[The first fatal Swedish case report of dog bite contaminated by a new bacterium].
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Animals↗
Biomedical subjects
H Fritz
Publications and source records attributed to H Fritz.
The acid-stable proteinase inhibitor of human mucous secretions (HUSI-I, antileukoprotease). Complete amino acid sequence as revealed by protein and cDNA sequencing and structural homology to whey proteins and Red Sea turtle proteinase inhibitor.
The complete amino acid sequence of human antileukoprotease has been determined by direct sequencing of the inhibitory active protein isolated from seminal plasma (HUSI-I) and by sequence analysis of cDNA reverse-transcribed from mRNA prepared from cervical tissue. The inhibitor (Mr 11726) consists of 107 amino acid residues including 16 cysteines presumably forming disulfide bonds. The molecule comprises two consecutive domains which are homologous to each other, to the second domain of the basic protease inhibitor from Red Sea turtle (chelonianin) and to both domains of the whey proteins of rat and mouse. Both domains contain a pattern of cysteines known as the 'four-disulfide-core' that has also been found in wheat germ agglutinin and neurophysin.
Amino Acid Sequence↗
Refined 1.2 A crystal structure of the complex formed between subtilisin Carlsberg and the inhibitor eglin c. Molecular structure of eglin and its detailed interaction with subtilisin.
The crystal structure of the complex formed between eglin c, an elastase inhibitor from the medical leech, and subtilisin Carlsberg has been determined at 1.2 A resolution by a combination of Patterson search methods and isomorphous replacement techniques. The structure has been refined to a crystallographic R-value of 0.18 (8-1.2 A). Eglin consists of a four-stranded beta-sheet with an alpha-helical segment and the protease-binding loop fixed on opposite sides. This loop, which contains the reactive site Leu45I--Asp46I, is mainly held in its conformation by unique electrostatic/hydrogen bond interactions of Thr44I and Asp46I with the side chains of Arg53I and Arg51I which protrude from the hydrophobic core of the molecule. The conformation around the reactive site is similar to that found in other proteinase inhibitors. The nine residues of the binding loop Gly40I--Arg48I are involved in direct contacts with subtilisin. In this interaction, eglin segment Pro42I--Thr44I forms a three-stranded anti-parallel beta-sheet with subtilisin segments Gly100--Gly102 and Ser125--Gly127. The reactive site peptide bond of eglin is intact, and Ser221 OG of the enzyme is 2.81 A apart from the carbonyl carbon.
Amino Acid Sequence↗
Total lymphoid irradiation of intractable rheumatoid arthritis.
Eleven patients with intractable rheumatoid arthritis were treated with fractionated total lymphoid irradiation at a total dose of 20 Gy. Lasting improvement in clinical symptoms was found in four patients during treatment and the remaining patients experienced a similar benefit within 2 months of irradiation. There was marked reduction in exacerbations and the number of joints involved. Morning stiffness, joint swelling and tenderness decreased. Complications included severe fatigue during treatment and acute bacterial arthritis in multiple joints in one patient. Four of the patients have since died, one of renal failure and another of cardiogenic shock following surgery 3 and 24 months after total lymphoid irradiation. Both had generalised amyloidosis. The third patient developed joint empyema and died of toxic cardiac failure. The fourth died 3 months after resection of a Kaposi's sarcoma complicated by wound infection which responded to treatment. Immunologically, total lymphoid irradiation resulted in suppression of the absolute lymphocyte count and a reduction in T-helper cells, while the number of T-suppressor cells remained unchanged. These data provide evidence of T-cell involvement in the pathogenesis of rheumatoid arthritis. Total lymphoid irradiation can induce sustained improvement in clinical disease activity, but severe, possibly fatal, side-effects cannot be ignored.
Aged↗
The primary structure of bdellin B-3 from the leech Hirudo medicinalis. Bdellin B-3 is a compact proteinase inhibitor of a "non-classical" Kazal type. It is present in the leech in a high molecular mass form.
A proteinase inhibitor was isolated from extracts of the leech Hirudo medicinalis by gel filtration and anion exchange chromatography. This inhibitor is similar to the bdellins in that it blocks the activity of trypsin, plasmin and sperm acrosin but has a molecular mass, as estimated by SDS polyacrylamide electrophoresis, of about 20 kDa, whereas the bdellins have molecular masses in the range 5-6 kDa. It is therefore designated as high-molecular mass bdellin B-3 (HMB). The amino-acid sequence of the inhibitor was elucidated as far as position 56. This revealed that the molecule consists of a bdellin B-3 moiety, corresponding to the N-terminal 46 residues, which is then extended at the C-terminus by a polypeptide chain of the composition Asx15, Glx25, Gly6, Val, His26-27 and Lys4. It has been formerly concluded from a partial amino-acid sequence that bdellin B-3 is a Kazal-type inhibitor. However, the complete sequence of bdellin B-3, represented by the N-terminal 46 residues of HMB, discloses that bdellin B-3 is a non-classical Kazal-type inhibitor when the number of amino-acid residues between half-cystines are considered. Presuming that formation of disulfide bridges principally follows the same pattern as in classical Kazal-type inhibitors the bdellin B-3 molecule was modeled based on the known three-dimensional structure of the third ovomucoid domains. This showed that a compact arrangement of the peptide chain of bdellin B-3 is conceivable.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acid Sequence↗
Inhibition of mast cell chymase by eglin c and antileukoprotease (HUSI-I). Indications for potential biological functions of these inhibitors.
Recombinant eglin c (originally isolated from the medical leech) and antileukoprotease (HUSI-I from human seminal plasma) were examined for their ability to inhibit the mastcell protease chymase. Both inhibitors react rapidly with the enzyme: when about equimolar concentrations (in the range of 10(-8) M) of chymase and HUSI-I or eglin c were incubated the complex formation was apparently at equilibrium after 1 or 5 min respectively. When a constant amount of chymase (approximately 3 X 10(-8) M) was incubated with increasing concentrations of inhibitor a concentration of HUSI-I of 7 X 10(-7) M was necessary to cause 50% inhibition of the initial enzyme activity, whereas 8 X 10(-8) M eglin c was sufficient. The dissociation constant of the chymase-eglin c complex was calculated to be 4.4 X 10(-8) M. These results are discussed with respect to the possible in vivo function of antileukoprotease as an inhibitor of mast cell chymase.
Animals↗
Isolation and characterization of hirudin isoinhibitors and sequence analysis of hirudin PA.
A five-step isolation procedure has been developed for the purification of isoforms of hirudin (isohirudins) from whole leeches. The final purification of two thrombin-inhibiting preparations by reversed-phase high-performance liquid chromatography yielded several isohirudins with either N-terminal valine or isoleucine but with identical inhibition characteristics, i.e. specific thrombin inhibiting activities of 680-720 IU/mg and dissociation constants Ki of the thrombin-inhibitor complexes close to 3 X 10(-11) mol/l. The inhibitor with N-terminal isoleucine was designated hirudin PA. This inhibitor contains 66 amino-acid residues and has a molecular mass of 7,087 Da. The complete amino-acid sequence of hirudin PA was established by automated solid-phase Edman degradation of the native and oxidized inhibitor and two of its tryptic fragments. On the basis of the primary structures two types of thrombin inhibitors from the leech can be distinguished, designated hirudin and hirudin PA. The degree of structural homology of both isoinhibitors is approximately 82%; both have a tyrosine-O-sulfate residue near the C-terminus.
Amino Acid Sequence↗
The combination of pivampicillin and pivmecillinam versus pivampicillin alone in the treatment of acute pyelonephritis.
96 patients with clinical symptoms of acute pyelonephritis were randomized to 2 weeks treatment with either a fixed combination of pivampicillin and pivmecillinam or to pivampicillin alone. If needed, treatment was first started with the respective parenteral equivalents of the drugs. Acute pyelonephritis was bacteriologically verified in 57 patients, in whom Escherichia coli was isolated in 80% of the cases, Klebsiella in 7% and Proteus mirabilis in 5%. 22 of the 39 patients excluded did not have significant bacteriuria (less than 10(8) c.f.u./l). Combination treatment was superior to pivampicillin/ampicillin alone, in terms of clinical effect, with successful treatment being noted in 93% in the combination group and in 53% in the ampicillin group (p = 0.002). The combination was also more effective bacteriologically and it did not select resistant strains in the urinary tract. Ampicillin treatment alone, was, however, associated with a significant increase in urinary strains resistant to ampicillin and to mecillinam. Unsuccessful responders had a significantly higher mean age (p less than 0.01) than successful responders. No serious side-effects were noted.
Acute Disease↗
Pathobiochemistry of sepsis: role of proteinases, proteinase inhibitors and oxidizing agents.
Degradation of structural elements and excessive consumption of humoral factors, especially of plasma proteinase inhibitors, by proteolysis and/or oxidation is a major cause of multiple organ failure in sepsis or septic shock. Such pathobiochemical reactions seem to be induced primarily by extracellularly liberated lysosomal proteins from PMN granulocytes (e.g. elastase, cathepsin G, myeloperoxidase, lactoferrin) as well as oxygen radicals produced during extensive phagocytosis. In clinical studies on septicemia and septic shock the consumption of plasma proteins including proteinase inhibitors was inversely correlated to the liberation of lysosomal factors, especially the granulocytic elastase. Administration of relatively specific elastase-cathepsin G-inhibitors (Bowman-Birk inhibitor, eglin) in experimental septicemia proved to be a promising therapeutic approach to reduce consumption of plasma proteinase inhibitors and development of interstitial lung edema in severe inflammation.
Animals↗
[Postreceptor defect in the effectiveness of insulin: significance of the kallikrein-kinin-prostaglandin system].
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Blood Glucose↗
Granulocyte proteinases as mediators of unspecific proteolysis in inflammation: a review.
In severe inflammatory response, various blood and tissue cells, including polymorphonuclear granulocytes, release lysosomal proteinases, extracellularly and into the circulation. Such enzymes, as well as normally intracellular oxidizing agents produced during phagocytosis, enhance the inflammatory response by degrading connective tissue structures, membrane constituents and soluble proteins by proteolysis or oxidation. We first used polymorphonuclear elastase (E) as a marker of such release reactions. The liberated proteinase competes with susceptible substrates, including alpha 1-proteinase inhibitor (alpha 1PI) and alpha 2-macroglobulin, and is eliminated finally as inactive enzyme-inhibitor complexes by the reticulo-endothelial system. Using an enzyme-linked immunosorbent assay, we determined the plasma levels of E-alpha 1PI following major abdominal surgery, multiple trauma and pancreatogenic shock. Whereas the operative trauma was followed by up to 3-fold increase of the E-alpha 1-PI, postoperative septicemia was associated with a 10 to 20 fold increase. The increase of E-alpha 1-PI and a concomitant decrease of plasma factors, such as antithrombin III, clotting factor XIII and alpha 2-macroglobulin, were correlated. Multiple trauma causes a substantial increase of E-alpha 1-PI up to 14 hours after accident. The released elastase seems to correlate with severity of injury, but assessing the relationship to consumption of plasma factors is complicated by concomitant transfusions. In acute pancreatitis, peaks, of E-alpha 1-PI coincide with a massive consumption of antithrombin III and alpha 2-macroglobulin during shock.
Blood Proteins↗
[Release of granulocytic elastase and plasma protein changes in traumatic hemorrhagic shock].
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Adult↗
[Total lymphoid irradiation in chronic polyarthritis--a new therapeutic concept].
Eleven patients with refractory rheumatoid arthritis were submitted to a total lymphoid irradiation up to a dose of 20 Gy. A constant improvement of clinical symptoms was observed in four out of the eleven patients already during the treatment and in the other patients not later than two months after. The frequency of attacks decreased and the number of joints involved in the attack was reduced. Morning rigidity and joint swellings decreased. One patient developed joint empyemas 4 and 26 months after the treatment. Four patients died in the meantime. In two patients the cause of death were renal insufficiency and a postoperative cardiogenic shock associated with generalized amyloidosis. The third patient died because of a toxically induced left cardiac decompensation with sepsis that could not be controlled by antibiotic drugs and multiple joint empyemas. The fourth patient developed an abscess after surgical treatment of a Kaposi syndrome. She died three months later from acute left cardiac decompensation. The therapy induced a lymphocytopenia with decrease of T helper lymphocytes and unchanged number of T suppressor lymphocytes. The constant therapy results of total lymphoid irradiation in primary chronic polyarthritis is probably due to this modification in the immune regulation.
Aged↗
Genealogy of mammalian cysteine proteinase inhibitors. Common evolutionary origin of stefins, cystatins and kininogens.
A model for the evolution of mammalian cysteine proteinase inhibitors has been constructed on the basis of sequence homology. This model suggests that the diversity of cysteine proteinase inhibitors has evolved from two ancestral units forming the building blocks of stefin and cystatin. Gene triplication of the archetypal inhibitor generated the kininogen heavy chain which contains three cystatin-like copies. Hence, the superfamily of mammalian cysteine proteinase inhibitors is constituted by at least three distinct families, with stefin, cystatin and kininogen as their prototypes.
Amino Acid Sequence↗
Human plasma kininogens are identical with alpha-cysteine proteinase inhibitors. Evidence from immunological, enzymological and sequence data.
Human high- and low-Mr kininogens were shown to be potent inhibitors of cysteine proteinases such as cathepsin L and papain (Ki = 17-48 pM). A strong immunological cross-reaction between the kininogens and low-Mr alpha-cysteine proteinase inhibitor from human plasma was found. Comparison of partial amino acid sequences from high- and low-Mr kininogen and low-Mr alpha-cysteine proteinase inhibitor demonstrated sequence identity for all segments analyzed. These findings suggest that the kininogens and the alpha-cysteine proteinase inhibitors from human plasma are identical proteins.
Amino Acid Sequence↗
Total lymphoid irradiation in patients with refractory rheumatoid arthritis.
Eleven patients with rheumatoid arthritis that had been refractory to conventional drug therapy were treated with total lymphoid irradiation (TLI). Followup continued for 6 months in 9 patients, 12 months in 6 patients, and 24 months in 3 patients. At 6 and 12 months post-TLI, a significant improvement in clinical disease activity was demonstrated. Side effects noted during TLI included fatigue, nausea, diarrhea, and vomiting. One patient died of cardiorespiratory arrest, 2 patients died of kidney failure secondary to generalized amyloidosis, and 1 patient died of septic shock secondary to a multilocular septic arthritis. One patient experienced 2 episodes of septic arthritis; 2 patients manifested delayed wound healing. Immunologic assessments showed consistent lymphopenia in all patients. T lymphocyte subsets decreased after TLI, and showed a transient increase at 6 months post-TLI. The suppressed mitogen responsiveness, which was noted 2 months after irradiation, was found to increase almost to the pre-TLI levels at 12 months. The observed increase in morbidity and mortality after TLI is evidence that discourages the use of this therapeutic technique, at least in its present form.
Antigen-Antibody Complex↗
The complete covalent structure of hirudin. Localization of the disulfide bonds.
Hirudin, the thrombin-specific inhibitor from the leech Hirudo medicinalis, is a single-chain polypeptide (65 amino-acid residues) linked by three disulfide bridges. Localization of the three disulfide bonds could be assigned on the basis of the structures of cystine peptides derived by high performance liquid chromatography separations of thermolysinolytic digest of native hirudin. By characterization of the nine major fragments by amino-acid analysis, N-terminal amino-acid determination and sequence analysis, the following disulfide linkages were identified: Cys6-Cys14, Cys16-Cys28 and Cys22-Cys39. Due to the lack of any closer sequence homology and topological structural homology to other serine proteinase inhibitor proteins, hirudin seems to be unique in its primary structure and hence designates an unknown inhibitor family.
Amino Acid Sequence↗
Released granulocytic elastase: an indicator of pathobiochemical alterations in septicemia after abdominal surgery.
To discover the role of lysosomal enzyme release from polymorphonuclear (PMN) leukocytes during septicemia, plasma levels of PMN elastase were measured with a newly developed enzyme-linked immunosorbent assay for detection of the PMN elastase-alpha 1-proteinase inhibitor complex (E-alpha 1PI). Plasma samples from 41 patients were assayed continuously before and after major abdominal surgery. The patients were divided into a group without infection (group A) and two septicemia groups (survivors in group B and nonsurvivors in group C). The E-alpha 1PI levels of the 11 patients in group A without any signs of pre- or postoperative infection were in the normal range (a normal value of 86.5 +/- 25.5 ng/ml has been reported in 153 healthy subjects), except for a small increase to 208.8 +/- 25.6 ng/ml 12 hours after surgery. When septicemia was confirmed clinically in patients in groups B and C, the E-alpha 1PI levels rose on average to six times the norm in group B (649.9 +/- 116.3 ng/ml) and to more than 10 times the norm in group C (985.0 +/- 154.6 ng/ml). Peak values greater than 2,200 ng/ml could be measured in both groups. In patients in group B, the E-alpha 1PI levels returned to normal during recovery, while in those in group C they remained significantly elevated (560.5 +/- 174.7 ng/ml) until death. Correlations were demonstrated between the amount of elastase released into the circulation and the decrease in the activities of antithrombin III, coagulation factor XIII, and alpha 2-macroglobulin, as well as the increased C-reactive protein in plasma. We conclude that release of elastase and other lysosomal factors from PMN cells plays a major role in the pathobiochemical alterations during septicemia. In addition, significantly elevated E-alpha 1PI levels in the postoperative course seem to be a suitable indicator for onset and persistance of sepsis as well as of the severity of this disorder in patients after major surgery.
Abdomen↗