PubMed Health⌕ Search

Biomedical subjects

M J Smit

Publications and source records attributed to M J Smit.

70 records · Page 4Linked to original sources
PubMed1991

[Pneumocystis carinii pneumonia in patients with a severe combined immunodeficiency].

We describe three patients with Pneumocystis carinii pneumonia as the initial presentation of severe combined immunodeficiency disease. The pneumonia in the first patient was treated successfully with trimethoprim/sulphamethoxazole (Tmp/Smz). The second patient died despite therapy with Tmp/Smz and pentamidine. The third patient failed to respond to therapy with Tmp/Smz and pentamidine. He was subsequently treated with trimetrexate and leucovorin. Treatment with the new folic acid antagonist trimetrexate resulted in complete recovery. The case histories of these children serve to illustrate the clinical symptoms and new therapeutic modalities of P. carinii pneumonia in patients with immunodeficiency disease.

Humans↗
PubMed1991

Is protein kinase C involved in histamine H1-receptor desensitization?

Histamine H1-receptor mediated effects in guinea-pig lung and intestine appear to desensitize homologously rather rapidly. Within a few minutes of exposure to a high concentration of histamine (30-100 microM) the c-GMP production in guinea-pig lung and the contraction of guinea-pig jejunum are markedly attenuated. In both tissues the responses to other stimulating agents (e.g. muscarinic agent, calcium ionophore) are not affected. The protein kinase C (PKC) activating phorbolester phorbol-12,13- dibutyrate (PDB) concentration-dependently depresses H1-receptor responses in both tissues. Yet, PDB does not only attenuate the H1-receptor responses but also affects responses to other stimulating agents. In the guinea-pig ileum muscarinic receptor mediated contractions are inhibited equipotently by PDB, whereas in lung tissue the c-GMP formation after calcium-ionophore addition is affected too. In view of these findings the possible role of PKC in H1-receptor desensitization is discussed.

Animals↗
PubMed1991

Effects of histamine H1-, H2- and H3-receptor selective drugs on the mechanical activity of guinea-pig small and large intestine.

1. In this study we have evaluated the possible contribution of acetylcholine release in histamine-induced contractions of guinea-pig large and small intestinal smooth muscle. Moreover, the presence of the histamine receptor types involved in smooth muscle relaxations and inhibition of electrically-induced twitches was studied by use of several selective agents. 2. Histamine-induced contractions appeared to be a pure H1-receptor-mediated effect. Responses were not attenuated by the presence of 0.1 microM atropine and were competitively and stereoselectively inhibited by the two enantiomers of chlorpheniramine with pA2 values of 6.73 +/- 0.08, 7.30 +/- 0.06, 6.93 +/- 0.03 and 7.19 +/- 0.04 for the L-isomer and 8.63 +/- 0.09, 8.85 +/- 0.09, 9.01 +/- 0.16 and 0.11 for the D-isomer in the duodenum, jejunum, ileum and colon, respectively. 3. There appeared to be a marked regional difference in sensitivity to histamine. In ileal and jejunal preparations pD2 values of 6.24 +/- 0.06 (n = 22) and 6.37 +/- 0.07 (n = 22) were found, whereas the pD2 values in the duodenum and colon were 5.55 +/- 0.05 (n = 36) and 5.68 +/- 0.06 (n = 31) respectively. 4. This regional difference in sensitivity to histamine was not due to variations in receptor affinity since pA2 values for the two enantiomers of chlorpheniramine did not differ markedly among the four tested preparations. Since a similar variation in sensitivity was found for methacholine, it is likely that the signal transfer mechanism in guinea-pig ileum and jejunum is more efficient than in the duodenum and colon. 5. The H2-agonists dimaprit and impromidine relaxed methacholine-precontracted (+/- 70% of maximum contraction) intestine at high concentrations (pD2 values of 3.79 + 0.03 and 4.44 + 0.09 for the jejunum). These relaxations could not be antagonized by 0.1 microM tiotidine, famotidine or mifentidine and were observed in all parts of the intestine investigated. 6. The dimaprit analogues nordimaprit and homodimaprit (inactive at H2-receptors) were equipotent in relaxing the methacholine-precontracted smooth muscle. Since several H2-antagonists were also able to produce relaxations, we do not consider these relaxations to be mediated by a H2-receptor subtype, but to be due to some nonspecific effects at the high concentrations used. 7. The histamine receptor involved in the inhibition of electrically-induced contractions in the presence of atropine could be classified as an H3-receptor effect. In all parts of the intestine the H3-agonist R-alpha-amethylhistamine inhibited the twitches with pD2 values ranging from 8.10 + 0.06 (ileum) to 8.27 + 0.03(colon). This effect was competitively antagonized with the selective H3-antagonist thioperamine (pA2 values are 8.09 + 0.07, 8.13 + 0.05, 8.15 + 0.04 and 8.36 + 0.04 in duodenum, jejunum, ileum and colon, respectively. 8. The guinea-pig intestine is a suitable preparation for the evaluation of either H1- or H3-receptor effects. H2-receptors, causing smooth muscle relaxation appear not to be present in our preparations. At high concentrations of H2-receptor agents (agonists and antagonists) relaxations might be observed, due to unknown nonspecific effects.

Animals↗
PubMed1991

Dietary fish oil-induced changes in intrahepatic cholesterol transport and bile acid synthesis in rats.

Hepatic cholesterol metabolism was studied in rats fed purified diets supplemented (9% wt/wt) with either fish oil (FO) (n-3 fatty acids) or corn oil (CO) (n-6 fatty acids) for 4 wk. Rats were equipped with permanent catheters in heart, bile duct, and duodenum to allow studies under normal feeding conditions. [3H]-cholesteryl oleate-labeled small unilamellar liposomes, which are rapidly endocytosed by hepatocytes, were intravenously injected to label intrahepatic cholesterol pools, and plasma and bile were collected. FO as compared to CO induced a lowering of plasma cholesterol levels by 38% and of triglyceride levels by 69%. This reduction in plasma lipids in FO rats was accompanied by: (a) an increased bile acid pool size (28%); (b) a fourfold increase in the ratio cholic acid/chenodeoxycholic acid in bile; (c) increased biliary excretion of cholesterol (51%); (d) accelerated excretion of endocytosed free cholesterol into bile; (e) accelerated incorporation of endocytosed cholesterol in bile acids; (f) a significant increase in the bile acid-independent fraction of bile flow; and (g) a threefold increase in hepatic alkaline phosphatase activity. The results show that FO induces changes in transport and metabolic pathways of cholesterol in the rat liver, which result in a more rapid disposition of plasma-derived cholesterol into the bile.

Alkaline Phosphatase↗
PubMed1990

Short- and long-term effects of biliary drainage on hepatic cholesterol metabolism in the rat.

The present study concerns short- and long-term effects of interruption of the enterohepatic circulation (EHC) on hepatic cholesterol metabolism and biliary secretion in rats. For this purpose, we employed a technique that allows reversible interruption of the EHC, during normal feeding conditions, and excludes effects of anaesthesia and surgical trauma. [3H]Cholesteryl oleate-labelled human low-density lipoprotein (LDL) was injected intravenously in rats with (1) chronically (8 days) interrupted EHC, (2) interrupted EHC at the time of LDL injection and (3) intact EHC. During the first 3 h after interruption of the EHC, bile flow decreased to 50% and biliary bile acid, phospholipid and cholesterol secretion to 5%, 11% and 19% of their initial values respectively. After 8 days of bile diversion, biliary cholesterol output and bile flow were at that same level, but bile acid output was increased 2-3-fold and phospholipid output was about 2 times lower. The total amount of cholesterol in the liver decreased after interruption of the EHC, which was mainly due to a decrease in the amount of cholesteryl ester. Plasma disappearance of LDL was not affected by interruption of the EHC. Biliary secretion of LDL-derived radioactivity occurred 2-4 times faster in chronically interrupted rats as compared with the excretion immediately after interruption of the EHC. Radioactivity was mainly in the form of bile acids under both conditions. This study demonstrates the very rapid changes that occur in cholesterol metabolism and biliary lipid composition after interruption of the EHC. These changes must be taken into account in studies concerning hepatic metabolism of lipoprotein cholesterol and subsequent secretion into bile.

Animals↗
PubMed1990

Infection of mice with lactate dehydrogenase-elevating virus destroys the subpopulation of Kupffer cells involved in receptor-mediated endocytosis of lactate dehydrogenase and other enzymes.

In previous experiments in rats, we have shown that the rapid plasma clearance of a number of clinically important enzymes is due to receptor-mediated endocytosis by Kupffer cells and other resident macrophages. Others have shown that infection of mice with lactate dehydrogenase-elevating virus, a virus that proliferates in macrophages, leads to reduced plasma elimination of these enzymes. This paper integrates these two sets of experiments. Plasma elimination of intravenously injected, radioactively labeled lactate dehydrogenase M4 and mitochondrial malate dehydrogenase in mice was shown to be caused in part by uptake in liver, spleen and bone. Uptake of lactate dehydrogenase M4 by these tissues was, to a large extent, saturable and the two dehydrogenases competitively inhibited each other's clearance. These results suggest that, also in mice, these enzymes are partly cleared from plasma by endocytosis by way of a common receptor on cells (probably macrophages) from liver, spleen and bone marrow. Morphometrical data showed that normal mouse liver contains 23 x 10(6) Kupffer cells/cm3. This number was reduced to about 30% of that of controls 24 hr after infection of mice with lactate dehydrogenase-elevating virus but returned to normal within the next 9 days. The saturable component of uptake of lactate dehydrogenase M4 by liver, spleen and bone had disappeared 24 hr after infection with the virus, and did not return after the Kupffer cell population had recovered. Our findings suggest that lactate dehydrogenase M4 is, to a large extent, removed from the circulation by way of a receptor on a subpopulation of macrophages that is permissive for replication of lactate dehydrogenase-elevating virus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Inhibition of mitogen-activated proliferation of human lymphocytes by hypochlorous acid in vitro: protection and reversal by ascorbate and cysteine.

Hypochlorous acid (HOCl) at concentrations of 6.25 microM and greater caused statistically significant, dose-related inhibition of mitogen-activated proliferation of human mononuclear leucocytes (MNL). The anti-proliferative effects of HOCl, which were evident using both undepleted and adherent-cell depleted MNL, could not be attributed to decreased mitogen binding by HOCl-treated cells. The anti-oxidants ascorbate and cysteine (50 microM), when added to MNL prior to exposure to HOCl (25 microM), prevented the anti-proliferative effects of the oxidising agent. Likewise reversal of oxidant-mediated inhibition of the responsiveness of MNL to mitogens was observed when ascorbate and cysteine were added after HOCl treatment of the cells. These results suggest that HOCl, derived from activated phagocytes, is a potential mediator of immunosuppression, especially in the setting of abnormal host anti-oxidant defences.

Ascorbic Acid↗
PubMed1990

Different profiles of desensitization dynamics in guinea-pig jejunal longitudinal smooth muscle after stimulation with histamine and methacholine.

1. In the present study we investigated desensitization phenomena of guinea-pig jejunal longitudinal smooth muscle responses after stimulation with 100 microM histamine or methacholine, using a superfusion method. 2. Histamine H1-receptor-mediated contractions appear to be rapidly reduced after application of 100 microM histamine. Muscarinic responses were not affected following desensitization with 100 microM histamine, indicating a homologous desensitization. 3. Initial contractions to 0.3 microM histamine were reduced by 90%, recovered quickly, but did not reach control levels within 1 h. Desensitization of histamine responses could be separated into two phases; a rapid, but transient, desensitization and a more sustained desensitization. As a consequence of this sustained effect the pD2 for histamine shifted from 6.7 +/- 0.1 (control) to 6.1 +/- 0.1 (desensitized). 4. Desensitization with 100 microM methacholine caused a heterologous desensitization, reflected by the development of a refractory period, in which neither histamine nor methacholine was able to elicit a contraction. After a few minutes responses to both agents recovered to control levels. 5. During the refractory period after methacholine desensitization, muscle strips were still responsive to 40 mM KCl but did not contract in response to 10 mM caffeine, suggesting that the heterologous desensitization is caused by a modification of an intracellular Ca2(+)-store, which is used by both histamine and methacholine. 6. The recovery of the responses after methacholine desensitization was not dependent on extracellular Ca2+, suggesting that the recovery is not dependent on refilling of the intracellular Ca2+ store with extracellular Ca2+. 7. The protein kinase C activator, phorbol-12,13-dibutyrate, concentration-dependently inhibited histamine- and methacholine-induced contractions. Protein kinase C seems therefore not to be implicated in the observed homologous H,-receptor desensitization. 8. These data suggest that different forms of desensitization can be distinguished in this model, each with a different time course and dependent on the applied stimulus.

Animals↗
PubMed1988

Catabolism of circulating enzymes: plasma clearance, endocytosis, and breakdown of lactate dehydrogenase-1 in rabbits.

Lactate dehydrogenase-1 (EC 1.1.1.27), intravenously injected into rabbits, was cleared with first-order kinetics (half-life 27 min), until at least 80% of the injected activity had disappeared from plasma. Radioactivity from injected 125I-labeled enzyme disappeared at this same rate. Trichloroacetic-acid-soluble breakdown products started to appear in the circulation shortly after injection of the labeled enzyme. Body scans of the rabbits for 80 min after injection of 131I-labeled enzyme revealed rapid accumulation of label in the liver, peaking 10-20 min after injection. Subsequently, activity in the liver declined and radioactivity (probably labeled breakdown products of low molecular mass) steadily accumulated in the bladder. Tissue fractionation of liver, 19 min after injection of labeled enzyme, indicated that the radioactivity was present both in endosomes and in lysosomes, suggesting uptake by endocytosis, followed by breakdown in the lysosomes. Measurements of radioactivity in liver and plasma suggest that the liver is responsible for the breakdown of at least 75% of the injected enzyme. Radioautography of tissue sections of liver and spleen showed accumulated radioactivity in sinusoidal liver cells and red pulpa, respectively. These results are very similar to those for lactate dehydrogenase-5, creatine kinase MM, and several other enzymes that we have previously studied in rats.

Animals↗
PubMed1987

Receptor-mediated endocytosis of lactate dehydrogenase M4 by liver macrophages: a mechanism for elimination of enzymes from plasma. Evidence for competition by creatine kinase MM, adenylate kinase, malate, and alcohol dehydrogenase.

We have previously shown that the rapid clearance of intravenously injected lactate dehydrogenase M4 from plasma is mainly due to endocytosis by macrophages in liver, spleen, and bone marrow. We have now studied endocytosis of lactate dehydrogenase M4 in detail, using freshly isolated rat liver macrophages (Kupffer cells) in vitro. 125I-lactate dehydrogenase M4 rapidly accumulated in the cells and was subsequently degraded to trichloroacetic acid-soluble material. Degradation was inhibited by leupeptin, an inhibitor of lysosomal proteases. Breakdown of the protein was also greatly diminished by treatment of the cells with chloroquine, a weak base which inhibits proteolysis by raising the pH in endosomes and lysosomes. High concentrations of chloroquine inhibited uptake. Lactate dehydrogenase M4 was not endocytosed by liver endothelial cells, although, under the same conditions, these cells were shown to accumulate horse radish peroxidase via a mannose-specific receptor. Uptake of lactate dehydrogenase M4 by Kupffer cells was strongly reduced after pretreatment of the cells with low concentrations of proteases. Endocytosis of lactate dehydrogenase M4 exhibited saturation kinetics (Km = 0.8 microM) and was competitively inhibited by mitochondrial and cytosolic malate dehydrogenase, alcohol dehydrogenase, adenylate kinase, and creatine kinase MM, enzymes which are rapidly cleared in vivo. Enzymes with long half-lives in plasma, namely lactate dehydrogenase H4, alanine aminotransferase, and cytosolic aspartate aminotransferase did not compete at concentrations up to 10 microM. Our results indicate that Kupffer cells contain a receptor that is involved in the clearance of lactate dehydrogenase M4 and a number of other tissue-derived enzymes from plasma. Uptake of lactate dehydrogenase M4 does not occur via a receptor that recognizes carbohydrate residues, for the enzyme is not a glycoprotein.

Adenylate Kinase↗
PubMed1986

Plasma clearance of mitochondrial aspartate aminotransferase in the rat: competition with mitochondrial malate dehydrogenase.

In previous experiments we have shown that the rapid clearance in rats of alcohol dehydrogenase, lactate dehydrogenase M4, and the mitochondrial and cytosolic isoenzymes of malate dehydrogenase is largely due to endocytosis by macrophages in liver, spleen and bone marrow. Competition experiments indicated that the dehydrogenases as well as adenylate kinase and creatine kinase MM are endocytosed via the same receptor. We suggested that this receptor contains a group with affinity for the nucleotide-binding sites of the enzymes. We now demonstrate that competition also occurs between mitochondrial malate dehydrogenase and mitochondrial aspartate aminotransferase, which does not require a nucleotide for its activity. At low doses, mitochondrial aspartate aminotransferase was cleared following first-order kinetics (half-life: 19 min). Simultaneous injection of a high dose of mitochondrial malate dehydrogenase strongly retarded the clearance of the aminotransferase. These results make unlikely the hypothesis that a nucleotide-binding site is involved in recognition of enzymes by macrophages.

Animals↗
PubMed1985

Several dehydrogenases and kinases compete for endocytosis from plasma by rat tissues.

Plasma contains many enzymes that are probably derived from damaged cells. These enzymes are cleared at characteristic rates. We showed previously that in rats the rapid clearance of alcohol dehydrogenase, lactate dehydrogenase M4 and the mitochondrial and cytosolic isoenzymes of malate dehydrogenase is largely due to endocytosis by macrophages in liver, spleen and bone marrow. We now demonstrate that uptake of each of the enzymes by these tissues is in general decreased by simultaneous injection of a high dose of one of the other dehydrogenases or a high dose of adenylate kinase or creatine kinase. A similar dose of colloidal albumin did not significantly decrease uptake of the four dehydrogenases. Nor was uptake of colloidal albumin, apo-peroxidase from horseradish or multilamellar liposomes influenced by a high dose of mitochondrial malate dehydrogenase. These results indicate that the four dehydrogenases and the two kinases are specifically endocytosed via the same receptor. We suggest that this receptor contains a group, possibly a nucleotide, with affinity for the nucleotide-binding sites of the enzymes.

Adenylate Kinase↗
PubMedDate not supplied

Immunological response in laparoscopic surgery.

Immunological response to surgical trauma may be protected during laparoscopic surgery. A less surgical trauma, in comparison with conventional surgery, may explained these important advantages. Plasma and macrophages studies have demonstrated that laparoscopic cholecystectomy causes less depression of cell mediated immunity than open cholecystectomy. What will be the impact of this immunological protection in laparoscopic advanced and oncological surgery? Experimental studies have showed that laparoscopic techniques in advanced and oncological surgery may have important advantages concerning the "preservation of the immune status" of the patient. That will imply in the future a lower percentage of infections, local recurrence and even a lower percentage of distant metastases. On the other hand, the appearance of tumor implants in the port sites after laparoscopic resection for cancer is a significant drawback of this procedure. Proper investigations have to be carried out in order to find the cause and the solution of this dilemma.

Acute-Phase Reaction↗