Vancomycin resistance in Enterococcus gallinarum.

The vancomycin resistance expressed by several strains of Enterococcus gallinarum was studied. Resistance was expressed constitutively, as demonstrated by analysis of growth and inhibition of peptidoglycan synthesis. E. gallinarum strains were moderately resistant to vancomycin (MIC, 16 micrograms/ml) but were as susceptible as vancomycin-susceptible enterococci to the glycopeptides, teicoplanin, A35512B, A47934, A4103A, and A41030E and the glycopeptide actaplanins A1, B2, and C1. Vancomycin resistance in E. gallinarum was inhibited by beta-lactam antibiotics at concentrations that saturated penicillin-binding protein 6 (PBP 6), as demonstrated by binding competition experiments. Spontaneous mutants (frequency, 10(-8)) were two- to fourfold more resistant to beta-lactam inhibition of vancomycin resistance than the parent strain. PBP binding competition experiments suggested that PBP 6 in the mutants bound less cefotaxime, while binding of penicillin and cefoxitin was unaffected. Both a bioassay method and high-performance liquid chromatography showed that E. gallinarum membranes have enzymatic activity which modifies a model pentapeptide yielding a product that is thought to be a tetrapeptide. This activity could be a D,D-carboxypeptidase. In both the parent E. gallinarum strain and its derivatives that were resistant to the synergistic drug combination, the activity was inhibited by beta-lactams at concentrations which correlated with those that inhibit vancomycin resistance and those that saturate PBP 6. These results suggest the possibility that PBP 6 may be involved in the vancomycin resistance of E. gallinarum and that the putative D,D-carboxypeptidase activity seen in E. gallinarum membranes may be attributable to PBP 6.


Pharmacokinetics of imipenem in serum and skin window fluid in healthy adults after intramuscular or intravenous administration.

The pharmacokinetic profiles of imipenem after intramuscular (i.m.) and intravenous injections were examined in adult volunteers. Levels of imipenem in serum after i.m. injection of a microcrystalline suspension of imipenem-cilastatin (500 mg each) reached a peak (8.0 micrograms/ml) at 1.5 h after administration, and concentrations were maintained in excess of 1.5 micrograms/ml for 6 h. Serum elimination half-life (1.3 h), volume of distribution (14.5 liters), and area under the curve (AUC; 27.8 micrograms.h/ml) after i.m. injection did not significantly differ from those of a comparable dose given by intravenous infusion. Bioavailability after i.m. injection was 89%. Imipenem levels in skin window fluid after i.m. administration were maximal (4.3 micrograms/ml) at 4 h after injection, at which time imipenem concentrations exceeded those produced by intravenous infusion. The AUCskin window/AUCserum ratio for skin window fluid after i.m. injection was 68%, indicating good penetration of the drug into skin fluid. This study shows that i.m. injection of 500 mg of imipenem-cilastatin results in concentrations of imipenem in serum and skin fluid that are, for at least 6 h, consistent with antimicrobial activity against susceptible organisms.


Endotracheal and aerosol administrations of ceftazidime in patients with nosocomial pneumonia: pharmacokinetics and absolute bioavailability.

Pharmacokinetic studies on ceftazidime, an aminothiazole cephalosporin with a wide spectrum of antibacterial activity, including activity against Pseudomonas aeruginosa, were performed in patients with nosocomial pneumonia. The concentration-time profiles of ceftazidime in plasma, urine, and bronchial secretions of 12 patients were investigated after intravenous (i.v.) (n = 12), endotracheal (n = 10), and aerosol (n = 5) administrations. In all cases a 1-g dose was administered. Concentrations of drug in all samples were assayed by high-performance liquid chromatography with UV detection. The elimination of the drug from the blood followed a biexponential (i.v. administration) or a monoexponential (endotracheal and aerosol administrations) decay, with an elimination half-life of 6 h and a total body clearance of 4.2 liters/h. The apparent volume of distribution was 0.36 liter/kg of body weight. Renal clearance of the drug accounted for 58% of the total clearance; 66% +/- 17.7%, 33.5% +/- 17.3%, and 6.59% +/- 3.45% of the administered dose were eliminated in urine as parent drug after i.v., endotracheal, and aerosol administrations, respectively. The absolute bioavailabilities were 0.47 and 0.08 for endotracheal and aerosol administrations, respectively. Very high concentrations were found in bronchial secretions after local administration. The MICs for 90% of the most important pathogens responsible for nosocomial infections were exceeded by concentrations in bronchial secretion for up to 12 h after i.v. infusion and for up to 24 h after endotracheal and aerosol administrations.


In vitro activity and beta-lactamase stability of LJC 10,627.

The in vitro activity of LJC 10,627, a new carbapenem, was compared with those of imipenem, cefotaxime, ceftazidime, and gentamicin. LJC 10,627 inhibited 90% of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Hafnia alvei, Citrobacter freundii, Citrobacter diversus, Proteus mirabilis, Morganella morganii, Proteus rettgeri, Serratia marcescens, Pseudomonas cepacia, salmonellae, shigellae, aeromonas, and yersiniae at less than or equal to 2 micrograms/ml. Haemophilus influenzae was inhibited by 0.5 microgram/ml, and moraxellae were inhibited by 0.12 microgram/ml. LJC 10,627 was twofold more active than imipenem against aerobic gram-negative organisms and inhibited ceftazidime-, cefotaxime-, and gentamicin-resistant members of the genera Klebsiella, Enterobacter, Citrobacter, and Serratia at less than or equal to 2 micrograms/ml. Xanthomonas maltophilia strains were resistant to the drug. Imipenem was two- to fourfold more active than LJC 10,627 against Staphylococcus aureus and Staphylococcus epidermidis. LJC 10,627 did not inhibit most methicillin-resistant Staphylococcus aureus or methicillin-resistant Staphylococcus epidermidis strains. LJC 10,627 inhibited Streptococcus pyogenes and Streptococcus pneumoniae at 0.06 and 0.12 microgram/ml, respectively. Bacteroides fragilis and other Bacteroides spp. were inhibited by 0.5 microgram of LJC 10,627 per ml. Serum (50%) did not affect the MICs. LJC 10,627 was not hydrolyzed by plasmid-mediated beta-lactamases of Bush types 2b, 2b', TEM-1, TEM-2, TEM-3, TEM-5, TEM-7, TEM-9, and SHV-1; the chromosomal beta-lactamases of Bush type 1; P-99; a Morganella enzyme; or a Citrobacter freundii enzyme. The Bush type 2c and 2d enzymes OXA-1, OXA-2, PSE-1, PSE-2, and PSE-4 did not hydrolyze LJC 10,627, nor did the beta-lactamases of Staphylococcus aureus, Moraxella spp., Bacteroides fragilis, and Proteus vulgaris. The beta-lactamase of Xanthomonas hydrolyzed LJC 10,627, albeit at approximately one-third the rate that imipenem was hydrolyzed.


Removal of vancomycin by high-flux hemodialysis membranes.

Levels of vancomycin in serum are traditionally believed to be unaffected by hemodialysis. By both in vivo and in vitro techniques, the effects of a newer, more permeable dialyzer membrane on vancomycin concentrations were investigated. Six patients who were receiving vancomycin and undergoing maintenance hemodialysis with polyacrylonitrile dialyzer membranes had postdialysis levels in serum that were 63% of predialysis levels; the intradialytic half-life was 5.7 h. Vancomycin concentrations in serum exiting the dialyzer were 68% of those simultaneously entering the dialyzer at the beginning of dialysis. When polyacrylonitrile and conventional cellulose membranes were perfused in vitro with a recirculating solution of vancomycin, vancomycin concentrations fell to 39 and 91%, respectively, of the original concentration. The vancomycin concentration in the ultrafiltrate collected from the polyacrylonitrile membranes was only 23% of the original perfusate concentration. A significant decrease in the serum vancomycin concentration may occur during hemodialysis with newer high-flux dialyzer membranes. It appears that vancomycin binds to polyacrylonitrile membranes; this binding does not require the presence of protein and is affected by the pH of the perfusate.


Simulation of human serum pharmacokinetics of cefazolin, piperacillin, and BRL 42715 in rats and efficacy against experimental intraperitoneal infections.

Studies were performed to determine the effects of BRL 42715, a potent beta-lactamase inhibitor, on the activity of cefazolin and piperacillin against experimental intraperitoneal infections caused by either Escherichia coli or Serratia marcescens in rats. Compounds were administered to rats as a continuous infusion of an exponentially diluted solution to simulate in rat plasma the concentration-versus-time curves obtained for humans following intravenous bolus administration. A simulated 1-g dose of cefazolin was ineffective in reducing the bacterial counts in blood and peritoneal fluid samples of animals infected with S. marcescens US20, which produced class Ia beta-lactamase, and as a result, mortality was similar to that of infected controls. Similarly, a simulated 2-g dose of piperacillin was ineffective in reducing bacterial numbers and mortality in animals infected with E. coli 41548, producing a TEM-1 beta-lactamase. However, when the antibiotics were coadministered with BRL 42715, bacterial numbers were reduced significantly and all animals survived at least 16 h after infection. These data demonstrate the ability of BRL 42715 to potentiate the activity of cefazolin and piperacillin against beta-lactamase-producing bacteria that would otherwise be resistant to these antibiotics and illustrate the application of a model to simulate human serum concentrations in conscious rats.


Effects of protease inhibitors on replication of various myxoviruses.

We studied the effects of eight protease inhibitors on the multicycle replications of various orthomyxoviruses and paramyxoviruses. Among the compounds, nafamostat mesilate, camostat mesilate, gabexate mesilate, and aprotinin, which are widely used in the treatment of pancreatitis, inhibited influenza virus A and B replication at concentrations that were significantly lower than their cytotoxic thresholds in vitro. None of the protease inhibitors had activity against respiratory syncytial virus, measles virus, or parainfluenza virus type 3 at the highest concentrations tested. Camostat mesilate was found to be the most selective inhibitor. Its 50% effective concentration for influenza virus A replication was 2.2 micrograms/ml, and the selectivity index, which was based on the ratio of the 50% inhibitory concentration for host cell proliferation to the 50% effective concentration for influenza virus A replication, was 680. When the in ovo antiviral activity of the compounds was tested by using chicken embryos, camostat mesilate at a dose of 10 micrograms/g markedly reduced the hemagglutinin titers of influenza viruses A and B.


Pharmacokinetics of meropenem and its metabolite in young and elderly healthy men.

The pharmacokinetics of meropenem and its ring-opened metabolite (ICI 213,689) were investigated with eight young (20- to 34-year-old) and eight elderly (67- to 80-year-old) healthy male volunteers given single 30-min intravenous infusions of 500 mg of meropenem. All subjects had normal age-correlated glomerular function. The mean terminal half-life of meropenem was 1.27 h in the elderly subjects versus 0.81 h in the younger subjects (P less than 0.001). This and similar increases in mean residence time and area under the concentration-time curve were explained by a reduction in total [139 versus 203 ml/(min.1.73 m2); P less than 0.001], renal, and nonrenal clearances in subjects at advanced ages. The apparent volume of distribution and urinary recovery over 8 h were not significantly altered. With the metabolite, prolonged serum half-life and mean residence time, enlarged area under the concentration-time curve, and lower renal clearance but no significant changes in peak plasma concentration or urinary recovery were found in the elderly. The reduction in the renal excretion rate of meropenem and its metabolite corresponds to the age-associated physiological decline in renal function. The capacity to metabolize meropenem may also be slightly impaired in people at advanced ages. Dose reduction of meropenem should be considered for elderly patients.


Mechanisms of antibacterial action of tachyplesins and polyphemusins, a group of antimicrobial peptides isolated from horseshoe crab hemocytes.

Tachyplesins I and II and polyphemusins I and II, cationic peptides isolated from the hemocytes of horseshoe crabs, show bactericidal activities with similar efficiencies for both gram-negative and gram-positive bacteria. Tachyplesin I inhibited bacterial growth irreversibly within 40 min. A subinhibitory concentration of tachyplesin I sensitized gram-negative bacteria to the bactericidal actions of novobiocin and nalidixic acid, although polymyxin B-resistant strains which have altered lipopolysaccharides were susceptible to tachyplesin I. This implies that tachyplesin permeabilizes the outer membrane and that the likely target of its action is outer membrane constituents other than lipopolysaccharides. On the other hand, a defensin-susceptible phoP strain of Salmonella typhimurium was also susceptible to tachyplesin I. Tachyplesin I rapidly depolarized the inverted inner-membrane vesicles of Escherichia coli. These results suggest that depolarization of the cytoplasmic membrane, preceded by the permeabilization of the outer membrane for gram-negative bacteria, is associated with tachyplesin-mediated bactericidal activity. The similarity between the actions of tachyplesin and those of defensin was discussed.


Aerosolized liposomal amphotericin B for treatment of pulmonary and systemic Cryptococcus neoformans infections in mice.

Cryptococcus infections of the lung and central nervous system have become major problems in immuno-compromised patients, leading to the need for additional treatment protocols. We have utilized a Cryptococcus-mouse model that mimics human cryptococcal disease to evaluate the efficacy of amphotericin B-liposomes (AmpB-Lip) when delivered by small-particle aerosol (SPA). In the model, initial intranasal inoculation leads to a pulmonary infection that spreads after 2 to 3 weeks to distant organs, including the brain. Aerosols of AmpB-Lip that were generated by a Collison nebulizer had mass median aerodynamic diameters of 1.8 microns and contained 10.3 micrograms of AmpB per liter. When AmpB-Lip SPA was begun at 24 h postinoculation, a single 2-h treatment (0.3 mg of AmpB per kg of body weight) was effective in reducing pulmonary Cryptococcus infection. This regimen was more effective than intravenous administration of AmpB-Lip given for 3 continuous days. This single 2-h exposure to AmpB-Lip also was effective in reducing pulmonary Cryptococcus infection when treatment was delayed for 7 or 14 days. At day 21, when organisms had spread to the brain in all animals, the single 2-h aerosol treatment reduced the number of cryptococci in the brain as well as in the lungs. AmpB-Lip SPA administered once for 2 h on days 7, 14, and 21 also was effective in increasing the duration of survival of infected animals. These results demonstrate that aerosolized AmpB-Lip can be effective in treating both local, pulmonary Cryptococcus disease and systemic disease.


Levels of cefmenoxime in sera and peritoneal tissues of patients undergoing gastrointestinal surgery.

It is not known whether a prophylactic antibiotic administered prior to surgery reaches adequate levels in the peritoneum, where peritonitis may take place. This study determined levels of cefmenoxime in sera and peritoneal tissues of patients undergoing gastrointestinal surgery. Fifteen patients who underwent elective gastrointestinal surgery received an intravenous drip infusion of cefmenoxime (2 g) over 1 h prior to surgery. In patients who underwent gastrectomy, the level of cefmenoxime in serum was 130.8 +/- 6.9 micrograms/ml at laparatomy and decreased to 5.0 +/- 0.7 micrograms/ml at 4 h. Levels in parietal peritoneal and omental tissues at laparotomy were 35.3 +/- 5.2 and 19.2 +/- 3.5 micrograms, respectively, and decreased time dependently. In patients who underwent cholecystectomy, the level of cefmenoxime in serum was 137.9 +/- 7.3 micrograms/ml at laparotomy and decreased to 5.0 +/- 1.2 micrograms/ml at 4 h. Levels in parietal peritoneal and omental tissues were 31.0 +/- 8.4 and 13.7 +/- 3.3 micrograms/g, respectively, and decreased time dependently. The level of cefmenoxime in serum correlated with the levels of cefmenoxime in parietal peritoneum (r = 0.64, P less than 0.01) and in omentum (r = 0.47, P less than 0.02). In patients with appendicitis who received a bolus injection of 2 g of cefmenoxime, the level of drug in inflammatory omental tissue correlated with the level in serum. The levels in peritoneal tissue during surgery lasting up to 2 h were significantly greater than in MIC of cefmenoxime against almost all bacteria reported. A preoperative single dose of 2 g of cefmenoxime probably is effective as a prophylactic for intraoperative contamination.


Preclinical pharmacology and pharmacokinetics of the anti-hepatitis virus agent 2'-fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil in mice and rats.

The preclinical pharmacology and pharmacokinetics of 2'-fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil (FEAU), a selective inhibitor of herpesvirus and hepatitis virus replication, were investigated in the mouse and rat. Following intravenous (i.v.) or oral (p.o.) administration, FEAU was cleared from the plasma primarily unchanged, with a terminal half-life of 58 to 80 min in the mouse and 63 to 78 min in the rat. The steady-state volumes of distribution times bioavailabilities of FEAU were approximately 2.1 and 3.4 times the total body water volumes after p.o. administration of 10 mg of drug per kg of body weight in mice and rats, respectively. A comparison of the area under the concentration-time curve after i.v. and p.o. FEAU administration indicated that the p.o. dose was completely absorbed in both species. When tritiated FEAU was used in mice, 35.0% of the i.v. dose and 33.5% of the p.o. dose were excreted in urine as unchanged FEAU, 8.1% (i.v. dose) and 9.2% (p.o. dose) were excreted as tritiated water, and 15.6% (i.v. dose) and 18.1% (p.o. dose) were excreted as unknown metabolite(s) in urine within 24 h of dosing. Only 1.24% (i.v. dose) and 2.6% (p.o. dose) of the total doses were found in urine as 3H2O when the FEAU dose was increased to 50 mg/kg. However, a higher percentage of the total dose (59.6% for the i.v. dose and 61.3% for the p.o. dose) was recovered within 24 h as intact FEAU in rat urine, less than 1.4% (i.v. dose) and 2.7% (p.o. dose) of the total dose were found to be 3H2O, and 5.6% (i.v. dose) and 6.7% (p.o. dose) of the total dose were excreted as known metabolite(s). The distribution ratios for total radioactivity in tissue relative to those in plasma were 0.5 to 1.3 in spleen, testes, muscle, and liver during the first hour after a 10-mg/kg dose in rats. Of the total FEAU radioactivity administered, only 1.38% was excreted in bile as unchanged FEAU. No FEAU glucuronide metabolite was detected. Tissue concentrations of 0.15 to 0.6 microM at 6 h after dosing are in the range of the effective antiviral concentration for FEAU. In conclusion, FEAU administered p.o. to mice and rats was well absorbed; FEAU was rapidly distributed into tissues and remained above in vitro antiviral concentrations for more than 6 h; in mice, [3H]FEAU showed metabolism-mediated tritium exchange with water; and in rats, FEAU was less extensively metabolized than in mice and clearance was primarily via renal processes, mainly in the form of unchanged FEAU.


Analysis of peptidoglycan precursors in vancomycin-resistant enterococci.

Analysis by high-pressure liquid chromatography of the cytoplasmic peptidoglycan precursors of a high- and a low-level vancomycin-resistant Enterococcus spp. was performed before and after induction of resistance. This analysis showed a decrease of the D-Ala-D-Ala and UDP-MurNac-pentapeptide pools, an increase of the UDP-MurNac-tripeptide pool, and the appearance of new UDP-MurNac-containing material. These results lead us to suggest that the vancomycin-induced carboxypeptidase activity cleaves the D-Ala-D-Ala (L. Gutmann, D. Billot-Klein, S. Al-Obeid, I. Klare, S. Francoul, E. Collatz, and J. van Heijenoort, Antimicrob. Agents Chemother. 36:77-80, 1992), which in turn would prevent formation of the normal UDP-MurNac-pentapeptide and thereby of the vancomycin target. The novel UDP-MurNac-containing material is thought to correspond to peptidoglycan precursors which might be synthesized by an alternate pathway (T. D. H. Bugg, G. D. Wright, S. Dutka-Malen, M. Arthur, P. Courvalin, and C. T. Walsh, Biochemistry 30:10408-10415, 1991) and which would be unable to bind vancomycin in glycopeptide-resistant enterococci.


Comparison of 5 milligrams of netilmicin per kilogram of body weight once daily versus 2 milligrams per kilogram thrice daily for treatment of gram-negative pyelonephritis in children.

The efficacy and safety of netilmicin, 5 mg/kg of body weight once daily or 2 mg/kg thrice daily for 10 days, for the treatment of gram-negative pyelonephritis in children were compared in a prospective, randomized trial. Explicit criteria were used to define the site of infection, treatment outcome, and adverse effects. Netilmicin was given to 74 children once daily and to 70 children three times daily. At 1 week posttreatment, 73 (99%) of 74 children treated with netilmicin once daily and 70 (100%) of 70 children treated with netilmicin three times daily were cured. At 4 weeks posttreatment, no relapse was detected and the rate of reinfection was essentially identical in the two treatment groups. Peak serum netilmicin concentrations were higher in patients given the once-daily regimen, whereas a higher trough level was detected in patients given the three-times-daily regimen. Nephrotoxicity, which was defined as an increase in the serum creatinine level of greater than or equal to 0.3 mg/dl over the baseline, was rare (3%) and reversible and occurred regardless of the treatment regimen. Ototoxicity, which was assessed by pure-tone audiometry (250 to 8,000 Hz) and brain stem-evoked response (6,000 Hz), occurred in 2 of 32 children who were evaluated. In these two children, who were given the once-daily regimen, wave V was not evokable monolaterally below 25 and 40 dB normal hearing level, respectively. Thus, it may be possible to treat childhood pyelonephritis with netilmicin once daily. However, this new approach needs to be confirmed in other studies.


Molecular basis of the non-beta-lactamase-mediated resistance to beta-lactam antibiotics in strains of Haemophilus influenzae isolated in Canada.

A study recently conducted across Canada showed that 64 of 2,503 clinical isolates of Haemophilus influenzae were resistant to beta-lactams without production of a beta-lactamase (L. D. Tremblay, J. L'Ecuyer, P. Provencher, M. G. Bergeron, and Canadian Study Group, Can. Med. Assoc. J. 143:895-900, 1990). The beta-lactamase-negative strains formed three distinct groups, with ampicillin MICs of 0.5 to 1, 2 to 4, and greater than or equal to 8 micrograms/ml for groups I, II, and III, respectively. We have investigated the mechanisms of resistance for eight strains originating from different infections and geographic areas. These strains were representative of groups I to III. Five strains were nontypeable, two were type B, and one was non-B. Chromosomal DNA extracted from each strain was used to transform the laboratory strain Rd. Transformants were selected on beta-lactam-containing plates and showed the same level of resistance to ampicillin as the donor strains. Differences in outer membrane proteins, porins, and lipopolysaccharide profiles on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) did not change with resistance. Functional analyses of purified porins in artificial lipid bilayer experiments did not explain resistance. Peptidoglycan synthesis was measured by incorporation of [14C]alanine into trichloroacetic acid-insoluble cell wall material in the presence of chloramphenicol. The growth rate and the rate of peptidoglycan synthesis observed for the transformants of the isogenic set did not correlate with resistance. Whole-cell labeling with 125I-penicillin revealed modifications in penicillin-binding proteins (PBPs) among the transformants. In particular, PBPs 3A and 3B (65 and 63 kDa, respectively) showed a decrease in affinity for beta-lactams in all transformants (groups I, II, and III) and correlated with an increased MIC except in the transformant of group III, which showed higher levels of resistance. Partial purification and proteolytic digestion of 125I-penicillin-labeled PBP 3B led to two types of CnBr peptide profiles on SDS-PAGE, the profiles of the transformed strains from groups I and II being different from those of the control group and group III. Finally, electron microscopy revealed a distinct cell filamentation for the group III transformants. These data clearly indicate that changes in PBPs are a common mechanism that results in a significant level of non-beta-lactamase-mediated beta-lactam resistance in H. influenzae despite serotype, origin of isolation, or geographic distribution.


Characterization of vanY, a DD-carboxypeptidase from vancomycin-resistant Enterococcus faecium BM4147.

VanY is a protein with a molecular mass of 34.8 kDa encoded by vanY, a member of the high-level vancomycin resistance gene cluster found on plasmid pIP816 in Enterococcus faecium BM4147. Extracts from Escherichia coli JM83 bearing plasmid pAT383, which contains the vanY gene, were examined for enzymatic hydrolysis of peptidoglycan precursors. VanY was associated with the cell membranes and cleaved the C-terminal D-alanine residue of UDP-muramyl-pentapeptide but did not display transpeptidase or beta-lactamase activities. The DD-carboxypeptidase activity was not inhibited by beta-lactam antibiotics. VanY released the C-terminal D-hydroxy acid from depsipeptides produced by the vancomycin resistance protein VanA. These results demonstrate that VanY should contribute in vivo to the hydrolysis of both the D-alanyl-D-alanine- and the depsipeptide-containing peptidoglycan precursors.


Didanosine pharmacokinetics in patients with normal and impaired renal function: influence of hemodialysis.

The pharmacokinetics of didanosine were investigated following oral administration of a single 375-mg dose to eight human immunodeficiency virus-seropositive patients with normal renal function and eight human immunodeficiency virus-seropositive uremic patients. In uremic patients, the plasma half-life was longer than that in control patients (respectively, 4.5 +/- 2.2 and 1.6 +/- 0.4 h). The ratio of total plasma clearance to absolute bioavailability was four- to fivefold lower in uremic patients than in patients with normal renal function (respectively, 491 +/- 181 and 2,277 +/- 738 ml/min). Because of the decrease in elimination, concentrations in plasma were higher for uremic patients than for control patients; the maximum concentrations of drug in plasma were, respectively, 3,978 +/- 1,607 and 1,948 +/- 994 ng/ml; the areas under the concentration-time curve were, respectively, 14,050 +/- 4,262 and 3,000 +/- 956 ng.h/ml. Didanosine was removed by hemodialysis with an extraction ratio of 53% +/- 8%, a hemodialysis clearance value of 107 +/- 21 ml/min, and a fractional drug removal during a 4-h dialysis of 20% +/- 8% of the dose. Dosage adjustments are necessary in uremic patients.


Comparison of nephrotoxicities of different polyoxyethyleneglycol formulations of amphotericin B in rats.

The aim of the present study was to assess whether amphotericin B (AmB)-Myrj 59, AmB-polyoxyethyleneglycol 24 cholesterol (PC), and AmB-Synperonic A50 (SA50) were less nephrotoxic than AmB-deoxycholate (DC). Rats were treated with the different AmB formulations (10 mg/kg of body weight) intraperitoneally or with the surfactants alone. A group of control rats receiving the vehicle was also examined. After 6 days of daily intraperitoneal injections of AmB-DC, decreased body weight and glomerular filtration rate as well as increased degree of diuresis, uremia, microalbuminuria, and N-acetyl-beta-D-glucosaminidase excretion in urine were noted. Urinary excretion of potassium and sodium was also decreased in AmB-DC-treated rats. Most of these effects were more pronounced with AmB-PC and AmB-SA50. In contrast, AmB-Myrj 59 was less nephrotoxic than AmB-DC. Indeed, after 6 days of treatment with AmB-Myrj 59, the natriuria, kaliuria, albuminuria, and glomerular filtration rates were unchanged compared with those of controls. Moreover, the body weight loss and uremia increase of the rats treated by AmB-Myrj 59 were less than those of the rats treated with the commercial preparation. Among the surfactants, only PC was toxic for the rats. The intrinsic toxicity of PC and the higher systemic exposure to AmB could contribute to increased toxicities of AmB-PC and AmB-SA50, respectively. AmB-Myrj 59 was less nephrotoxic than AmB-DC at equivalent areas under the plasma concentration-time curves. These preliminary results suggest that this formulation could be a good alternative to the commercial product.


Pharmacokinetics of meropenem in subjects with various degrees of renal impairment.

Five healthy volunteers and 18 patients with various degrees of renal impairment received 500 mg of meropenem intravenously as a 30-min infusion. Five dialysis patients were dosed 2 h prior to hemodialysis, and four of them were also dosed between hemodialysis treatments. Plasma and urine samples were collected for up to 48 h and 12 h, respectively. Concentrations of meropenem and its open ring metabolite ICI 213,689 were determined by high-performance liquid chromatography and radioimmunoassay, respectively. The subjects were divided into four groups with glomerular filtration rates (GFR) of greater than 80, 30 to 80, 5 to 29, or less than 5 ml/min. There were linear correlations between the GFR and the rates for total plasma clearance as well as renal clearance of meropenem (group mean values for total clearance of 186, 74, 53, and 19 ml/min/1.73 m2, respectively). In subjects with normal renal function, nonrenal clearance accounted for approximately 20% of total elimination, increasing to about 50% in patients with GFR between 5 and 29 ml/min/1.73 m2. The terminal half-life of meropenem increased from 0.9 h in the healthy volunteers to 6.8 h in patients with end-stage renal disease. The half-life of ICI 213,689 was 2.31 h in the healthy volunteers and increased to 23.6 h in patients with GFR of 5 to 29 ml/min. In patients with end-stage renal disease, half-lives could not be measured, as concentrations were hardly declining during the 48-h observation period. The area under the concentration-time curve for meropenem increased more than 10-fold. Both meropenem and its open ring metabolite were readily dialyzable, with dialysis clearances of 79 and 81 ml/min/1.73 m2, respectively.


Stereochemical evaluation of the relative activities of the cinchona alkaloids against Plasmodium falciparum.

Quinine and quinidine were over 100 times more active than 9-epiquinine and 9-epiquinidine against chloroquine-sensitive Plasmodium falciparum and over 10 times more active against chloroquine-resistant P. falciparum. Since the only structural difference between quinine, quinidine, 9-epiquinine, and 9-epiquinidine is their three-dimensional configuration, the three-dimensional structures of these four alkaloids were examined in order to explain the large difference in relative activities between the 9-epi alkaloids and quinine and quinidine. The crystal structure of 9-epiquinidine hydrochloride monohydrate was determined by X-ray diffraction and was compared with the crystal structures of quinine, quinidine sulfate dihydrate, and 9-epiquinine hydrochloride dihydrate. The crystallographic parameters for 9-epiquinidine hydrochloride monohydrate were as follows: chemical formula, C20H25N2O2+.Cl-.H2O; M(r), 378.9; symmetry of unit cell, orthorhombic; space group, P2(1)2(1)2(1); parameters of unit cell, a was 7.042 +/- 0.001 A (1 A = 0.1 nm), b was 9.082 +/- 0.001 A, c was 31.007 +/- 0.005 A; the volume of unit cell was 1,983.1 +/- 0.6 A3; number of molecules per unit cell was 4; the calculated density was 1.27 g cm-3; the source of radiation was Cu K alpha (lambda = 1.54178 A); mu (absorption coefficient) was 18.82 cm-1; F(000) (sum of atomic scattering factors at zero scattering angle) was 808; room temperature was used; final R (residual index) was 5.72% for 1,501 reflections with magnitude of F(o) greater than 3 sigma (F). The intramolecular distance from N-1 to O-12 in 9-epiquinidine and 9-epiquinine, although shorter than the corresponding distance in quinine and quinidine, was similar to those of other active amino alcohol antimalarial agents. In all four alkaloids, both the hydroxyl and amine groups formed intermolecular hydrogen bonds, showing the potential for forming hydrogen bonds with cellular constituents. However, the positioning of the N+-1--H-N1 and O-12--H-O12 groups relative to each other was quite different in the 9-epi alkaloids versus quinidine. This difference in positioning may determine the relative strengths, of the formation of hydrogen bonds with cellular constituents important to antimalarial activity and, therefore, may determine the relative strength of antimalarial activity.


Use of an enzyme-linked immunosorbent assay to assess penetration of amoxicillin into lung secretions.

An enzyme-linked immunosorbent assay (ELISA) was developed to measure total amoxicillin concentrations penetrating lung secretions, which were compared with "active" concentrations measured by conventional bioassay. An antibody was raised in rabbits to amoxicillin conjugated to bovine serum albumin and used in a competitive binding ELISA (sensitivity, 10 ng/ml; precision [coefficient of variation], 9%). The measurement of amoxicillin in lung secretions by using the ELISA method was verified by high-performance liquid chromatography. Amoxicillin concentrations were found to be similar in both whole sonicated sputum and sol-phase sputum obtained by ultracentrifugation following single oral doses of 3 g (4.6 mg/liter for sonicated and 4.7 mg/liter for sol-phase preparations) and 250 mg (0.23 mg/liter for both preparations). Eight patients with bronchiectasis received 500 mg of amoxicillin three times daily. On the second day of therapy (4 h after the morning dose), the mean concentration of amoxicillin in sputum was 0.88 mg/liter (standard error of the mean [SEM], 0.11) by ELISA and 0.40 mg/liter (SEM, 0.05) by bioassay, suggesting a significant degree of local inactivation. This difference between total and active amoxicillin levels was found to correlate significantly (r = 0.693; P less than 0.05) with beta-lactamase levels (mean, 29.5 mU/ml; SEM, 9.4). A pharmacokinetic study on day 3 revealed maximum levels in secretions 2 to 4 h after dosing (mean, 1.36 mg/liter; SEM, 0.26). At the end of successful therapy (day 14), total and active levels were lower (mean, 0.48 mg/liter; SEM, 0.11 [total]; mean, 0.21 mg/liter; SEM, 0.06 [active]); this result was associated with a reduction in lung inflammation (decreased serum-derived albumin in the lung secretions). In conclusion, antibiotic penetration is partly dependent on the degree of lung inflammation. The differences observed in total and active levels of amoxicillin and the relationship to beta-lactamase activity in sputum suggest why higher doses of antibiotic may be required to produce a therapeutic response in some patients.


Two- and four-day rifampin chemoprophylaxis regimens induce oxidative metabolism.

The effects of two short-term chemoprophylaxis regimens of rifampin (2 or 4 days) on oxidative metabolism were investigated in 14 healthy subjects. Seven subjects received 600 mg of rifampin twice daily on study days 6 and 7 (group A), and seven subjects received 600 mg of rifampin once daily on days 4, 5, 6, and 7 (group B). Antipyrine (18 mg/kg of body weight) was administered orally on days 1, 8, and 15. Short-term rifampin regimens increased oral clearance of antipyrine in both groups compared with the baseline value (P less than 0.05), and group B displayed a larger percent increase over the baseline value than group A did (70.5 +/- 14.3 versus 33.1 +/- 18.1; P less than 0.05). The partial metabolic clearance (CLM) of antipyrine to 3-hydroxymethylantipyrine (HMA) on day 8 increased 71 and 108% for regimens A and B, respectively (P less than 0.05 for both). The corresponding increases in CLM to norantipyrine (NORA) were 57 and 98% (P less than 0.05 for both). CLM to 4-hydroxyantipyrine (OHA) on day 8 increased 64% for regimen A (P = 0.08) and 97% for regimen B (P less than 0.05) compared with the baseline. Although CLM to HMA and OHA on day 15 remained greater than 50% over the baseline with both regimens, CLM to NORA on day 15 was less than 25% over the baseline with both regimens. Thus, both short-term rifampin chemoprophylaxis regimens increased antipyrine clearance for at least 1 week. The increase tended to be higher with the 4-day regimen. The pattern observed for the CLMS suggests that more than one P-450 enzyme is affected.


Inconsistent bactericidal activity of triple-combination therapy with vancomycin, ampicillin, and gentamicin against vancomycin-resistant, highly ampicillin-resistant Enterococcus faecium.

Combination therapy with ampicillin, vancomycin, and gentamicin in vitro against several clinical isolates of vancomycin-resistant, highly ampicillin-resistant Enterococcus faecium, including VanA and VanB strains, was evaluated. The MICs of ampicillin were not significantly decreased by induction with vancomycin, and the combination of ampicillin and vancomycin was not inhibitory for any strain. Triple-combination therapy was least active against highly resistant VanA isolates, achieving a reduction of less than 1 log CFU at 24 h, but demonstrated slightly more activity against VanB strains.


Intraocular penetration of rifampin in humans.

The penetration of rifampin into human aqueous humor was determined in 15 patients undergoing elective cataract surgery. Between 0.9 and 5.5 h after administration of a single 600-mg oral dose, concentrations ranged from 6.0 to 21.5 mg/liter in serum and from less than 0.2 to 1.3 mg/liter in aqueous humor.


Stability of meropenem and effect of 1 beta-methyl substitution on its stability in the presence of renal dehydropeptidase I.

The stability of meropenem in the presence of renal dehydropeptidase I (DHP-I) varied extremely with the animal source of the enzyme. Meropenem, compared with imipenem, was rather easily hydrolyzed by DHP-Is from mice, rabbits, and monkeys, while it showed a higher resistance to guinea pig and beagle dog DHP-Is. In addition, meropenem was four times more resistant than imipenem to human DHP-I. The 1 beta-methyl substituent on carbapenems, i.e., meropenem and 1 beta-methyl imipenem, made them considerably more resistant to mouse and swine DHP-Is than the 1-unsubstituted derivatives are.


Evaluation of the usefulness of a novel injectable cephalosporin, E1040, and ceftazidime for management of complicated urinary tract infections caused by Pseudomonas aeruginosa and Proteus mirabilis by using the rat urolithiasis model.

A novel injectable cephalosporin, E1040, significantly eradicated Pseudomonas aeruginosa from the urine, in contrast to ceftazidime, in rats with complicated P. aeruginosa urinary tract infections associated with urinary stones, suggesting that E1040 is a prospective therapeutic agent in the management of refractory Pseudomonas urinary tract infections.


Eating style and eating behaviour in adolescents.

The relationship between eating style, attitudes towards food and food intake was investigated in 846 British adolescent schoolchildren. Eating style was assessed with the Dutch Eating Behaviour Questionnaire, attitudes towards food with a series of specially prepared questions, and food intake with a diet history taken by a dietitian. The results showed that restraint, external and emotional eating were associated with very different profiles of attitudes and behaviour. Restrained subjects had a higher body weight, more negative attitudes towards food, a lower likelihood of overeating and a lower overall energy intake. External eaters had a lower body weight, positive attitudes to food, and reported a higher energy intake. Emotional eaters fell in between in some ways, with some signs of situational loss of control combined with a negative attitude towards overeating. While external eating appeared to be attenuated by restraint, emotional eating was enhanced by it. The implications of these eating styles for later patterns of eating and weight are discussed.


Perceptions of spreading fats among women in Helsinki whose households use only butter or margarine.

This study sought to investigate whether women's perceptions about butter and soft margarine vary by the use of these fats. From interviews in 1984 with 102 middle-aged women from a follow-up dietary survey in Helsinki 27% of their households were classified as exclusive butter users, 46% used both butter and margarine and 27% used only margarine. The women evaluated margarine less "tasty" but "lighter", and "healthier" than butter. Women whose households used butter exclusively rated it more "useful" than those who used margarine, whereas women whose households used exclusively margarine rated it higher on taste than did exclusive butter users. Butter is a valued traditional food in Finland, and probably the taste of butter is still a reference standard for all spreads. Nevertheless some of the respondents had evidently come to like the soft vegetable margarine that was not available in their childhood.


Food preferences in human obesity: carbohydrates versus fats.

A large clinical sample of obese men and women were asked for a self-generated list of ten favorite foods. The lists were characterized by frequent instances of foods that are major nutrient sources of fat in the American diet. While obese men listed mainly protein/fat sources (meat dishes) among their favorite foods, obese women tended to list predominantly carbohydrate/fat sources (doughnuts, cookies, cake) and foods that were sweet. There was no evidence that selective preferences for a single macronutrient, carbohydrate, were a standard feature of human obesity. Rather, preferences for major nutrient sources of fat as opposed to carbohydrate may be a primary characteristic of human obesity syndromes.


Experience with a macronutrient source influences subsequent macronutrient selection.

We examined the influence of experience with a macronutrient on subsequent macronutrient selection. For 4 days, rats ate chow, or chow and a single macronutrient source. They then had simultaneous access to protein, carbohydrate (CHO) and fat sources, according to a standard macronutrient self-selection paradigm. When selecting among the macronutrient sources, rats pre-exposed to CHO ate more CHO, and those pre-exposed to fat ate more fat, relative to the other groups. Rats pre-exposed to protein ate more protein than did those pre-exposed to CHO or fat but not more than those that received no macronutrient pre-exposure. These selection patterns persisted for at least 12 days, when the test was ended because of the low protein intakes and poor growth of the rats pre-exposed to the CHO and fat sources. After 34 days of recovery with only chow to eat, the rats were again allowed to choose among the three macronutrients, and their patterns of selection were essentially unchanged. Similar results were found in a second experiment in which a 5-day interval was interposed between macronutrient pre-exposure and macronutrient selection. These findings show that experience with the macronutrients typically used in self-selection experiments can have a large, long-lasting, and sometimes detrimental effect on subsequent food selection by rats. Prior experience can be a more powerful influence than nutritional wisdom in determining the rat's food choice.


Behavioral assessment of satiety in bulimia nervosa.

The abnormalities in eating behavior associated with bulimia nervosa suggest that patients with this illness may have a disturbance in satiety. The present study employed a six-meal protocol to assess satiety in both binge and non-binge eating episodes in women with bulimia nervosa and normal controls by examining whether an increase in the size of a soup preload led to a decrease in the amount of food consumed in a subsequent test meal. In control subjects, the increase in preload size was associated with an increase in fullness and a reduction in consumption of the non-binge test meal. Patients did not report consistent changes in ratings of hunger and fullness in response to the change in preload size, and few patients were able to complete the non-binge meals and refrain from vomiting afterwards. When instructed to binge eat, patients ate considerably more than control subjects, but patients did significantly reduce their intake of the test meal after the large compared to the small preload. These findings demonstrate that, although patients with bulimia nervosa exhibit abnormalities in the development of satiety, some mechanisms responsible for the control of food intake are functional during binge eating episodes.


Amperometric enzyme sensor for glucose based on graphite paste-modified electrodes.

Amperometric enzyme electrode for glucose is described based on the incorporation of glucose oxidase (GOD) into graphite paste modified with tetracyanoquinodimethane (TCNQ). The incorporated enzyme exhibits high activity and long-term stability over the earlier TCNQ-based glucose sensor (1). The sensor provides a linear response to glucose over a wide concentration range. The response time of the sensor is 15-50 sec, and the detection limit is 0.5 mM. Stable response to the substrate was obtained during a period of 35 d. Application of the sensor in the plasma analysis is reported.


Obtaining mutants for protoplast fusion of gibberellin-forming Gibberella fujikuroi strains.

Auxotrophic, drug-resistant, nitrate-nonutilizing, and albino mutants have been isolated in Gibberella fujikuroi following UV mutagenesis. Protoplasts of complementing auxotrophic strains, mutants with resistance markers, or mutants blocked in different steps of the nitrate assimilatory pathway have been fused to form heterokaryons, diploids, or recombinant haploids. The properties of fusant strains, including gibberellic acid productivity, have been examined and compared to parent strains.


[Wunderlich syndrome secondary to the rupture of an aneurysm of the renal artery. Review of the literature].

We report a case of Wunderlich's syndrome secondary to spontaneous rupture of a renal artery aneurysm. Wunderlich's syndrome, also called spontaneous perirenal hematoma, may arise from several causes, the most common being renal tumors, particularly angiomyolipoma and hypernephroma. Spontaneous perirenal hematoma secondary to a ruptured renal artery aneurysm is rare and very few cases have been reported in the literature. We discuss the usefulness of the different noninvasive imaging techniques (US, CT and arteriography), our therapeutic approach and those advocated by others.


[Nephrogenic adenoma of the upper and lower urinary tract. Apropos of 22 cases].

Nephrogenic adenoma (NA) is a lesion that can present in the urothelium--from the renal pelvis to the urethra-, and is considered to be immature metaplasia arising from chronic aggression. We report 22 cases of NA in 21 patients that had been diagnosed and treated in our service from 1975 to 1990. The lesion was found at all levels of the urinary tract: renal pelvis (1 case), ureter (1 case), bladder (16 cases) and urethra (4 cases). The present series was comprised of 15 males (one with bladder NA and recurrence in urethra) and 6 females, with ages ranging from 24 to 79 years (mean 55). The diagnosis was made on the histological findings in all cases and the etiology of the lesion was multiple: previous surgery (11 cases), previous or coexisting urothelial carcinoma (8 cases), intracavitary chemotherapy and/or pelvic radiotherapy (3 cases), previous history of tuberculosis (5 cases), interstitial cystopathy (4 cases), lithiasis (2 cases), permanent catheter (3 cases) and urethral stenosis (1 case). Treatment and prognosis was influenced by the underlying urological disease. NA per se does not carry an unfavourable prognosis.


[Does the surgical approach used for radical nephrectomy change the prognosis of renal carcinoma?].

To determine the influence of the surgical approach on survival, we conducted a retrospective study in 133 patients with renal carcinoma stage T1-T3 N0 M0 (UICC classification, 1987) submitted to radical nephrectomy. Overall no significant difference was observed in the 5 and 10-year survival rates for the different approaches (lumbotomy, transperitoneal laparotomy and thoracophrenolaparotomy). The 10-year survival rate for the cases with tumor stage T1-T2 varied significantly according to the approach: Thoracoabdominal (100%), lumbotomy (60%) and laparotomy (40%). No difference was observed for those with tumor stage T3a. For T3b the survival rate was higher for the lumbotomy approach and a significant difference was observed versus thoracophrenolaparotomy. The results show that the surgical approach does not influence the prognosis of renal carcinoma and choice depends on tumor size, location and invasion of the renal vein and/or vena cava.


[Cystine calculi: x-ray diffraction study. Infrared spectroscopy and SEM].

The present study investigated cystinuria and cystine calculi. Inexplicably, of 987 calculi that had been analyzed ultrastructurally at the Department of Urology of the University Hospital of Salamanca over a period of 15 years only 3 (0.3%) were cystine. The foregoing finding does not coincide with the 0.5-1% incidence reported in the world literature. Apart from the chemical analyses, infrared spectroscopy disclosed the typical findings of multiple bands 1600-625 cm-1. Analysis by x-ray diffraction revealed a slight variation from the ASTM values. One of the calculi, which we considered to be a mixed calculus (probably of calcium phosphate), showed a peak at 43 degrees, instead of the usual 34.5. Scanning electron microscopy disclosed two forms of crystallization: The typical hexagonal form of cystine stones and the rectangular form of different sizes. The material comprising the matrix was observed in many areas, covering and joining the crystals as if it were cement. Whenever possible, treatment of these recurrent calculi should be conservative. Some advocate the use of ESWL, although others consider these calculi to be extremely hard and, therefore, not amenable to ESWL. Chemical dissolution is advocated by some, although its critics consider it to be of little use. Concerning prophylaxis, forced fluids and alkalinization may reduce recurrence. Ultrastructural studies have provided further insight into the structure and composition of cystine calculi. The foregoing may be useful in determining the most appropriate form of treatment based upon stone size, shape, composition (pure or mixed), etc.


[Treatment and evolution of 100 cases with staghorn lithiasis].

We reviewed 100 selected cases of staghorn stone that have been followed for at least 3 years after treatment. The results achieved by surgery (e.g., intrasinusal pyelolithotomy) and non-surgical treatment (e.g., ion exchanger) are presented. Overall, good results were achieved in 57% of the cases.


[New classification of vesicoureteral reflux].

Five illustrative cases of vesicoureteral reflux, of different age and sex, are described. All patients were submitted to urodynamic evaluation. A new classification based on the underlying cause is purported. Ureterovesical reflux may be passive or active. The latter type may be involuntary, voluntary or caused by abdominal pressure. In our view, this new classification could be useful in the management of vesicoureteral reflux.


[Pyeloureteral junction syndrome. Associated vesicoureteral reflux].

We reviewed our series comprised of 106 children that had undergone surgery for congenital hydronephrosis from ureteropelvic junction obstruction. Following our protocol, all patients were evaluated by serial micturition cystourethrography. The only anomaly that had been detected was vesicoureteral reflux in 11.32% of the cases. This incidence is reduced to 8.25% if only the renoureteral systems with both congenital anomalies are considered. This finding is not statistically significant (p less than 0.05) relative to patient age, sex or clinical symptoms. The results of the present study show that children with ureteropelvic junction obstruction are not at risk of developing vesicoureteral reflux. Thus, routine serial micturition cystourethrography appears to be unwarranted.


[Surgical correction of congenital penile curvatures using the Nesbit technique. Apropos of 24 cases].

We present our experience of 24 cases with congenital penile deviation without hypospadias. Treatment was by surgical correction of the curvature using the Nesbit technique. We briefly describe the diagnostic methods and the parameters utilized for surgical planning and evaluation of the results of surgery. This simple procedure achieved good results in all of our cases.


[Lymphatic involvement predominating and revealing prostatic carcinoma].

The lymphatic system is the most common site of metastasis of prostatic carcinoma. However, carcinoma of the prostate presenting as lymphadenopathy is rare. It can present at any site and may sometimes mimic lymphoreticular tumors. The diagnosis is based on the histological findings. Histochemical techniques using immunoperoxidase demonstration of acid phosphatase and prostate specific antigen are fundamental in detecting the occult tumor of the prostate. Treatment is palliative and enlargement may occasionally remit with hormone therapy. The prognosis is invariably poor. Survival is less than 5 years irrespective of the response to treatment. Three cases are described herein: 2 presented as retroperitoneal mass and 1 as left lateral cervical lymphadenopathy.


[Pure squamous carcinoma of the ureter. Review of a case].

We report a case of squamous cell carcinoma of the ureter with periureteral infiltration. Three years following radical surgery, no evidence of tumor progression has been observed. Only 1% to 1.6% of urothelial tumors of the upper urinary tract are purely squamous cell tumors. This tumor type carries a poor prognosis. Currently, the best results can be achieved by early diagnosis and radical surgery.


[Polycythemia as the first and only manifestation of renal adenocarcinoma].

We report on a 40-year-old patient with adenocarcinoma of the right kidney whose first and only manifestation was the erythrocytosis that had been detected on routine analytical work up. The diagnostic methods (US, IVP, CT, aspiration biopsy cytology and renal arteriography) and treatment (right nephrectomy via extended thoracophrenolaparotomy incision at the level of the ninth rib) are briefly described. The polycythemia remitted following nephrectomy. The etiopathogenesis and hypotheses that have been put forward relative to polycythemia in renal adenocarcinoma are briefly discussed. Renal tumor, particularly renal adenocarcinoma, should be suspected in the presence of polycythemia of unknown origin. Persistent or recurrent polycythemia should prompt us to suspect incomplete tumor excision or metastasis. Surgical risks (embolism, hemorrhage, etc.) may be reduced if hematocrit levels are brought down to within normal levels by bleeding.


[Leiomyoma of the renal capsule. Presentation of a case and review of the literature].

Leiomyoma of the renal capsule is rare and very difficult to diagnose preoperatively. We report on a patient in whom a solid renal mass had been incidentally detected during ultrasound evaluation for a gastroenterological condition. A CT scan confirmed the presence of a solid mass. The intraoperative biopsy showed it was a benign tumor and conservative surgery was performed. According to the literature, this tumor type has, as yet, not been diagnosed preoperatively. However, some angiographic features may indicate the presence of this condition. This is the fourth case of leiomyoma of the renal capsule reported in the literature and the second case treated by conservative surgery.


[Primary malignant tumor of the ureter. Presentation of a case].

Herein we report a case of malignant primary tumor of the ureter that had been seen and treated in the Department of Urology of Hospital Docente Clinico Quirurgico "10 de Octubre", in Havana, Cuba. The incidence, possible etiology, classification, forms of presentation, diagnosis, treatment and prognosis of this disease entity are discussed. The national and the world literature are reviewed.


[Rhabdomyosarcoma of the epididymis].

A 5-year-old boy with intrascrotal rhabdomyosarcoma arising from the epididymis is described. The patient was submitted to radical orchidectomy via the inguinal approach and high ligation of the spermatic cord. The anatomopathological examination revealed germ cell rhabdomyosarcoma of the epididymis with no testicular or spermatic cord involvement, which corresponded to stage I of the IRS classification (Intergroup Rhabdomyosarcoma Study). Its clinical and histological features and treatment are discussed.


Phase I-II pilot study on the efficacy and tolerability of neoadjuvant chemotherapy (Rescue M-VEC) and preoperative radiation therapy for infiltrating bladder cancer: results of an 18-month follow-up.

In spite of the improvement of surgical techniques used alone or in combination with preoperative radiation therapy, more than 50% of the patients with infiltrating transitional cell carcinoma (TCC) of the bladder die of distant metastases. Systemic antiblastic polychemotherapy has been reported to achieve a complete remission rate of approximately 30% in patients with infiltrating bladder TCC, although there are still doubts relative to the duration of such complete remissions. This study investigated the efficacy and tolerability of a preoperative chemo- and radiotherapeutic treatment modality and the possibility of performing preservative surgery. Thirty-seven patients with bladder TCC stage T2-T4, N0, M0, have been subjected to neoadjuvant chemotherapy according to the "Rescue M-VEC" scheme of methotrexate 30 mg/m2 +folinic acid 15 mg. after 24 hours on days 1, 15, 22; vinblastine 3 mg/m2 on days 1, 15, 22; epidoxorubicin 30 mg/m2 on day 1 and cisplatin 70 mg/m2 on day 1. The course was repeated from day 29. After 2 "Rescue M-VEC" courses, the patients received pelvic cobalt tele-therapy (CTT) combined with cisplatin 24 mg/m2/week. The patients were then restaged. Those with complete remission (CR) received consolidation radiotherapeutic boost combined with cisplatin 24 mg/m2/week, avoiding radical cystectomy. Such treatment was also given to patients with significant partial remission (PR) who had undergone TUR or partial cystectomy. In all the remaining cases we carried out radical cystectomy. We obtained 45.7% CR, 31.4% PR and 22.8% were non-responders (NR), of 35 patients who were evaluable at restaging. Only 9 radical cystectomies were performed in this series. The overall survival rate was 80.6% at a mean follow-up of 18.1 months.(ABSTRACT TRUNCATED AT 250 WORDS)


[Retroperitoneal abscess: analysis of 26 cases].

Herein we present the experience of our hospital, which spans a period of 10 years, in the diagnosis and treatment of retroperitoneal abscess. The clinical features, origin and localization of the abscesses are described. We underscore the diagnostic value of ultrasound (US) and computerized tomography (CT) which afford a sensitivity of 86.3% and 100%, respectively. An increased incidence of abscess from gram-positive bacteria was observed in i.v. drug addicts.


[Fournier's gangrene. Report of 6 cases].

Fournier's gangrene is an uncommon pathological condition that affects the perineoscrotal region. Its course is fulminant and it carries a high mortality. We present 6 cases that had been treated over a period of 24 months. The mortality rate was 33.3%. The mean patient age was 53 years. The clinical and therapeutic aspects are discussed. The need to perform wide repeated debridement and the usefulness of the epidural catheter are underscored.


[Prophylaxis in prostatic surgery with aztreonam. Our experience].

Aztreonam is a monobactam antibiotic with a very specific spectrum of action for gram-negative aerobic bacteria. Since these bacteria are responsible for most of the urinary tract infections, we conducted a study to determine its efficacy in the prophylaxis and treatment of infections in prostate surgery, one of the most common procedures performed in our field. Thirty-two patients received 1 gm Aztreonam at the time of anesthetic induction and q 8 h thereafter to a total dose of 3 gm. Cultures were performed before and 72 h after surgery. Twenty-eight patients had no complications and a sterile urine culture or less than 10,000 colonies, 2 developed wound infection from Staph, aureus and 1 had more than 100,000 colonies of Enterococci in urine. The foregoing findings indicate that Aztreonam is useful for prophylaxis and treatment of urinary tract infections in prostate surgery.


[Incidence of urothelial carcinoma of the bladder in males with chronic urinary retention].

The author studied all of the 1361 male patients that had been hospitalized from December 1986 to September 1990 for chronic urinary retention to determine the incidence of urothelial tumor of the bladder. Sixty-nine (5.07%) were found to have primary urothelial carcinoma of the bladder. However, in another study group comprised of 433 males over 55 with no problems of obstruction, 0.23% had a bladder tumor. This study underscores the role of urinary stasis in the development of urothelial carcinoma of the bladder.


[Neonatal urinary ascites. Considerations on its diagnosis and treatment].

Seven cases with neonatal urinary ascites are described. In all of the cases the underlying cause was an anatomical or functional obstructive uropathy of the lower urinary tract, the most common pathology being neurogenic bladder secondary to lumbosacral dysphagia. The techniques utilized for patient evaluation (ultrasound, serial micturition cystourethrography and IVP) are described and the findings afforded by each diagnostic technique are presented. The value of serial micturition cystourethrography is underscored. In our view, it is convenient to perform initial diversion by percutaneous nephrostomy, suprapubic punction or placement of a urethral catheter, according to the level of the etiologic process. The definitive surgical approach will depend on the results of subsequent radiologic controls and the existing uropathy.


[Doppler color echography in varicocele].

The authors report their experience with the color Doppler ultrasound in the diagnosis and follow-up of patients with varicocele. The features and advantages afforded by this technique are described and attention is focussed to the contribution of technological advancement to the urological armamentarium. We report on 18 cases of varicocele, 2 of which were grade I (preclinical), that had been diagnosed by this technique and confirmed at surgery. In this series the scrotal scintiscan proved to be less specific and was falsely negative in one of the two grade I varicoceles.


[Simultaneous presentation of bilateral renal adenocarcinoma. Therapeutic possibilities].

Bilateral renal adenocarcinoma accounts for 1.4% to 5% of all renal adenocarcinomas. Currently, an increased incidence of synchronous bilateral renal adenocarcinoma has been observed, which can be ascribed to the availability of more sophisticated high resolution ultrasound and computed tomography. Several surgical options exist, such as bilateral radical resection, radical surgery combined with partial nephrectomy or tumor enucleation for the contralateral side, and partial nephrectomy or tumor enucleation for both sides. Two cases of synchronous bilateral renal adenocarcinoma are described. One case was submitted to a left superior partial nephrectomy and enucleation of the tumor in the right kidney. The other patient underwent a left radical nephrectomy and excision of the inferior pole of the right kidney.


[Flow studies in patients with sexual erectile dysfunction. Review of the physiology and the adopted method].

Further insight into the physiology of erection acquired in recent years had led to the development of new methods that have enhanced the evaluation of erectile dysfunction. These new methods will permit a more precise diagnosis and, consequently, the management of this condition can be based on scientific and not empirical methods. To date, many questions remain unanswered and many points have not been elucidated. Using a precise methodology will permit us to corroborate or correct what has been done up until now and to develop new methods of investigation. The present study briefly reviews the physiology of erection and describes a method we routinely use.


[Giant urethral lithiasis].

Calculi in the male urethra are rare and are generally associated with urethral disorder (diverticuli, stricture, complication posturethroplasty, etc.). Treatment is generally by excision and resolution of the underlying cause. We report a case of urethral calculus, of apparently idiopathic etiology, that had treated by endoscopic ultrasonic disruption. The importance of preoperative etiologic diagnosis is underscored.


[Piezoelectric extracorporeal lithotripsy in ambulatory care].

The surgical approach for stone disease has completely changed during the last decade. Since 1980, ESWL and Endourology (percutaneous nephrolithotomy, ureteroscopy) have been used worldwide in the treatment of nephrolithiasis and today open surgery is necessary only in less than 5% of the cases. The second generation Wolf Piezolith 2300 is a lithotripter for the painless treatment of the majority of renal and ureteral stones. Treatment of stone patients on an out patient basis in a private clinic commenced in 1988 because of the low complications and side effects related to its use. We report the records of the first 70 patients treated in this way and controlled for at least 3 months after the treatment.


[Primary carcinoma of the male urethra: review of the literature and presentation of a new case].

A primary carcinoma of the male urethra is described. The etiology, diagnosis, clinical features and treatment of this uncommon tumor are discussed. Because this tumor frequently presents as a benign urethral process, biopsies should be performed in urethral conditions with a torpid clinical course.


[Nonpenetrating trauma of the penis. Rupture of corpus cavernosum albuginea].

We report a case of penile trauma that had been treated early by surgery. The value of ultrasound in diagnosing rupture of the corpus cavernosum albuginea is highlighted. The good functional and cosmetic results afforded by early surgical treatment is underscored.


[Bulbocavernosus reflex and somatosensory evoked potential of the pudendal nerve in diabetic impotence].

The present study investigated the sensitivity of the bulvocavernosus reflex (BCR) and the somatosensory evoked potential (SEP) of the pudendal nerve in neurogenic impotence, the study comprised 22 males with diabetes type II. Of these, 11 had neurogenic impotence. The SEP was found to be normal in all cases, whereas BCR changes were observed in 36.4% of the patients who were not impotent and in 63.6% of the impotent males. This difference, however, is not statistically significant. The results show that in diabetic pelvic neuropathy compromise of the vegetative fibers does not necessarily mean injury to the somatic.


Present role of thoracoscopy in the diagnosis and treatment of diseases of the chest.

Since thoracoscopy was originally described in 1910, the application has been limited mainly to the diagnosis and treatment of pleural disease. Recent advancements in endoscopic equipment and refinement of surgical techniques have expanded the application of this procedure. Using video thoracoscopic techniques in 70 patients over the past 9 months, we have been able to perform a variety of procedures previously accomplished by "open" techniques. These procedures include (1) wedge resections of pulmonary nodules in 21 patients, using endoscopic mechanical stapling devices; (2) excision of the pericardium and drainage of the pericardial space in 6 patients; (3) dorsal thoracic sympathectomy in 6 patients; (4) apical blebectomy and pleurodesis in 6 patients; (5) lung biopsies for diagnosis of diffuse lung disease in 5 patients. Additional procedures performed include biopsy of hilar masses (3), biopsy of esophageal mass, excision of a mediastinal cyst, and the drainage of a spinal abscess. The remaining 20 procedures were performed for the diagnosis and treatment of pleural disease. There was no mortality associated with the procedure and morbidity was lessened, compared with standard thoracotomy procedures. The postoperative hospital stay after elective procedures performed in well patients averaged 3 days and was often as short as 1 day. Our experience indicates a markedly expanded role for thoracoscopy in the diagnosis and treatment of thoracic diseases with less postoperative morbidity.


[Sexually transmitted recurrent urinary infection of the male].

We describe a case of recurrent urinary tract infection in a male patient that had been repeatedly associated with sporadic sexual intercourse with his partner. The timing of the episodes and the bacteriological findings indicate this to be another uncommon case of urinary tract infection sexually transmitted by the female to the male.


Videothoracoscopic wedge excision of the lung.

Recent advances in video technology and endoscopic instrumentation have expanded the use of thoracoscopy from diagnosis to treatment of pulmonary parenchymal disease. We recently performed 14 pulmonary wedge excisions using videothoracoscopic techniques in 10 patients (7 women and 3 men). Median age was 60 years (range, 21 to 82 years). Indications were small peripheral solitary pulmonary nodules in 4 patients, diffuse pulmonary infiltrates in 4, and recurrent pneumothoraces in 2. Thoracoscopic wedge excisions were accomplished using double-lumen endotracheal anesthesia and a percutaneous stapling device. Tissue diagnosis was obtained in all patients; 6 had benign disease, 3 had metastatic cancer, and 1 had diffuse bronchoalveolar cell carcinoma. Median operating time was 90 minutes (range, 40 to 140 minutes). There were no operative deaths. The single complication was a prolonged air leak. Median hospitalization was 5 days (range, 3 to 16 days). All patients returned to full activity within 10 days of discharge. Median follow-up was 6 months (range, 5 to 8 months). We conclude that videothoracoscopic wedge excision is a safe and effective procedure for selected small peripheral indeterminate pulmonary nodules, diffuse interstitial lung diseases, and recurrent spontaneous pneumothoraces. Further evaluation and prospective studies are indicated.


[Iatrogenic invagination of the ureteral mucosa in renal transplantation].

A case of antegrade invagination of the ureteral mucosa is described. This iatrogenic complication of endourology resulted from percutaneous dilatation with teflon catheters of a stricture in the ureter of a renal graft transplanted 4 years earlier. Definitive correction was by open surgery, which achieved good results.


Thoracoscopic resection of 85 pulmonary lesions.

Advances in endoscopic surgical equipment and laser technology have expanded the role of thoracoscopy to include thoracoscopic pulmonary resection. Eighty-five thoracoscopic pulmonary resections were performed on 61 consecutive patients with small lesions (less than 3 cm) in the outer third of the lung. Patients with preoperative histologic evidence of bronchogenic carcinoma were excluded unless there was impairment of cardiopulmonary function, advanced age, or concomitant extrathoracic malignancy. These thoracoscopic pulmonary resections were accomplished with the neodymium:yttrium-aluminum garnet laser (31), endoscopic stapler (29), or both (25). The mean diameter of the lesions was 1.3 cm (range, 0.4 to 2.7 cm). There has been one late death (38th postoperative day) unrelated to the operation. Morbidity consisted of postoperative atelectasis (2), pneumonia (2), bleeding requiring transfusion (1), and bronchopleural fistula of greater than 7 days duration (3). There were no wound problems. The mean period of chest tube drainage was 3.3 +/- 3.0 days. Mean postoperative stay was 5.7 +/- 4.9 days. The pathologic diagnosis was benign disease in 28 patients (interstitial fibrosis/pneumonitis, 15; radiation fibrosis, 1; sclerosing hemangioma, 1; rheumatoid nodules, 1; granuloma, 2; nocardia, 1; infarct, 1; hamartoma, 4; scar, 1; cytomegalovirus pneumonia, 1), metastatic malignancy in 20 patients, and bronchogenic carcinoma in 13 patients. Five patients found at thoracoscopic pulmonary resection to have bronchogenic cancer had adequate pulmonary function and therefore underwent formal segmentectomy (3) or lobectomy (2). Thoracoscopic pulmonary resection was the only operation performed on patients with benign disease, patients with metastatic lesions, and selected patients with limited stage bronchogenic carcinoma at increased risk for thoracotomy.(ABSTRACT TRUNCATED AT 250 WORDS)


One hundred consecutive patients undergoing video-assisted thoracic operations.

Video-assisted thoracic surgery is a new modality that allows visualization of and access to the intrathoracic organs without making a thoracotomy incision. One hundred consecutive patients underwent 113 thoracic procedures using this technique. Eight wedge resections for metastatic lesions, 6 pericardial windows, 1 bronchogenic cystectomy, 4 explorations of the aortopulmonary window, 1 decortication, 5 pleural scleroses, 8 bullous ablations, 25 lung biopsies, 19 wedge resections for carcinoma, 9 explorations of the thorax, 3 lobectomies, 1 esophageal cystectomy, 14 wedge resections for benign lesions, 4 pleurectomies, 1 excision of a neurogenic tumor, 3 mediastinal explorations, and 1 imaged axillary dissection were performed. There was no mortality. Ten patients had complications from which they recovered completely. Patients undergoing video-assisted thoracic operations seem to have reduced postoperative pain, shorter hospitalization, and quicker recovery times. Currently, this new modality appears to have beneficial value for patients; however, only further experience will determine its true merits.


Composite valve graft replacement of the proximal aorta: comparison of techniques in 348 patients.

Composite valve graft replacement of the ascending aorta is being increasingly used, although it is not clear which technique, the Bentall, Cabrol, or button, is the best method for coronary artery ostial reattachment. We retrospectively analyzed our results with respect to these three techniques in 348 consecutive patients operated on between September 17, 1979, and January 29, 1991. Variables included aortic arch replacement in 88 patients (25%), need for deep hypothermia and circulatory arrest in 119 (34%), aortic dissection in 131 (38%), acute dissection in 34 (9.8%), reoperation in 79 (23%), and insertion of St. Jude prostheses in 270 (78%). The 30-day survival rate was 91% (316/348), the in-hospital survival rate was 90% (312/348), and the 30-day incidence of postoperative new transient (n = 6) and permanent (n = 6) stroke was 3% (12/348). The 30-day survival rates for each method were as follows: Cabrol, 92% (144/157); button, 91% (39/43); and Bentall, 91% (125/137). On stepwise multivariate logistic regression analysis with control for operative date and independent prognostic factors, operative technique was not an independent determinant of early mortality or stroke. On late follow-up, the Kaplan-Meier 5-year survival rate was 71% with no significant difference between the groups (3-year survival: Cabrol, 76%; Bentall, 79%; and button, 81%; p = 0.28). The 3-year freedom from reoperation was 95% (Cabrol, 97%; Bentall, 91%; and button, 100%; p = 0.17). We conclude that for patients undergoing reoperation or complicated repairs or when tension on the ostial anastomoses may occur, the Cabrol technique is preferable. If feasible, however, the button technique has better long-term results for both survival and rate of reoperation. An alternative technique is to use an interposition graft to reattach the left coronary artery and excise an aortic button for the right coronary artery reattachment. This has the advantages of technical ease in reattaching the left coronary artery, good results for reattachment of the right coronary artery, minimal tension on the anastomoses, and visualization of all anastomoses.


[Pulmonary fibrosis secondary to nitrofurantoin].

Herein we report a case of pulmonary fibrosis secondary to chronic administration of nitrofurantoin following radical surgery for a bladder tumor and urinary intestinal diversion. The patient developed pulmonary superinfection and acute respiratory failure. She initially responded to treatment, but relapsed after two weeks. She died from the underlying disease.


Factors affecting mitral valve reoperation in 317 survivors after mitral valve reconstruction.

From a very heterogeneous group of 340 patients undergoing mitral valve reconstruction from 1969 through 1988, 313 hospital survivors were analyzed for factors affecting the occurrence of reoperative mitral valve procedures related to native mitral valve dysfunction. Follow-up was 100% and extended from 1 year to 20 years (mean follow-up, 7.2 years). Sixty-three patients (18.5% of the 340) required mitral valve reoperation at a mean postoperative interval of 6 years (range, 1 to 15 years). Incremental risk factors analyzed for the event late mitral valve failure included age, sex, preoperative New York Heart Association class, cause of valvular disease, pathophysiology of the mitral valve, previous mitral valve operation, mitral valve pathology, and estimation of mitral valve function at operation after repair. Mitral valve pathophysiology affected the actuarial freedom from mitral valve replacement (p = 0.023 [log-rank]). Actuarial freedom from mitral valve reoperation was 90% at 5 years and 80% at 8 years in patients who had either pure mitral regurgitation or isolated mitral stenosis compared with 80% and 72% at 5 and 10 years, respectively, in patients who had mixed mitral stenosis and regurgitation (p = 0.023). Patients undergoing late reoperation were younger (51.7 +/- 1.56 years [+/- the standard error of the mean]) than those not having reoperation (p less than 0.0003). Durability of the repair was less in patients with rheumatic heart disease (p less than 0.025) and greater in patients with ischemic heart disease (p less than 0.004). Seventy-three percent of patients undergoing reoperation had concomitant operations compared with 68% of those not having reoperation (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


Embolotherapy of priapism.

Some cases of idiopathic priapism are due to uncontrolled, penile arterial inflow. These cases can be successfully treated by percutaneous transcatheter embolization of one or both internal pudendal arteries. Autologous clot is ideal for embolization as it permits revascularization and helps avoid impotence. The authors describe a 10-day old case of refractory priapism which was successfully treated angiographically.


A randomized study of the systemic effects of warm heart surgery.

The technique of warm heart surgery is defined as continuous warm blood cardioplegia and normothermic cardiopulmonary bypass. Although the systemic effects of traditional myocardial protection are well known, the effects of warm heart surgery are not. In a prospective trial, 204 patients undergoing coronary artery bypass grafting were randomized to the warm heart surgery technique (normothermic group) or traditional intermittent cold blood cardioplegia and cardiopulmonary bypass (hypothermic group). The groups had similar heparin sodium requirement, activated clotting times, urine output, hematocrit, and blood product utilization. There were no differences in hemodynamics immediately after cardiopulmonary bypass. The normothermic patients had a higher incidence of spontaneous defibrillation at cross-clamp removal (84%) than the hypothermic patients (33%) (p less than 0.01). An increase in the flow rate of low K+ cardioplegia was necessary to eradicate electrical activity during aortic occlusion more often in the normothermic patients (20%) than in the hypothermic patients (3%) (p less than 0.01). When low K+ cardioplegia was ineffective, high K+ cardioplegia was necessary to eradicate electrical activity in 31% of the normothermic patients compared with 10% of the hypothermic patients (p less than 0.05). The total cardioplegia volume delivered to the normothermic group (4.7 +/- 1.9 L) was higher than that delivered to the hypothermic group (2.6 +/- 0.8 L) (p less than 0.01). Although urine output was similar in both groups, the serum K+ levels were higher in the normothermic group (5.7 +/- 0.8 mmol/L) than in the hypothermic group (5.3 +/- 0.8 mmol/L) (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


Optimum treatment of discrete subaortic stenosis.

Discrete subaortic stenosis typically appears as a well-defined membrane beneath the aortic valve. To assess the merits of alternative approaches to this problem, we have reviewed the results of operations for discrete subaortic stenosis from 1978 through 1990. Excision of the subaortic membrane alone was performed in 16 patients (group I). Excision of the membrane with resection of septal muscle was performed in 24 patients (group II). The groups were similar in age at operation, duration of follow-up, and preoperative and postoperative transvalvar gradients. There were no operative or late deaths. Reoperations for recurrent subaortic stenosis were performed in 4 group I patients (25%; 70% confidence limits, 16% to 38%) and 1 group II patient (4%; 70% confidence limits, 2% to 11%). Pacemakers were inserted for postoperative complete heart block in 1 group I patient (6%; 70% confidence limits, 2% to 16%) and 2 group II patients (8%; 70% confidence limits, 4% to 16%). We conclude that muscle resection combined with membrane excision in patients with discrete subaortic stenosis does not increase the risk of death or heart block, and does lower the risk of reoperation for recurrent subaortic stenosis.


Normothermic cardioplegia: is aortic cross-clamping still synonymous with myocardial ischemia?

The enthusiastic clinical reports on normothermic blood cardioplegia contrast with the paucity of data on the myocardial metabolic effects of this technique. The present study was therefore designed to assess whether normothermic blood cardioplegia really provides an aerobic environment during aortic cross-clamping. Thirty-one patients undergoing coronary (16 patients), valve (13 patients), and transplantation (2 patients) procedures were given continuous normothermic blood cardioplegia through the coronary sinus. Myocardial metabolism was assessed either immediately before aortic unclamping (16 patients) by collecting blood simultaneously from the cardioplegia infusion line and the aortic effluent or during reperfusion (15 patients) by collecting blood simultaneously from the radial artery and the coronary sinus. All samples were assayed for markers of anaerobiosis (blood gases, lactates), leukocyte activation (elastase), and lipid peroxidation (malondialdehyde, vitamin E). At the end of arrest, oxygen extraction was low, whereas the production of lactates was small, thereby suggesting the efficacy of normothermic blood cardioplegia in maintaining a predominantly aerobic metabolism. This was confirmed by postarrest data, as oxygen extraction measured immediately after cross-clamp removal was unchanged from prearrest values, whereas lactate metabolism yielded transient and limited production followed by prompt recovery of normal extraction patterns. There was no release of elastase from the myocardium, which suggests adequate protection of the coronary endothelium from ischemic injury and the related increase in leukocyte activation. Likewise, postarrest coronary sinus concentrations of malondialdehyde and vitamin E were identical to the respective arterial concentrations, thereby ruling out the occurrence of intramyocardial lipid peroxidation at the time of reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)


Subcutaneous use of erythropoietin in heart surgery.

The effect of subcutaneous administration of recombinant human erythropoietin (rHuEPO) in ameliorating anemia resulting from autologous blood donation was compared with intravenous administration of rHuEPO. Forty patients undergoing coronary artery bypass procedures were divided into three groups. Group I (12 patients) received intravenous administration of rHuEPO (100 U.kg-1.day-1) and intravenous iron preparations for 14 days before operation; group II (14 patients) had subcutaneous administration of rHuEPO (600 U/kg) on preoperative days 14 and 7 and oral iron preparations for 14 days; and group III (14 patients) received oral iron preparations alone and served as the controls. Each patient predonated 800 mL of blood in the 2 weeks before operation. The reticulocyte count increased significantly in groups I and II (p less than 0.01), but little in group III. The hemoglobin level just before operation was higher in groups I (p less than 0.01) and II (p less than 0.05) compared with group III. Four patients (29%) in group III required homologous blood transfusion versus none in groups I and II (p less than 0.05). Subcutaneous administration of rHuEPO once a week was as effective as daily intravenous administration. Preoperative autologous blood donation can be performed over a short period on an outpatient basis with subcutaneous administration of rHuEPO.


Atrioventricular pacing in congenital heart disease.

We have attempted to optimize cardiac performance in patients with congenital heart disease requiring artificial pacing by using pacemakers capable of both sensing and pacing both the atrium and the ventricle (DDD). We reviewed our results with 88 patients receiving DDD devices to determine the safety and dependability of these devices in children. Age ranged from 1 hour to 25 years. Endocardial leads were used in 68 patients, whereas epicardial leads were used in 20 patients. Previous cardiac procedures had been done in 30 patients. There were nine deaths but none due to pacemaker malfunction. Endocardial leads functioned better than epicardial leads. Ninety-eight percent of patients with endocardial leads and 62% of patients with epicardial leads were maintained in the DDD mode. Complications were infrequent and all were corrected without long-term sequelae. The DDD mode may offer considerable benefits to children who require artificial pacing. Our data allow us to conclude that most children can be paced safely and dependably in the DDD mode.


Thoracoscopic lung biopsy.

Progress in instrumentation and techniques developed for laparoscopic surgery have paved the way for a resurgent interest in thoracoscopic procedures. Traditional thoracoscopy was limited by access, restricted visualization, and surgical devices. Recent cases provided an opportunity to successfully perform thoracoscopic pulmonary wedge excisions using state-of-the-art technology and instruments adapted from laparoscopy. These preliminary cases provided an opportunity to modify and adapt these techniques to thoracic procedures. Video thoracoscopy is rapidly evolving in both methods and instrumentation.


Human cardiac nerve stimulation.

Cardiovascular responses were elicited in 12 patients undergoing cardiac operations when cardiopulmonary neural elements between the aortic root and pulmonary artery or in the right atrial ganglionated plexus were stimulated. Heart rate and left ventricular intramyocardial systolic pressure were augmented when cardiopulmonary nerves between the aorta and pulmonary artery were stimulated in 11 of the 12 patients. Right ventricular intramyocardial systolic pressure was augmented in 7 of these 11 patients. Cardiodepressor responses were elicited when the right atrial ganglionated plexus (9 patients) or a cardiopulmonary nerve (2 patients) was stimulated. These results demonstrate that electrical stimulation of the human extrinsic and intrinsic cardiac nervous systems can alter cardiodynamics, different responses being elicited when different neural structures are stimulated. These data are in accord with those obtained from canine experiments and suggest that the human extrinsic and intrinsic cardiac nervous system contains functionally similar neural elements to those found in other mammals.


Is use of the intraaortic balloon pump in octogenarians justified?

Increasing numbers of octogenarians are seen in the operating room or critical care unit with circumstances for which intraaortic balloon pump (IABP) assistance is appropriate, but it has been suggested that the complication rate for IABP use in octogenarians is excessive. From 1980 to 1990, 25 octogenarians needed an IABP in our institution, as an adjunct to operation in 20 patients (1 had repair of a ventricular rupture and 19 underwent coronary grafting); 5 patients did not have operation. The indications for IABP use were unstable angina, 12 (48%); cardiogenic shock, 10 (40%); and difficulty weaning off cardiopulmonary bypass, 3 (12%)--these 3 were the only ones who had insertion through a femoral cut-down. No serious insertion difficulties were noticed with the percutaneous route in the other 22 patients. Without operation, 4 of 5 patients died in the hospital (80%), and the 5th died 2 years 8 months after discharge. After operation, there were two hospital deaths (10%) and two late deaths, neither from cardiac causes. A fatal outcome occurred in 6 of 9 patients with cardiogenic shock. Intraaortic balloon pump-related complications were rare, minor, and unrelated to IABP assistance duration, which ranged from 24 to 146 hours (mean, 49.9 hours). No long-term vascular complications resulted. Hospital stay averaged 22.2 days. At follow-up from 9 to 81 months (mean, 51.8 months), of the 16 survivors, 12 (75%) were in New York Heart Association class I/II and 2 each were in classes III and IV.(ABSTRACT TRUNCATED AT 250 WORDS)


Multicenter trial of automated nitroprusside infusion for postoperative hypertension. Titrator Multicenter Study Group.

Hypertension is common after a cardiac operation and may result in postoperative hemorrhagic and other complications. Most often this problem has been treated using manually controlled doses of intravenous sodium nitroprusside. To evaluate the clinical impact of an automated closed-loop administration system on patients after cardiotomy, a prospective trial was conducted at nine clinical centers. Patients with hypertension were managed by either manual nitroprusside titration (n = 532) or a closed-loop automated titration system (n = 557). Patient groups were not significantly different in age, weight, or height. Moreover, the types of surgical procedures were comparable: primary coronary artery bypass grafting, 59.2% and 58.9%, manual group versus automated group; repeat coronary artery bypass grafting, 10.5% and 8.6%, respectively; valve procedures, 11.3% and 15.1%, respectively; and other cardiac procedures, 19.0% and 17.4%, respectively (all p = not significant). The automated group showed a significant reduction in the number of hypertensive episodes per patient (1.8 +/- 0.2 versus 0.6 +/- 0.07; p = 0.0001. At the same time, the number of hypotensive episodes per patient was reduced with automated closed-loop titration (0.40 +/- 0.05 versus 0.30 +/- 0.03; p = 0.02). Chest tube drainage (866 +/- 37 mL versus 693 +/- 23 mL [mean +/- standard error of the mean]; p = 0.0001), percentage of patients receiving transfusion (40.0% versus 33.0%; p = 0.02), and total amount transfused (2.4 +/- 0.12 units versus 2.0 +/- 0.10 units; p = 0.0003) were all reduced significantly by the use of an automated titration system.(ABSTRACT TRUNCATED AT 250 WORDS)


Modified Fontan procedure for severe Ebstein's malformation with predominant tricuspid stenosis.

Two children, aged 7 and 6 years, had severe Ebstein's malformation of the tricuspid valve and underwent operation because of progressive cyanosis (saturation, 70%). Preoperative angiography demonstrated linear attachment of the distal edges of the displaced anterosuperior and mural leaflets, leaving only a "keyhole" communication between the atrialized and functional portions of the right ventricle. Operation was directed toward completely excising these dysplastic leaflets, which were obstructing the flow of blood. The continuity between the functional right ventricle and pulmonary trunk was left intact. In addition, an atriopulmonary truncal connection was established. Postoperatively, both children were in functional class I with arterial saturation of 95%. Angiography and Doppler echocardiography demonstrated that there was a dominant phase of systolic flow of blood up the pulmonary trunk from the right ventricle, and also diastolic filling of the pulmonary arteries through the atriopulmonary truncal connection. The filling patterns did not change over time for the follow-up period of 4 and 1.5 years, respectively. This modified Fontan procedure appears to be an effective surgical alternative for some patients with severe Ebstein's malformation and predominant tricuspid stenosis.


Experience in 100 transthoracic balloon pumps.

We retrospectively reviewed our last 100 consecutive patients who had an intraaortic balloon pump (IABP) placed through the ascending aorta for postoperative cardiogenic shock. Eighty-one patients survived to have their IABP removed and were evaluated for complications. Complications that may have been related to the transthoracic route of IABP introduction included balloon rupture in 6.2% (5/81), cerebral vascular accident in 2.5% (2/81), transient ischemic attack in 1.2% (1/81), bleeding at the IABP arteriotomy site in 3.7% (3/81), and mediastinitis in 3.7% (3/81). Compared with expected rates of development of complications in this high-risk group of patients, it appeared that balloon rupture and mediastinal bleeding were increased because of the transthoracic placement of the IABP. The rates of neurologic events and mediastinal infection do not appear to be increased. Transthoracic IABP placement avoids ischemic problems in the lower extremities and has proved a useful route for IABP introduction.


Long-term results of St. Jude Medical valve in the tricuspid position.

Little is known of the St. Jude Medical heart valve's long-term clinical performance in the tricuspid position. Fourteen patients underwent tricuspid valve replacement between 1981 and 1984. Ages of the patients ranged from 32 to 81 years. Eight patients (68%) were in New York Heart Association class IV preoperatively. Twelve patients had other concomitant cardiac operations. One patient (8%) died within 30 days after operation, due to cerebrovascular accident. Postoperatively, all patients were anticoagulated with warfarin sodium and showed improvement in functional class. There were no mechanical valve failures or thromboses in patients on the anticoagulation regimen. Follow-up in all patients extended over 7 to 10 years with a mean of 8 years. There were six late deaths unrelated to valve function. The actuarial survival curve with these patients is 50% over 10 years. In conclusion, the St. Jude Medical valve is a good mechanical substitute in the tricuspid position, and we recommend its use when reconstruction is not possible and there is no contraindication for anticoagulation.


Coagulation defects in neonates during cardiopulmonary bypass.

We examined components of the coagulation system in 30 neonates (age, 1 to 30 days) undergoing deep hypothermic cardiopulmonary bypass (CPB). A coagulation profile consisting of activated clotting time; prothrombin time; partial thromboplastin time; factors II, V, VII, VIII, IX, X, and I (fibrinogen); antithrombin III; platelet count; and heparin levels was evaluated before bypass, at three intervals during bypass (1 minute after initiation of bypass, stable hypothermic CPB, warm CPB), after weaning from CPB and administration of protamine, and 2 to 3 hours after skin closure. The initiation of CPB resulted in a 50% decrease in circulating coagulation factors and antithrombin III levels. Platelet counts were reduced by 70% with CPB initiation. Neither deep hypothermic temperatures nor prolonged exposure to extracorporeal surfaces had any additional effect on the coagulation profiles. This suggests that the coagulation system of a neonate undergoing CPB is profoundly and globally effected by hemodilution. We believe that treatment of post-CPB coagulopathy in neonates must address these global deficits.