PubMed Health⌕ Search

Biomedical subjects

U Giger

Publications and source records attributed to U Giger.

At least 91 records · Page 5Linked to original sources
PubMed1989

Muscle bio-energetics in acute glycolytic block: in vivo phosphorus-nuclear magnetic resonance study of iodo-acetate injected rats.

In vivo phosphorus nuclear magnetic resonance spectroscopy of muscle was performed at rest, during work and during postexercise recovery in rats injected with iodo-acetate (IA) (35-40 mg.kg-1, intra-arterially), in order to follow bio-energetic changes in muscle with acute glycolytic block. Three animals with contracture had very low ratios of phosphocreatine:inorganic phosphate (PCr:Pi) at rest (0.5-0.9). The PCr:Pi were normal at rest (6.9 +/- 2.0, +/- 2 SD) in all other rats. Exercise-induced continuous accumulation of phosphomonoesters (PME), the characteristic finding of glycolytic block, was observed. The end-exercise levels of PME correlated with the degree of block measured in vitro. During steady-state work, induced by nerve stimulation at four frequencies, PCr:Pi values were significantly lower (p less than 0.02) than the control values at 0.25, 1.0 and 2.0 Hz. The ATP levels fell during exercise to reach 75% +/- 7% of initial values. The recovery of PCr:Pi from exercise and the disappearance of PME were slow. Two animals which survived the IA injection demonstrated much lower PME accumulation 18 h later. It is concluded that in acute muscle glycolytic block: (1) energy metabolism is impaired during exercise and also at rest, (2) accumulating PME can serve as an indicator of the degree of glycolytic block, (3) ATP levels fall during work, and (4) postexercise recovery is slow. The findings are compared with 31P-NMR observations in chronic muscle glycolytic disorders.

Adenosine Triphosphate↗
PubMed1989

Effect of Desmopresssin in Normal Dogs and Dogs with von Willebrand's Disease.

Desmopressin acetate (DDAVP(R)), a synthetic analogue of vasopressin was slowly administered intravenously to 12 healthy dogs of various breeds and 10 Doberman Pinschers with mild-to-moderate type I von Willebrand's disease at a dose of 0.3, 1.0 and 3.0 micro g/kg body weight. Plasma von Willebrand factor:antigen was measured by an electroimmunoassay prior to and 30, 60, 90, 120 and 180 minutes after desmopressin infusion. Desmopressin induced only very modest and statistically insignificant increases in von Willebrand factor in both groups. We conclude that the response to desmopressin as measured by circulating von Willebrand factor is much less pronounced in healthy dogs and in Doberman Pinschers with von Willebrand's disease than in humans.

Journal Article↗
PubMed1988

Metabolic myopathy in canine muscle-type phosphofructokinase deficiency.

In vivo 31phosphorus nuclear magnetic resonance spectroscopy (P-NMR) of the anterior tibialis muscle was used to investigate the metabolic myopathy of inherited muscle-type phosphofructokinase (PFK) deficiency in four (homozygous) dogs who had mild exercise intolerance, rare muscle cramps, increased serum creatine kinase activity, but no myoglobinuria. During isometric muscle work induced by indirect electrical stimulation, and subsequent recovery, changes in the ratio of phosphocreatine (PCr) and inorganic phosphates (Pi) were comparable in muscle of PFK-deficient and normal dogs and indicated a large capacity for arobic oxidative phosphorylation in canine muscle. The progressive accumulation of sugar phosphates (PME) during graded exercise clearly demonstrated the glycolytic block in PFK-deficient dogs. During a muscle contracture, induced by acute muscle stimulation, PFK-deficient muscle became completely depleted of PCr and ATP, accumulated large amounts of PME, and recovered very slowly. We conclude that PFK-deficient dogs have a metabolic myopathy that demonstrated some but not all the features recognized in the human disorder.

Animals↗
PubMed1988

Biochemical studies of canine muscle phosphofructokinase deficiency.

Skeletal muscle from four dogs with erythrocyte phosphofructokinase (PFK; EC 2.7.1.11) deficiency were studied in vitro. Muscle PFK activities were severely decreased to 1% of the normal mean. The residual activities had a high Km for fructose-6-phosphate (F6P). Anaerobic lactate production of PFK-deficient muscle was minimal with the addition of glycogen and hexose-monophosphates, but was normal with fructose-1,6-diphosphate (FDP). Muscle glycogen concentration was twice normal, indicating a glycogen storage disorder. Histochemical studies for muscle PFK activity showed no enzymatic staining with F6P as substrate. In two muscle biopsies from asymptomatic related dogs, intermediate PFK activities were found. These data characterize canine muscle PFK deficiency in vitro.

Animals↗
PubMed1987

Hemolysis caused by phosphofructokinase deficiency in English springer spaniels: seven cases (1983-1986).

Seven English Springer Spaniels (6 adult males and 1 female) with chronic hemolysis and sporadic intravascular hemolytic crises were determined to have a deficiency in erythrocyte phosphofructokinase (PFK) activity, a key regulatory enzyme of anaerobic glycolysis. Intermittent severe pigmenturia concomitant with weakness, lethargy, and anorexia were the major clinical signs and commonly were related to exercise or other stressful situations that caused panting or barking (hyperventilation). Pale or icteric mucous membranes, fever, mild hepatosplenomegaly, and muscle wasting sometimes were evident. Results of routine laboratory testing indicated a persistent marked bilirubinuria and reticulocytosis with normal PCV, to severe anemia and intermittent hemoglobinuria and hyperkalemia. Erythrocyte PFK activities were severely reduced to 8% to 22% of values for control dogs. The block of glycolysis at the PFK step caused a markedly diminished erythrocyte 2,3-diphosphoglycerate content, resulting in an increased hemoglobin-oxygen affinity and compensatory accelerated erythrocyte production. Phosphofructokinase-deficient erythrocytes had increased alkaline fragility in vitro and in vivo. Hemolytic crises were induced in vivo by hyperventilation that caused transient, mild alkalemia. Studies of family members of a PFK-deficient dog suggested an autosomal recessive mode of inheritance. Carrier dogs with half-normal erythrocyte PFK activities appeared clinically normal.

Anemia, Hemolytic, Congenital↗
PubMed1987

Deficiency of leukocyte surface glycoproteins Mo1, LFA-1, and Leu M5 in a dog with recurrent bacterial infections: an animal model.

A dog with severe recurrent bacterial infections, impaired pus formation, delayed wound healing, and severe persistent leukocytosis was the result of a mother-son mating. Assessment of leukocyte function revealed profound abnormalities in adherence-dependent activities including impaired granulocyte adhesion to glass/plastic surfaces or nylon wool, decreased granulocyte aggregation and chemotaxis, and diminished lymphocyte blastogenesis, but normal neutrophil oxidative activity, serum immunoglobulin, and complement levels. By immunofluorescence analysis, CD11b and CD18 monoclonal antibodies specific for the 155-kd alpha polypeptide of Mo1 (gp 155, 94) and the 94 kd beta peptide common to Mo1, LFA-1 (gp 170, 94), and Leu M5 (p 150, 94) (surface molecules that promote leukocyte adhesion) failed to bind to unstimulated and A23187 calcium ionophore-stimulated granulocytes or mononuclear cells of the affected dog as compared with strong specific binding to canine control cells. The Mo1 glycoproteins were only barely detectable by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of immunoprecipitates from lysates of 125I surface-labeled neutrophils from the affected dog as compared with intense bands seen with canine control cell precipitates. We conclude that this dog has a severe leukocyte surface glycoprotein deficiency syndrome that is similar, if not identical, to that recently recognized in humans. Dogs with deficiency of leukocyte Mo1, LFA-1, and Leu M5 expression may represent a useful animal model to characterize further the molecular basis for an inherited disorder in leukocyte effector function.

Animals↗
PubMed1986

Autosomal recessive inherited phosphofructokinase deficiency in English springer spaniel dogs.

Three families of English springer spaniel dogs with phosphofructokinase (PFK) deficiency causing haemolysis were studied. Four male dogs and one female dog with chronic haemolysis and haemolytic crises were found to have markedly reduced PFK activity in erythrocytes (8-20% of control English springer spaniels). PFK-deficient erythrocytes exhibited an extreme alkaline and sucrose lysis. The oxygen dissociation curve of erythrocyte suspensions was shifted to the left with a 50% saturation of haemoglobin at a partial oxygen pressure of 16-17 mmHg (normal 26-31 mmHg). Muscle wasting and mildly increased serum creatine phosphokinase activity were also noted. Six clinically normal first degree relatives of affected dogs had erythrocyte PFK activities that were 38-51% of controls. In these family members, there was an erythrocytosis and mild reticulocytosis probably due to a mildly enhanced haemoglobin-oxygen affinity but no increase in serum creatine phosphokinase. These studies confirm the familial nature of muscle-type PFK deficiency in English springer spaniels and support the conclusion that this animal model of the human glycogen storage disease type VII is inherited as an autosomal recessive trait.

Animals↗
PubMed1985

Sulfadiazine-induced allergy in six Doberman pinschers.

Treatment with sulfadiazine-trimethoprim caused serious, but reversible, allergic drug reactions in 6 Doberman Pinschers 10 to 21 days after the first drug exposure and/or within 1 hour to 10 days after reexposure. Nonseptic polyarthritis was found in all dogs. Glomerulonephropathy, focal retinitis, polymyositis, skin rash, fever, anemia, leukopenia, and thrombocytopenia were found in some dogs. These clinical abnormalities were typical of an immune-mediated vasculitis and mimicked other immune-mediated disorders. In a drug challenge study, 1 dog was given sulfadiazine and trimethoprim separately. Administration of trimethoprim alone did not result in any abnormalities; however, exposure to sulfadiazine caused recurrence of the polyarthritis, glomerulonephropathy, and focal retinitis within 5 days, suggesting that sulfadiazine likely was the offending agent in all cases. In addition, during the sulfadiazine reexposure, marked complement activation was documented at the time clinical signs were apparent, supporting the suggestion that sulfadiazine caused an immune complex disease (type-III hypersensitivity reaction). Since all dogs were of the same breed, a genetic predisposition of some Doberman Pinschers to react adversely to sulfadiazine was suspected.

Animals↗
PubMed1985

Characterization of the enzymatic lesion in inherited phosphofructokinase deficiency in the dog: an animal analogue of human glycogen storage disease type VII.

Mammalian phosphofructokinase (PFK; ATP:D-fructose-6-phosphate 1-phosphotransferase, EC 2.7.1.11) exists in multimolecular forms, which result from random tetramerization of three distinct subunits, M (muscle-type), L (liver-type), and P (platelet-type), each under a separate genetic control. Human muscle and liver contain homotetramers M4 and L4, respectively, whereas erythrocytes contain a mixture of M4, M3L, M2L2, ML3, and L4 isozymes. Homozygous deficiency of the M subunit in man results in glycogen storage disease (GSD) type VII, which is characterized by exertional muscle weakness and compensated hemolysis; the residual erythrocyte PFK consists of isolated L4 isozyme. Recently, PFK deficiency associated with isolated hemolytic anemia has been identified among English springer spaniel dogs. We investigated the genetic control of the dog PFK system and the nature of the enzymatic defect in two PFK-deficient animals, using chromatographic and immunological techniques. Our studies indicate the existence of a trilocus isozyme system for the dog, as is the case with other mammals. Muscle PFK consists of M4 isozyme, whereas the predominant species of liver and platelet consists, respectively, of the L4 and P4 isozyme; erythrocyte PFK consists of a three- or four-membered set composed of M and P subunits. PFK deficiency in the dogs was found to result from a total and universal lack of the M subunit, as is the case in man. However, the probands consistently exhibited L4 isozyme in their muscle; P4, L4, and hybrids thereof in their erythrocytes; and an increase in the L-containing isozymes in their platelets, indicating a generalized anomalous presence of the L subunit. The apparent absence of muscle disease in these animals is most likely accounted for by both the well-known high oxidative potential of the canine muscle in general and the presence of liver PFK in the M-deficient muscle in particular. In contrast, presence of hemolysis despite residual P4 and hybrids of P and L in the erythrocytes may be inferred to result in severe glycolytic handicap under existing intraerythrocytic conditions.

Animals↗
PubMed1985

Inherited phosphofructokinase deficiency in dogs with hyperventilation-induced hemolysis: increased in vitro and in vivo alkaline fragility of erythrocytes.

Two male English springer spaniel dogs with a chronic hemolytic anemia and sporadic hemolytic crises, historically related to "stress" situations, were studied. Although canine erythrocytes are in general known to be more alkaline fragile, erythrocytes from both patients began to lyse earlier, at significantly lower pH values (near pH 7.4 at 37 degrees C), than erythrocytes from control dogs. Hyperventilation induced by 30 minutes of exercise, placement in a 39 degrees C water bath, or intravenous doxapram increased venous blood pH in dog 1 and control dogs, but transient hemoglobinemia, hemoglobinuria, and severe bilirubinuria occurred only in the studied patient. The erythrocyte phosphofructokinase (PFK) activity was severely decreased in both dogs (10% of controls). The erythrocyte 2,3-diphosphoglycerate content was markedly reduced and the cell chloride content was consequently increased. This change in cell chloride content is related to an increase in the erythrocyte pH, which may partially explain the pathogenesis of hemolysis in canine PFK deficiency. Thus, these studies demonstrate a presumably inherited erythrocyte PFK deficiency in English springer spaniels, which causes an increased in vitro and in vivo erythrocyte alkaline fragility. Dogs with PFK deficiency and inducible hemolytic crises may become a valuable genetic animal model in which to study the pathophysiology of hemolysis.

Anemia, Hemolytic↗
PubMed1984

Stimulation of DNA synthesis and mitotic activity of chick embryo hepatocytes in primary culture. Effect on induction of polysubstrate monooxygenase activity.

Monolayer cultures were prepared from hepatocytes of 15 d chick embryos and maintained at high cell density in a chemically defined medium. In the absence of growth stimulatory conditions DNA synthesis was observed only during the first 10 to 16 h of culture. Thus, after a 12 h exposure to [3H]thymidine ([3H]dThd, 4 to 16 h) 9.1 +/- 1% (mean +/- SD, n = 4) of the hepatocyte nuclei were labeled. Labeled mitotic nuclei, up to late telophase, were regularly observed in these cultures. Beyond 16 h less than 2% labeled nuclei were found (12 h of [3H]dThd), which indicates that the hepatocytes entered proliferative quiescence. DNA synthesis of "resting" hepatocytes was stimulated by insulin and, only slightly, by hydrocortisone, glucagon, or fetal bovine serum. Triiodothyronine (T3), or the nucleoside inosine (i) did not stimulate. Combination of insulin (I) with hydrocortisone (H), T3 (T), or glucagon (G) resulted in a more than additive effect. Nearly maximal stimulation occurred with the combinations IHT and ITG. Labeling increased at 10 ng/ml of each component and was maximal at 1 to 10 micrograms/ml. A lag period of 8 to 10 h after hormone administration (IHiTG, 10 micrograms/ml) was observed before nuclear labeling increased. Within the subsequent 10 h a considerable proportion of the hepatocytes (up to 30% or more) entered DNA synthesis. Mitotic activity (with nuclei in prophase up to late telophase) also was stimulated. An increase of both total DNA and protein content was measured in several experiments. Hormonal stimulation of hepatocyte DNA synthesis and mitotic activity was associated with decreased beta-naphthoflavone-mediated induction of cytochrome P450. A causal relationship between these two phenomena remains to be established. It is suggested that chick embryo hepatocyte cultures are a useful tool for studies on hepatocyte proliferation and differentiation.

Animals↗
PubMed1983

Effect of succinylacetone on heme and cytochrome P450 synthesis in hepatocyte culture.

The effects of succinylacetone, a tyrosine metabolite, on the hepatic biosynthesis of heme and cytochrome P450 were studied in primary culture of chick embryo hepatocytes. Succinylacetone potentiated the phenobarbital-mediated induction of delta-aminolevulinate synthase, strongly inhibited porphobilinogen synthase activity, reduced cellular heme concentration and impaired induction of cytochrome P450. Enhanced induction of delta-aminolevulinate synthase and decreased cytochrome P450 induction may be explained by the succinylacetone-mediated inhibition of porphobilinogen synthase and the subsequent depletion of intracellular heme, since these effects of succinylacetone were reversed by addition of heme. These results suggest clinical implications for patients with tyrosinemia, who accumulate succinylacetone.

5-Aminolevulinate Synthetase↗
PubMed1983

Halothane-induced ATP depletion in platelets from patients susceptible to malignant hyperthermia and from controls.

Since the cellular defect of malignant hyperthermia (MH) may occur in tissues other than muscle and since platelets share certain contractile characteristics with muscle cells, testing platelets has been suggested as a way to diagnose susceptibility to MH. In analogy to the in vitro depletion of muscle adenosine triphosphate (ATP), the authors compared platelet basal nucleotide levels and halothane-induced depletion of ATP from 10 MH-susceptible patients and from 12 unrelated nonsusceptible controls. A rapid and simple isocratic high-pressure liquid chromatography technique was used to analyze acid-extracted platelet nucleotides. Halothane added to platelet-rich plasma at 37 degrees C significantly decreased ATP in platelets in a dose-dependent as well as a time-dependent manner. In contrast, adenosine diphosphate (ADP) and adenosine monophosphate (AMP) were not changed significantly. Other volatile anesthetic agents also depleted ATP in platelets. Although ATP in platelets exposed to halothane was depleted significantly, there was no difference between platelets from MH-susceptible patients and nonsusceptible controls. Therefore, halothane-induced ATP depletion in platelets is not a reliable test for diagnosing MH susceptibility.

Adenosine Diphosphate↗
PubMed1982

The substituted pyridines metyrapone and nicotinamide are inducers of 5-aminolevulinate synthase and cytochrome P-450 in hepatocyte culture.

The effects of metyrapone and nicotinamide, two substituted pyridines, were studied in cultured chick embryo hepatocytes, a system characterized by preserved inducibility of cytochrome P-450 hemoproteins. Both metyrapone and nicotinamide caused a dose-dependent increase in cytochrome P-450 concentration. Their inducing potencies differed by one to two orders of magnitude and correlated with the known difference in the binding affinity of these two pyridines to cytochrome P-450. The increase of cytochrome P-450 concentration after metyrapone and nicotinamide was additive to the induction of cytochrome P-450 by phenobarbital and beta-naphthoflavone and was abolished by cycloheximide. Treatment of hepatocyte cultures with metyrapone resulted in an increase in a microsomal protein with an apparent mol. wt of 52,000. In addition, induction of cytochrome P-450 by the substituted pyridines was associated with enhanced 5-aminolevulinate synthase, the rate-limiting enzyme of heme biosynthesis. These data suggest that in cultured chick embryo hepatocytes the substituted pyridines metyrapone and nicotinamide induce cytochrome P-450.

5-Aminolevulinate Synthetase↗
PubMed1981

Induction of delta-aminolevulinate synthase and cytochrome P-450 hemoproteins in hepatocyte culture. Effect of glucose and hormones.

Addition of glucose to cultured chick embryo hepatocytes caused a concentration-dependent impairment of phenobarbital-mediated induction of delta-aminolevulinate (ALA) synthase resembling the "glucose effect" observed in rodents in vivo. This glucose effect occurred in the complete absence of extrahepatic factors such as serum and hormones. Fructose, glycerol, and lactate mimicked the inhibitory glucose effect on ALA synthase induction, whereas 2-deoxyglucose and 3-O-methylglucose augmented the induction evoked by phenobarbital. 2-Deoxyglucose reversed the effect of glucose, glycerol, and lactate on ALA synthase induction suggesting that the glucose effect is mediated by free glucose or glucose 6-phosphate or a nonglycolytic metabolite of glucose 6-phosphate. The phenobarbital-mediated induction of cytochrome P-450 hemoprotein(s) and its monooxygenase function were concomitantly diminished by glucose. However, this inhibitory effect or glucose was reversible by the addition of exogenous heme or ALA suggesting that the primary target of the glucose effect is ALA synthase induction and not synthesis of apocytochrome P-450. Glucagon and dibutyryl cAMP enhanced the induction of ALA synthase and cytochrome P-450 by phenobarbital and partially counteracted the glucose effect on both enzymes suggesting that the glucose effect may be mediated by changes in cAMP levels. Although insulin did not alter induction of ALA synthase, it impaired induction of cytochrome P-450 even in the presence of glucagon and cAMP. These data may be relevant for the treatment with glucose and heme of patients with "inducible" hepatic porphyria.

3-O-Methylglucose↗
PubMed1981

[Acquired, vitamin B6-responsive, primary sideroblastic anemia, an enzyme deficiency in heme synthesis].

The activity of delta-aminolevulinic acid synthetase (ALAS), the rate-limiting enzyme in heme synthesis, has been found to be markedly reduced (13% of controls) in erythroblasts of a patient with acquired, primary sideroblastic anemia. Administration of vitamin B6 (pyridoxin, 200-600 mg/d) resulted in complete reconstitution of erythroblastic ALAS-activity with concomitant disappearance of all hematologic abnormalities. The findings show that the therapeutic efficacy of pyridoxin in primary sideroblastic anemia is due to its effect on defective ALAS. More generally, the data support the view that almost all features of primary sideroblastic anemia can be ascribed to a disturbance of heme synthesis in erythroblasts.

5-Aminolevulinate Synthetase↗
PubMed1981

Role of haem in the induction of cytochrome P-450 by phenobarbitone. Studies in chick embryos in ovo and in cultured chick embryo hepatocytes.

The role of haem synthesis during induction of hepatic cytochrome P-450 haemoproteins was studied in chick embryo in ovo and in chick embryos hepatocytes cultured under chemically defined conditions. 1. Phenobarbitone caused a prompt increase in the activity of 5-aminolaevulinate synthase, the rate-limiting enzyme of haem biosynthesis, and in the concentration of cytochrome P-450. This induction response occurred without measurable initial destruction of the haem moiety of cytochrome P-450. 2. When intracellular haem availability was enhanced by exogenous haem or 5-aminolaevulinate, phenobarbitone-medicated induction of cytochrome P-450 was not affected in spite of the well known repression of 5-aminolaevulinate synthase by haem. These data are consistent with the concept that haem does not regulate the synthesis of cytochrome P-450 haemoproteins. 3. Acetate inhibited haem biosynthesis at the level of 5-aminolaevulinate formation. When intracellular haem availability was diminished by treatment with acetate, phenobarbitone-medicated induction was decreased. 4. This inhibitory effect of acetate on cytochrome P-450 induction was reversed by exogenous haem or its precursor 5-aminolaevulinate. These data suggest that inhibition of haem biosynthesis does not decrease synthesis of apo-cytochrome P-450. Moreover, they indicate that exogenous haem can be incorporated into newly formed aop-cytochrome P-450.

5-Aminolevulinate Synthetase↗