Biomedical subjects
Publications and source records attributed to L Gutmann.
The authors report two cases of muscular tuberculosis in patients with dermatomyositis treated with steroids. Antituberculous therapy with Rifampicin led to a severe relapse of the dermatomyositis in both cases, suggesting enzymatic induction inhibiting the action of the steroids.
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The mode of action of beta-lactam antibiotics, and the non-enzymatic resistance mechanisms to their activity, are intimately linked to the structure and biosynthesis of the bacterial cell wall. The bacteriostatic effect of beta-lactam antibiotics is related to their various interactions and concomitant inhibition of essential enzymes (transpeptidases, carboxypeptidases) involved in the terminal stages of peptidoglycan biosynthesis. These cytoplasmic membrane-associated target enzymes bind the antibiotics covalently, and hence are known as penicillin-binding proteins (PBPs). The bactericidal effect of these antibiotics is due to a second step following on from the inhibition of cell division and growth, in which the activation of an autolytic system causes cell death. Resistance to beta-lactam antibiotics in Gram-positive bacteria, in the absence of a beta-lactamase, is due to various modifications of the PBPs. Such mechanisms are often found in enterococci, pneumococcus, ans staphylococci. With Gram-negative bacteria such modifications of PBPs are only a rare basis for resistance. The presence of an outer membrane brings another factor into the activity of beta-lactam antibiotics, which is the facility with the antibiotics can diffuse through specialised proteins termed porins. It is generally a modification of the amounts of these proteins, or some other components of the outer membrane, which causes the non-enzymatic mechanism of resistance, particularly in species such as Klebsiella, Enterobacter, Serratia and Pseudomonas.
Combinations of two beta-lactam antibiotics may be advantageous in certain clinical situations, providing a synergistic activity against specific organisms or a broad spectrum of antibiotic coverage. Depending on the combination and the bacteria, synergism, indifference, or antagonism can be observed. Synergism may occur when two beta-lactam antibiotics, acting on different penicillin-binding proteins, are combined or when a penicillinase-susceptible beta-lactam antibiotic is protected by another beta-lactam antibiotic acting as a beta-lactamase inhibitor in strains producing a penicillinase (chromosomal or plasmidic). With different species, such as Enterobacter, Citrobacter, indole-positive Proteus, Serratia, Aeromonas, and Pseudomonas, which produce an inducible chromosome-encoded cephalosporinase, antagonism will appear if one of the two combined antibiotics causes induction of the beta-lactamase and the other becomes inactivated by the increased amount of the enzyme. Although most combinations of new beta-lactam antibiotics (ureido-penicillins, third-generation cephalosporins, monobactams) appear to be indifferent, antagonism and possible selection of resistant mutants are the drawbacks of such combinations. Nevertheless, highly active compounds, if used at doses above the minimal inhibitory concentrations, especially in the case of potential cephalosporinase-inducers, may be safe in vivo as far as avoiding antagonism is concerned, but not necessarily with respect to the selection of resistant mutants.
Fluorescent protease histochemical analysis of muscle biopsy specimens from two patients with nemaline myopathy revealed the apparent absence of one proteolytic enzyme, dipeptidyl peptidase. Although the function of peptidases in normal muscle is obscure, this abnormality suggests that proteases may participate in posttranslational modification of proteins that are to be assembled into Z lines or, alternatively, in the disassembly and degradation of Z-line material.
A 43-year-old woman who indiscriminately took colchicine for five years developed a progressive multisystem syndrome that included severe axonal neuropathy and a pathologically striking myopathy. The neuropathy and myopathy were similar to experimental animal colchicine-induced neuromuscular toxicity.
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In six patients with characteristic symptoms of carpal tunnel syndrome, electrophysiologic studies were normal, except for an initial positive deflection of the thenar muscle action potential with median nerve stimulation at the elbow but not at the wrist. This phenomenon is only seen with coexistent carpal tunnel syndrome and median to ulnar nerve communication and suggests carpal tunnel syndrome is present in these patients. As normal electrophysiologic studies occur in carpal tunnel syndrome (up to 8%) and median to ulnar communications are common (15%-31%), this observed finding is of practical clinical importance in the diagnosis of mild carpal tunnel syndrome despite otherwise normal electrophysiologic studies.
New quinolones are very potent compounds against Gram-negative bacteria, including Pseudomonas, and staphylococci. They are particularly interesting because of their oral availability and their pharmacokinetic properties. When combined with other common antibiotics they appear to have mostly indifferent effects in vitro. Clinical results have shown their efficacy when used alone for the treatment of osteomyelitis, complicated urinary tract infections and prostatitis. Nevertheless, in 6% of cases resistant strains were selected (Klebsiella, Enterobacter, Serratia, P. aeruginosa and staphylococci). The use of combinations of quinolones with other antibiotics was successful in the treatment of osteomyelitis and severe nosocomial infections including bacteraemia, and seems to prevent emergence of resistant strains.
The results of 20 physiological and fermentation tests and examination of the penicillin-binding proteins (PBPs) of 85 enterococcal strains demonstrated that the genus Enterococcus could be divided into at least nine distinct species: E. faecalis, E. faecium, E. durans, E. hirae, E. avium, E. gallinarum, E. casseliflavus, E. malodoratus and E. mundtii. Each species had a specific pattern of at least five PBPs, with molecular masses in the range of about 40-130 kDa. The pattern of PBPs may be useful for identification purposes, since some strains with unusual fermentation characteristics were assigned to species by this technique.
YTR 830, a new beta-lactamase inhibitor, combined with amoxicillin or carbenicillin, showed a synergistic effect similar to that observed with clavulanic acid, and generally better than that with sulbactam, against strains harboring chromosome-encoded penicillinases and broad-spectrum beta-lactamases or plasmid-determined beta-lactamases. With ampicillin, YTR 830 showed the best synergistic activity of the inhibitors against Proteus morganii, Citrobacter freundii, and Enterobacter cloacae and their mutants with a derepressed chromosome-encoded cephalosporinase.
Compared with cefotaxime, ceftazidime, moxalactam, and aztreonam, ceftriaxone produced the best lytic and bactericidal effects when each was added at about 10 times the MIC to Escherichia coli W7. When each of these antibiotics was added at its MIC, only bacteriostasis occurred, but the simultaneous addition of amdinocillin (mecillinam) was synergistic in causing rapid lysis and bactericidal effects. Induction of lysis of two E. coli mutants containing either a thermosensitive penicillin-binding protein (PBP) 2 or 3 by relatively PBP 3-specific (aztreonam) and PBP 2-specific (amdinocillin) antibiotics indicated that inhibition of only PBPs 2 and 3 can cause lysis. Examination of the interactions of cefotaxime, aztreonam, and cefsulodin, with or without amdinocillin, with their targets suggested that other combinations of PBPs could be involved in the onset of lysis. However, inhibition of both PBPs 2 and 3 may explain the better lysis-inducing activity of ceftriaxone (which binds well to both of these PBPs), as well as the synergistic effect of amdinocillin when added together with low concentrations of other beta-lactam antibiotics that interact with PBP 3.
In five patients with Guillain-Barré syndrome, clinical myokymia increased and myokymic burst amplification occurred when ionized Ca++ was lowered by hyperventilation. Myokymia decreased when ionized Ca++ was increased after IV infusion of CaCl2. These responses were absent or diminished in the four patients with myokymia due to brainstem lesions, suggesting that the blood-brain barrier impedes the effects of altered serum ionized Ca++ on axonal excitability. Altering serum Ca++ can distinguish peripheral and central myokymia.
A marked decrease in the amplitude of the evoked thenar compound muscle action potential followed brief exercise at room temperature in two patients with paramyotonia congenita. This decline was more rapid and pronounced in our patient with coexistent thyrotoxicosis. The prolonged recovery period in paramyotonia congenita differs from the brief exercise-induced decreased compound muscle action potential seen in myotonia congenita and myotonic dystrophy. These findings suggest that exercise, like cold exposure, decreases membrane excitability in paramyotonia congenita.
Target fibers are generally considered a specific indicator of denervating disease. We found large numbers of target fibers in a biceps biopsy from a patient with MS and spastic quadriparesis. There was no evidence of denervation. Target fibers are not seen only in denervation.
A 23-year-old woman with congenital intestinal lymphangiectasia developed a progressive spinocerebellar syndrome and neuropathy. The clinical findings were typical of vitamin E deficiency, which was documented in the patient. Intestinal lymphangiectasia is an additional vitamin E-deficient disease that may cause this neurologic syndrome.
We describe morphologically documented necrotizing cerebral vasculitis in a young man with ulcerative colitis. This case supports the evolving concept that ulcerative colitis may be accompanied by systemic vasculitis. The cerebral vasculitis was treated successfully with immunosuppressive therapy.