate postoperative phase (i.e. from 1.-3. postoperative day) we found a marked reduction in the serum levels of glucoplastic amino acids (about 30%), albumin (40%), pre-albumin (80%) and cholesterol (50%). We therefore suggest that, apart from electrolyte solutions, patients with an ileus should receive fructose (1600 kcal/day) preoperatively and from the first postoperative day amino acids (1 g/kg of body weight) and human albumin (as required) should be administered in addition.

Amino Acids↗
PubMed1989

Faecal short-chain fatty acids after colonic surgery.

Carbohydrates from dietary fibre and starch are broken down by the anaerobic microflora to short-chain fatty acids (SCFA) in the caecum and ascending colon. In this study the adaptation of the remaining distal colon or ileum to resection of various lengths of the proximal colon was investigated. Faecal SCFA concentrations (mumol/g wet weight) were measured after right hemicolectomy (n = 10), subtotal colectomy (n = 3) and total colectomy (n = 8) and compared with SCFA in control subjects (n = 21). After right hemicolectomy faecal SCFA (48.7 +/- 5.6) were not different from values obtained in control subjects (47.8 +/- 4.0). SCFA levels after subtotal colectomy (14.5 +/- 0.8) and total colectomy (6.7 +/- 1.4) were significantly lower than after right hemicolectomy and in controls. It is concluded that, after right hemicolectomy, the remaining left colon offers conditions favourable to bacterial fermentation. After subtotal or total colectomy, however, postoperative conditions do not allow a normal fermentative activity. The consequences of a reduced SCFA production for sodium and fluid absorption are discussed.

Adult↗