Biomedical subjects
Publications and source records attributed to A Holstege.
Methyl-t-butylether is a new agent to dissolve gallstones. The substance proves to be very successful and acts very rapidly. A percutaneous transhepatic drainage supplies an adequate access route to dissolve calculi within the bile ducts. We report the case of a patient where before insertion of an internal stent a stone in the common bile duct was dissolved within 3 1/2 hours.
A causal relationship exists between the incidence of peptic ulcer and smoking: smoking is significantly associated with a higher prevalence of gastric duodenal ulcer. Either type of peptic ulcer demonstrates a lower healing rate in smokers as compared to non-smokers and impaired spontaneous and drug-induced healing. Smoking is a major factor for rapidity of duodenal ulcer recurrence. Incidence, healing rate, and recurrence rate correlate with the number of cigarettes smoked. Beyond this, smoking increases the likelihood of ulcer perforation. The normal life expectancy is reduced in smokers after gastric surgery for peptic ulcer disease. Moderate alcohol and caffeine consumption presumably have no effect on the incidence of peptic ulcer. However, continuous alcohol abuse seems to increase the prevalence of duodenal ulcer. In ulcer disease, it seems unwarranted to exclusively interdict caffeine-containing or alcoholic beverages while permitting other equally potent stimulants of gastric acid secretion like milk.
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Radiology and endoscopy are usually used to diagnose stenosis of the duodenum, but the cause of the stenosis may still escape detection. Three pathologic processes--multiple duodenal polyps, duodenal wall cysts, and annular pancreas--are presented to demonstrate how ultrasound, under specific conditions, can provide decisive diagnostic information. The cause of the stenosis may be made accessible to sonographic study through administration of oral fluids and intravenous hyoscin-n-butylbromid (Buscopan).
Percutaneous transhepatic drainage (PTD) is associated with many long-term complications. Therefore a large-diameter endoscopic endoprosthesis is preferentially employed to bridge a malignant obstruction of the biliary tract. Only if the placement of an endoprosthesis fails, must PTD be established. We present a simple method for converting PTD into a large endoprosthesis (14 F) with the aid of endoscopy. We have performed this conversion successfully in 8 patients without complications.
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In TA3 mammary carcinoma cells in suspension culture, D-glucosamine X HCl (GlcN) induced a diversion of uridylate from UTP into UDP-N-acetylhexosamines, reducing the intracellular pool of UTP and eliciting an increased rate of de novo uridylate synthesis. This rise in de novo synthesis was completely suppressed by addition of 6-azauridine (6-AzaUrd) to the cell suspension in vitro or in the solid TA3 mammary tumor in NMRI mice in vivo. A synergistic depletion of UTP pools to less than 6% of the UTP in controls was observed in TA3 cell suspensions exposed to GlcN and 6-AzaUrd. In solid TA3 tumors in vivo, UTP was reduced by this combination to 19% of the control value. A high sensitivity of the solid tumor to inhibition of pyrimidine synthesis de novo was indicated by the reduction of the UTP content after administration of 6-AzaUrd alone. UTP deficiency in TA3 tumor cells was accompanied by CTP deficiency. In addition, 6-AzaUrd caused a lowering of GTP in the neoplastic tissue. Host liver was resistant to 6-AzaUrd but responded to treatment with GlcN with a decrease in UTP to 67%. Uridine-cytidine kinase was less inhibited in the presence of lowered UTP and CTP, which are potent feedback inhibitors of the enzyme, and enabled an enhanced formation of phosphorylated derivatives of 5-fluorouridine (FUrd). Aside from the formation of 5-fluoro-UTP, we have identified 5-fluoro-UDP-N-acetylhexosamines (FUDPHexNAc), which accumulated when FUrd and GlcN were sequentially administered. Treatment of TA3 cells with FUrd after a pretreatment with 6-AzaUrd and GlcN resulted in a 2.5-fold increase in [14C]FUrd uptake and a duplication of 5-fluorouridylate incorporation into the RNA. The proportion of FUDPHexNAc increased to 58% of the phosphorylated FUrd metabolites, as compared to 6% in TA3 cells exposed exclusively to FUrd. In vivo chemotherapy of mice bearing TA3 ascites tumors was most effective with respect to tumor growth inhibition and animal survival when GlcN and FUrd were combined.
The inhibitory effect of 5-diazouracil on the catabolism of circulating uracil and 5-fluorouracil was examined in the rat in vivo. Measurements of the activity of the entire enzymatic pathway of uracil catabolism in the cytosolic supernatant of different rat organs as well as the determination of the total amount of 5-fluorouracil catabolites, accumulated in these tissues, served to clarify their role in the complete systemic breakdown of uracil or 5-fluorouracil. The activity of the enzymatic pathway involved in uracil catabolism was estimated from the 14CO2 produced from [2-14C]uracil in the cytosolic supernatants. Complete degradation of uracil was detected only in the liver and, at a much lower rate, in the kidneys. Fifteen min after the i.p. injection of a tracer dose of 5-fluoro[6-14C]-uracil, more than 90% of the total radioactivity in blood plasma was associated with 5-fluorouracil catabolites. The relative amount of the major catabolite alpha-fluoro-beta-alanine and of dihydrofluorouracil in blood plasma was considerably suppressed after a pretreatment with 5-diazouracil inversely correlated with a 27-fold increase in the absolute amount of unchanged 5-fluorouracil. Control animals accumulated by far the highest amount of total acid-soluble radioactivity from 5-fluoro[6-14C]uracil in liver and kidneys. Total radioactivity in all other organs was much lower and was comparable to the amount of label in blood plasma. In liver and kidneys, the sum of total acid-soluble catabolites including dihydrofluorouracil, alpha-fluoro-beta-ureidopropionic acid, and alpha-fluoro-beta-alanine made up more than 98% of the label correlating with minimal salvage utilization of the base analogue in both organs. Injection of 5-diazouracil 2 h before a tracer dose of 5-fluoro[6-14C]uracil strongly inhibited the accumulation of labeled catabolites in liver and kidneys causing a fall in total acid-soluble radioactivity in both tissues by 75 and 66%, respectively. In blood plasma and all other organs, however, pretreatment with 5-diazouracil was followed by a 2-fold enhancement of the radioactivity contents, mostly due to the appearance of unchanged 5-fluorouracil. Under these conditions, there was a 2.6- to 4-fold increase in the relative proportion of cis-diol group-containing anabolites of 5-fluorouracil in liver and in kidneys. Within 2 h, 12.7% of the administered radioactivity from 5-fluorouracil was excreted into bile. 5-Diazouracil lowered the biliary excretion of radioactivity to 2% of the injected dose.(ABSTRACT TRUNCATED AT 400 WORDS)
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The indication for radiologic or endoscopic examinations in ulcerative colitis and Crohn's disease depends on the stage of the disease. Advantages of the colonoscopy are the possibility to take biopsies, the coloured few of lesions and the avoidance of X-rays in the management of young patients. Radiology is superior to endoscopy in estimating shortening of the bowel, stenoses and fistulas.
Kupffer cells, endothelial cells, and hepatocytes were separated by centrifugal elutriation. The rate of uracil formation from [2-14C]uridine, the first step in uridine catabolism, was monitored in suspensions of the three different liver cell types. Kupffer cells demonstrated the highest rate of uridine phosphorolysis. 15 min after the addition of the nucleoside the label in uracil amounted to 51%, 13%, and 19% of total radioactivity in the medium of Kupffer cells, endothelial cells, and hepatocytes, respectively. If corrected for Kupffer cell contamination, hepatocyte suspensions demonstrated similar activities as endothelial cells. In contrast to non-parenchymal cells, hepatocytes continuously cleared uracil from the incubation medium. The lack of uracil consumption by Kupffer cells and endothelial cells points to uracil as the end-product of uridine catabolism in these cells. Kupffer cells and endothelial cells did not produce radioactive CO2 upon incubation in the presence of [2-14C]uridine. Hepatocytes, however, were able to degrade uridine into CO2, beta-alanine, and ammonia as demonstrated by active formation of volatile radioactivity from the labeled nucleoside. There was almost no detectable formation of thymine from thymidine or of cytosine, uracil, or uridine from cytidine by any of the different cell types tested. These results are in line with low thymidine phosphorolysis and cytidine deamination in rat liver. Our studies suggest a co-operation of Kupffer cells, endothelial cells, and hepatocytes in the breakdown of uridine from portal vein blood with uridine phosphorolysis predominantly occurring in Kupffer cells and with uracil catabolism restricted to parenchymal liver cells.
A case of enterogenous cysts of the duodenum in a 44-yr-old man complicated by duodenal obstruction and relapsing pancreatitis is presented. The cystic duodenal lesions were visualized by endoscopic retrograde cholangiopancreatography and for the first time by computed tomography and abdominal sonography. Thus, the diagnosis was made preoperatively. The cysts were excised successfully during a Whipple procedure. Awareness of this rare condition combined with modern x-ray, sonographic, and endoscopic techniques permit accurate preoperative diagnosis.
The combination of 3 types of antipyrimidines was studied in AS-30D hepatoma cells in suspension culture and in the rat in vivo. Cellular UTP and CTP pools can be depleted most effectively by combining an inhibitor of de novo UMP synthesis with sugar analogs diverting UMP to UDP-sugar analogs. The following UMP-trapping sugar analogs were employed: D-galactosamine, D-galactosone, D-glucosone, and D-glucosamine. These D-galactose and D-glucose analogs intensified the depletion of UTP and CTP pools induced by the following inhibitors of de novo UMP synthesis: acivicin, PALA, lapachol, pyrazofurin, and 6-azauridine. The sugar analogs, in the absence of inhibitors of the de novo pathway, enhanced the rate of de novo UMP synthesis several-fold, as indicated by incorporation of 14CO2 into intermediates and products of the pathway and by the expansion of the acid-soluble uracil nucleotide pool. Reduction of UTP and CTP contents to less than 5 and 15% of control, respectively, by D-galactosamine and PALA resulted in a decrease of the rate of RNA synthesis to 19% of control as calculated from the changes in specific activities of [14C]CTP and of [14C]cytidine in RNA after labeling with [14C]uridine. Hepatoma cells released uridine and cytidine into the extracellular fluid. This release was reduced to one third in UTP-deficient cells, indicating that pyrimidine nucleoside excretion is regulated by pyrimidine nucleotide levels, possibly by UTP and CTP regulation of uridine kinase. Determination of the rates of de novo pyrimidine synthesis, of the formation of RNA pyrimidines, and of pyrimidine nucleoside excretion indicates that de novo synthesis provides only about 67% of the pyrimidines required for the consuming processes. The difference, as well as the dilution of labeled pyrimidine nucleotide pools under conditions of a blocked de novo pathway, suggests a considerable salvage of pyrimidine nucleosides derived from RNA. This salvage of pyrimidines may be intracellular and/or by an excretion and re-uptake process. Depletion of UTP and CTP pools, induced in hepatoma cells by D-galactosamine and 6-azauridine, leads to growth inhibition in suspension culture; this inhibition becomes irreversible in an increasing percentage of cells, killing all cells after 20 hr of UTP deficiency. The enhanced uptake of 5-fluorouridine by UTP-deficient cells was associated with an increase of FUMP incorporation into RNA up to 4-fold and with stronger inhibition of cell growth.(ABSTRACT TRUNCATED AT 400 WORDS)
The inhibition of cytosolic carbamoyl-phosphate synthetase II by acivicin was used to study the role of the cytosolic carbamoyl phosphate pool as the exclusive substrate source for de novo pyrimidine synthesis in rat hepatocytes. De novo pyrimidine synthesis was stimulated: 1. by uridine triphosphate deficiency (incubation with D-galactosamine) leading to a stimulation of cytosolic carbamoyl phosphate synthesis, and 2. by accumulation and efflux of mitochondrial carbamoyl phosphate (incubation with ammonium ions and L-norvaline). The stimulated orotate formation from cytosolic carbamoyl phosphate in UTP depleted cells was completely blocked by acivicin. It was not influenced by an inhibition of mitochondrial carbamoyl phosphate synthesis mediated by 4-pentenoate, since mitochondrial carbamoyl phosphate did not participate in cytosolic pyrimidine synthesis even in the presence of ammonium ion concentrations maintaining physiological rates of urea synthesis. An excess of ammonium ions led to an artificial accumulation and efflux of mitochondrial carbamoyl phosphate, which could be avoided by 4-pentenoate. The non-regulated stimulation of pyrimidine synthesis from surplus mitochondrial carbamoyl phosphate was not inhibited by acivicin. Utilization of mitochondrial carbamoyl phosphate for de novo pyrimidine synthesis presumably does not occur under physiological conditions because mitochondrial CP efflux depends on the accumulation of this metabolite in the mitochondria under experimental or pathological circumstances. Acivicin inhibition of CPS II thus cannot be bypassed by mitochondrial CP. It is suitable as inhibitor of the physiological de novo pyrimidine synthesis.
Uridylate-trapping analogs of D-galactose or D-glucose divert the uridylate moiety of UDPglucose and/or UTP to UDP-sugar analogs that accumulate while the pools of UTP and of related pyrimidine nucleotides are depleted. The uridylate-trapping action of sugar analogs is determined by the enzyme pattern of the target tissue. D-Galactose analogs are preferentially metabolized by hepatoma cells and hepatocytes. TA3-mammary tumor cells are susceptible to the action of D-glucosamine and other D-glucose analogs. A high rate of de novo pyrimidine synthesis and/or an active salvage of extracellular uridine compensate for the uridylate-trapping action of sugar analogs and prevent depletion of UTP pools. Accordingly, synergistic actions are induced by combining sugar analogs, such as D-galactosamine or D-glucosamine, with inhibitors of de novo pyrimidine synthesis, such as lapachol or 6-azauridine. Uridylate-trapping by D-galactosamine, acting on hepatocytes, shifts the balance between uridine consumption and uridine release by the liver and results in a fall of uridine and cytidine concentrations in blood plasma (20). Cultured hepatocytes produce uridine and cytidine. Combination of 5-fluorouridine with sugar analogs results in the formation of fluorinated UDP-sugar analogs in hepatoma cells or in mammary tumor cells. Formation of FUDP-sugar analogs transiently removes intracellular FUTP, but FUDP can be released subsequently in glycosyltransferase reactions (22). Pretreatment of hepatoma cells or of TA3-mammary tumor cells with an uridylate-trapping sugar analog in combination with an inhibitor of de novo pyrimidine synthesis enhances the uptake of 5-fluorouridine, its incorporation into RNA, and its growth inhibitory effect. The chemotherapeutic action of 5-fluorouridine in rats and mice, carrying the AS-30D and the TA3 ascites tumor, respectively, is significantly improved by pretreatment with an amino sugar together with 6-azauridine.
Sixteen unselected patients with non-resectable hepatocellular carcinoma were treated in a phase I study with 261 cycles of D-galactosamine and 6-azauridine prior to 5-fluorouridine. Thirty % of the patients survived for more than one year without signs of tumor progression and with an unchanged performance status. The compatibility of this chemotherapeutical method was quite satisfactory. The only extrahepatic side effect was a leucopenia and/or thrombocytopenia which was reversible upon reduction of the 5-fluorouridine dose. The heterogeneity of the 16 patients treated to date does not allow a definite statistical evaluation of the reported clinical observations and results. A final decision about the clinical applicability of this concept of a selective chemotherapy of hepatocellular carcinoma requires further experience.
Pyrimidine nucleosides in blood plasma of rats were identified by different procedures, including chemical peak shift methods, before their quantification by reversed-phase high-performance liquid chromatography. The concentrations of uridine, cytidine, and deoxycytidine were 1.0 +/- 0.2, 10.6 +/- 1.9, and 33.4 +/- 5.4 mumol/l, respectively. Six hours after the administration of D-galactosamine, the level of circulating cytidine was severely depressed to 25% of control values; uridine decreased to 54% while deoxycytidine remained unchanged. 24 h after the dose of the amino sugar, the levels of cytidine and uridine returned to control values in blood plasma. Total acid-soluble uridine, cytidine, guanosine, and adenosine was determined by reversed-phase HPLC after treatment of the neutralized acid-soluble supernatant of freeze-clamped rat livers with phosphodiesterase and alkaline phosphatase. Six hours after its administration, D-galactosamine induced a 2.2-fold and a 1.6-fold rise in total acid-soluble uridine and cytidine, respectively. Co-administration of N-(phosphonoacetyl)-L-aspartate, an inhibitor of de novo pyrimidine synthesis, suppressed the increase in total acid-soluble uridine observed after D-galactosamine alone, but was without effect on the enhancement of total cytidine. Three hours after D-galactosamine and 15 min after [2-14C] cytidine, there was a rapid fall of the labeled nucleoside in blood plasma to 49% of control animals accompanied by a 2.8-fold rise in the total radioactivity of rat liver homogenates. From these results it can be concluded that the hepatocellular rise in total acid-soluble cytidine after D-galactosamine, in contrast to the increase in total acid-soluble uridine, originates from the phosphorylation of blood plasma cytidine via the salvage pathway. The depletion of circulating cytidine in the presence of hepatocellular UTP deficiency points to the importance of the liver and the hepatic UTP level for the clearance of blood plasma cytidine.
We report a case of Wegener's granulomatosis (WG) which differed significantly from the WHO-definition. The patient presented himself with fever and skin lesions which exacerbated after penicillin therapy. The nasal biopsy did not reveal the expected classical vasculitis and granulomas, which were present at autopsy only in the liver and spleen. We emphasize that vasculitis and granulomas may be absent in the biopsy specimen. We stress the institution of chemotherapy with cyclophosphamide, once the clinicopathological impression of WG is probable.