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1.  Activities of 5,6-Dihydro-5-Azathymidine Against Herpes Simplex Virus Infections in Mice 
5,6-Dihydro-5-azathymidine (DHAdT), a nucleoside antibiotic inhibitory for herpes simplex virus (HSV) in cell cultures (H. E. Renis, Antimicrob. Agents Chemother. 13: 613–617, 1978), was evaluated in mice with experimental HSV infections. DHAdT protected mice infected with HSV type 1 (HSV-1) when the virus was inoculated intravenously and the drug was given by subcutaneous or oral routes. The activity observed was dependent on the dose and schedule of treatment. Doses of 100 to 400 mg/kg given three to four times daily (at 4-h intervals) for 4 to 5 days gave greater protection than less frequent treatment for shorter time intervals. DHAdT treatment reduced the rate of isolation as well as the HSV-1 titers in homogenates prepared from spinal cords and brains, whereas the titers in kidney homogenates were only marginally affected. The above treatment regime with DHAdT afforded only partial protection to mice infected intracerebrally with HSV-1 or mice inoculated intravaginally with HSV-1 or HSV-2. The antiviral activity of DHAdT was reversed by the co-administration of thymidine. Under these conditions, DHAdT was not toxic in mice.
PMCID: PMC352635  PMID: 426515
2.  Enhancement of post-ultraviolet killing in Escherichia coli K-12 through the action of gyrase inhibitors: evidence for associated gyrase-recBC deoxyribonuclease function. 
This work in conjunction with the results presented in an earlier report (M. A. Purdy and K. L. Yielding, Antimicrob. Agents Chemother. 10:182--184, 1976) showed the following. (i) Nalidixic acid and novobiocin could inhibit post-ultraviolet and post-X-ray survival, implicating gyrase function in deoxyribonucleic acid repair. (ii) The inhibition of post-ultraviolet survival requires the action of functional recBC deoxyribonuclease. (iii) Structural changes in the gyrase could (a) cause recBC mutants to exhibit enhancement of post-ultraviolet killing in the presence of novobiocin, (b) increase the ultraviolet sensitivity of recBC mutants, and (c) enhance the thermal lability of a recBCts mutant.
PMCID: PMC352839  PMID: 228590
3.  Clinical Pharmacokinetics and Safety of High Doses of Ceforanide (BL-S786R) and Cefazolin 
The pharmacokinetics and safety of ceforanide and cefazolin were compared in normal subjects after 30-min intravenous infusions of 2-, 3-, and 4-g single doses and 4-g twice-daily doses for 10 days. No significant differences were observed in plasma-renal pharmacokinetic parameters between single and multiple doses of ceforanide. Half-life (t½, 2.8 h), plasma clearance (Clp, 48 ml/min per 1.73 m2), and renal clearance (Cl0−12hr, 47 ml/min per 1.73 m2; tubular secretion, 44%, and glomerular filtration, 56%) did not change with increased dose or on multiple dosing. No significant change was observed in t½ (1.9 h), area under the plasma concentration-time curve, Clr (60 ml/min per 1.73 m2; tubular secretion, 80%, and glomerular filtration, 20%), or Clp (75 ml/min per 1.73 m2) for 4-g single doses compared with twice-daily administration of cefazolin. A small increase in cefazolin clearance was observed when plasma concentrations were greater than 100 μg/ml, when the single dose was increased from 2 to 4 g; this was a result of the decrease in percentage of plasma protein binding and increased renal clearance due to increased glomerular filtration. The increase in renal clearance resulted in a lack of linear proportionality of the plasma area under the curve with dose over a range of 2 to 4 for both cephalosporins, although this effect was much less marked with ceforanide. Both compounds were well tolerated both locally and systemically. There was no evidence of any change in renal function based on clearances of drug, p-aminohippuric acid, or creatinine, and other standard clinical parameters.
PMCID: PMC352915  PMID: 526003
4.  Correlation of Netilmicin Disk Diffusion Susceptibility and Agar Dilution Susceptibility 
The minimal inhibitory concentration of netilmicin determined by the agar dilution method was correlated with the disk diffusion zone of inhibition against 322 clinical isolates. Regression line analysis revealed good correlation, r = −0.90, and suggested that isolates with zone sizes ≤14 mm should be considered resistant.
PMCID: PMC352768  PMID: 475365
5.  Susceptibility of Gram-Negative Aerobic Bacilli Resistant to Carbenicillin in a General Hospital to Piperacillin and Ticarcillin 
During an 8-month period, 858 gram-negative aerobic rods resistant to carbenicillin (minimum inhibitory concentration, ≥128 μg/ml) were isolated. Susceptibility testing of 233 of these suggested that piperacillin might be active against more of these organisms than would carbenicillin or ticarcillin.
PMCID: PMC352614  PMID: 426501
6.  Evaluation of gentamicin and penicillin as a synergistic combination in experimental murine listeriosis. 
The administration of a combination of penicillin and gentamicin to mice given an intraperitoneal challenge of a highly pathogenic strain of Listeria monocytogenes resulted in increased survival as compared with groups receiving penicillin alone or gentamicin alone or a control group that received no antibiotic. The median survival of animals that eventually died was no longer than in groups receiving single antibiotics and suggests that additional studies should be carried out to further investigate the possibility of synergism in animal models.
PMCID: PMC352967  PMID: 533266
7.  In Vitro Activity of Furazlocillin (Bay k 4999) Compared with Those of Mezlocillin, Piperacillin, and Standard Beta-Lactam Antibiotics 
The activity of furazlocillin (Bay k 4999) was compared with those of mezlocillin, piperacillin, and standard beta-lactam antibiotics against a number of gram-positive and gram-negative organisms. These new expanded-spectrum penicillins were less active than penicillin G against most gram-positive organisms. Furazlocillin, mezlocillin, and piperacillin showed activity comparable to ampicillin and penicillin G against Haemophilus influenzae and penicillin-susceptible neisseriae, respectively. None of the drugs tested was effective against penicillin-resistant gonococci. The activity of furazlocillin was greater than that of mezlocillin, piperacillin, ampicillin, or carbenicillin against many Enterobacteriaceae. However, certain beta-lactam-resistant strains among these organisms were not highly susceptible to any of the three new penicillins. Furazlocillin was less active than piperacillin against Pseudomonas aeruginosa but was more active than carbenicillin or mezlocillin. Inoculum effects and discrepancies between minimal inhibitory concentrations and minimal bactericidal concentrations were observed with furazlocillin, mezlocillin, and piperacillin against several genera. The kinetics of bacterial killing by the new penicillins were often slow and incomplete over 24 h, especially in tests with Enterobacter and P. aeruginosa. Synergy was demonstrated between furazlocillin and aminoglycosides against a variety of gram-negative bacilli and Streptococcus faecalis.
PMCID: PMC352759  PMID: 475364
8.  Pharmacokinetics of Intravenous Amoxicillin in Pediatric Patients 
Pharmacokinetic parameters were obtained from 14 infants and children receiving intravenous amoxicillin. Peak serum values increased proportionally to the increase in dose; the serum half-life was similar in the three dose groups studied.
PMCID: PMC352722  PMID: 464594
9.  Autoradiographic Localization of [3H]Gentamicin in the Proximal Renal Tubules of Mice 
The site of localization of [3H]gentamicin within mouse kidney is shown to be the proximal renal tubule by coincidence of the radioactivity, as visualized by autoradiography, and the mucopolysaccharide-rich microvilli characteristic of proximal convoluted tubules, as visualized by histochemical staining.
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PMCID: PMC352612  PMID: 426500
10.  In vitro activity of three tetracycline antibiotics against Acinetobacter calcoaceticus subsp. anitratus. 
The in vitro activity of three tetracycline antibiotics against 127 strains of Acinetobacter calcoaceticus (Herella vaginicola) were compared. Almost all strains were susceptible to minocycline and doxycycline, whereas most strains were resistant to tetracycline.
PMCID: PMC352932  PMID: 526013
11.  Ceftizoxime (FK 749), a new parenteral cephalosporin: in vitro and in vivo antibacterial activities. 
FK 749 is a new parenteral cephalosporin derivative which is more active against various gram-negative bacilli, including the opportunistic pathogens such as Enterobacter, Citrobacter species, and Serratia marcescens, than cephalosporins and cephamycins such as cefotiam, cefamandole, cefuroxime, cefotaxime, and cefmetazole. FK 749 was especially active against gram-negative organisms resistant to these related antibiotics. FK 749 was more potent in bactericidal activity than the other antibiotics, and the activity was clearly enhanced in the presence of 90% defibrinated rabbit blood. The therapeutic effect of subcutaneously injected FK 749 in mice infected with various gram-negative bacilli was far superior to that of cefotiam, cefamandole, cefuroxime, and cefmetazole and was almost the same as that of cefmetazole in mice infected with Staphylococcus aureus and that of ticarcillin in mice infected with Pseudomonas aeruginosa. FK 749 has, in general, nearly the same in vitro and in vivo antibacterial activities as cefotaxime. The former had more potent bactericidal activity in the presence of the blood than the latter and showed more excellent therapeutic effect than cefotaxime against infections caused by large inoculum sizes.
PMCID: PMC352902  PMID: 525994
12.  Collaborative Evaluation of a Proposed Reference Dilution Method of Susceptibility Testing of Anaerobic Bacteria 
An agar dilution method for susceptibility testing of anaerobic bacteria was evaluated to determine whether results obtained would be consistent enough to recommend it as a reference method. The study was conducted in 10 laboratories where the minimum inhibitory concentrations of six antibiotics (carbenicillin, cefoxitin, chloramphenicol, clindamycin, penicillin G, and tetracycline) were determined against 10 bacterial strains on Wilkins-Chalgren agar prepared by three manufacturers. Minimum inhibitory concentrations falling on the modes varied from 57 to 80% of all determinations and on the mode or within ±1 log2 dilution of the mode from 87 to 100% within each laboratory. When data from all laboratories were pooled, minimum inhibitory concentrations from each laboratory agreed with the overall mode 48 to 71% of the time, with an overall agreement at ±1 log2 dilution of 96%. This degree of reproducibility allows for recommendation of the procedure as a reference method. Results with three of the test strains were very consistent, and these strains are recommended as control strains: Clostridium perfringens ATCC 13124, Bacteroides fragilis ATCC 25285 and Bacteroides thetaiotaomicron ATCC 29741. The minimum inhibitory concentrations for these strains were on the mode or within ±1 log2 dilution of the mode 98, 99, and 99% of the time, respectively. The remaining anaerobic bacteria are recommended as reference strains.
PMCID: PMC352888  PMID: 518079
13.  Antimicrobial susceptibility of clinical isolates of Serratia marcescens. 
The in vitro susceptibilities of 242 isolates of Serratia marcescens to 17 antibacterial drugs have been determined. Oxolinic acid, nalidixic acid, cefoxitin, and amikacin were the most active drugs. Ampicillin, kanamycin, and cephalothin were among the least active. A 4-year study showed that resistance of S. marcescens to dibekacin, tobramycin, sisomycin, and gentamicin has increased at least one order of magnitude in that period, whereas resistance to amikacin showed but a twofold increase.
PMCID: PMC352893  PMID: 391150
14.  In vitro activity of LY127935. 
The activity of LY127935, a beta-lactam antibiotic of novel structure, was studied in vitro against facultative gram-negative bacilli, Staphylococcus aureus, and Bacteroides fragilis. The strains were recent clinical isolates, many of which were relatively resistant to other antibiotics. LY127935 exhibited striking activity against Escherichia coli, Klebsiella pneumoniae, Enterobacter sp., Proteus sp., Serratia marcescens, and B. fragilis with median minimum inhibitory concentrations of less than or equal to 1.0 micrograms/ml. It was somewhat less active against Pseudomonas aeruginosa and S. aureus. Cefotaxime (HR 756) showed very similar activity except that it was substantially weaker against B. fragilis. LY127935 was more active than cefamandole, cefoxitin, or piperacillin; it was also as potent as tobramycin or amikacin against all species except for P. aeruginosa.
PMCID: PMC352847  PMID: 507785
15.  Activity of β-Lactam Antibiotics Against Pseudomonas aeruginosa Carrying R Plasmids Determining Different β-Lactamases 
Azlocillin, carbenicillin, cefsulodin, mezlocillin, nocardicin A, piperacillin, pirbenicillin, sulbenicillin, and ticarcillin, but not HR756, showed reduced activity against Pseudomonas aeruginosa strains producing seven types of β-lactamase.
PMCID: PMC352832  PMID: 114107
16.  Variability of Agar Dilution-Replicator Method of Yeast Susceptibility Testing 
The agar dilution method of in vitro susceptibility testing of fungi was analyzed with a Steers-type inoculum replicator, ten strains, and three drugs. The replicator reproducibly delivered the same inoculum to each series of plates. The minimal inhibitory concentrations of ketoconazole (an imidazole) and 5-fluorocytosine, but not that of the polyene nystatin, were dependent on the initial inoculum size. With the former two drugs, but not with the latter, minimal inhibitory concentrations were highly variable depending on the time of reading. Results with agar and broth dilution methods were divergent, and the differences in minimal inhibitory concentrations were variable in serial comparisons by the two methods. If the agar dilution minimal inhibitory concentrations were determined at first appearance of control growth, a commonly used end point, small variations in the time of reading (as could occur by variation in observer perception of when initial growth appears) induced large variations in the minimal inhibitory concentrations of 5-fluorocytosine and ketoconazole, particularly with rapidly growing strains. Results at 35 and 30°C were similar. The differences in results with the three drugs suggest different mechanisms of action. The variability quantitated with the agar dilution method could result in variability in results between laboratories and even observers in the same laboratory.
PMCID: PMC352755  PMID: 573098
17.  Cefamandole Therapy in Anaerobic Infections 
Thirty-one adult patients with infections due to anaerobic bacteria were treated with cefamandole. Bacteroides fragilis group (17) and Bacteroides melaninogenicus (13) were the most frequent anaerobes isolated. Duration of therapy varied from 2 to 49 days. Results were judged satisfactory in 26 cases, and unsatisfactory in 1 case. Four cases could not be evaluated. Adverse reactions occurred in 16 patients and included positive direct Coombs' test without hemolysis, transient liver function abnormalities, phlebitis, reversible neutropenia, fever, eosinophilia, and toxic epidermal necrolysis. The more significant reactions were associated with prolonged therapy. None was lethal. These data suggest that cefamandole is effective in treatment of most anaerobic infections.
PMCID: PMC352661  PMID: 380458
18.  Effect of Clavulanic Acid on the Minimum Inhibitory Concentration of Benzylpenicillin, Ampicillin, Carbenicillin, or Cephalothin Against Clinical Isolates Resistant to Beta-Lactam Antibiotics 
The effect of clavulanic acid on the minimum inhibitory concentration of benzylpenicillin, ampicillin, carbenicillin, or cephalothin against 353 clinical isolates of penicillin- and/or cephalothin-resistant strains was estimated.
PMCID: PMC352651  PMID: 311619
19.  Methicillin-Resistant Strains of Staphylococcus aureus Phage Type 92 
Methicillin-resistant (Mecr) strains of Staphylococcus aureus received for phage typing from several hospitals in New York City were resistant to the international set of typing phages but susceptible to experimental phage 92. Subsequently, strains of type 92 were detected in two outbreaks with Mecr strains in two other locations in the United States. In all instances, type 92 was predominant among the Mecr strains isolated in each hospital. With the exception of one strain, the methicillin resistance of the Mecr strains investigated was homogeneous. In most instances, isolates from the same hospital were closely similar in their antibiotic resistance patterns. The strains isolated in New York City could be divided into three groups by the host range of their lysogenic phages and by antigenic structure. Transduction experiments indicated that the transfer of chromosomal tetracycline resistance from Mecr strains into a strain susceptible to several international typing phages renders the latter nontypable. However, the acceptor strain remains susceptible to experimental phages 92 and 88. Transduction of methicillin resistance had no effect on the phage susceptibility of the acceptor strain. It is possible that the presence of chromosomal tetracycline resistance is a determining factor in the phage susceptibility of Mecr strains isolated in New York City.
PMCID: PMC352603  PMID: 154874
20.  Antibacterial activities, nephrotoxicity, and ototoxicity of a new aminoglycoside, Win 42122-2. 
Win 42122-2 is a new aminoglycoside antibiotic obtained from a mutant strain of Micromonospora purpurea. In vitro and in vivo comparisons of Win 42122-2 with gentamicin and amikacin revealed that Win 42122-2 generally was less active than gentamicin against Pseudomonas and many Enterobacteriacae, especially Klebsiella and indole-negative Proteus. Against most gentamicin-susceptible isolates, Win 42122-2 was more active than amikacin. Gentamicin-resistant clinical isolates were usually resistant to Win 42122-2, although it was active against certain gentamicin-resistant organisms, depending upon the aminoglycoside-modifying enzymes harbored by the organism. However, Win 42122-2 was markedly less toxic than gentamicin in subacute nephrotoxicity studies in rats, ototoxicity experiments in guinea pigs, and ataxia determinations in cats. This series of antibacterial determinations and toxicity evaluations indicated that the reduced toxicity of the antibiotic may be sufficient to provide an improved therapeutic ratio over gentamicin and other aminoglycosides, even though Win 42122-2 is less potent than gentamicin against some bacteria.
PMCID: PMC352959  PMID: 533261
21.  Rosaramicin Versus Penicillin G in Experimental Pneumococcal Meningitis 
Rosaramicin, a new macrolide antibiotic, was compared with penicillin G in the treatment of pneumococcal meningitis in rabbits. Animals were infected intracisternally with 104 colony-forming units of Streptococcus pneumoniae type III (rosaramicin minimal inhibitory/bactericidal concentrations, 0.25/0.5 μg/ml; penicillin G minimal inhibitory/bactericidal concentrations, 0.03/0.06 μg/ml). Treatment was instituted 96 h later. Infusion of rosaramicin at 25 mg/kg per h intravenously for 8 h produced a peak cerebrospinal fluid (CSF) drug concentration of 1.54 μg/ml (range, 0.87-3.6 μg/ml). During this infusion the numbers of pneumococci in CSF decreased from 6.2 ± 0.5 to 3.36 ± 1.12 log10 colony-forming units per ml. Penicillin G, infused at 30 mg/kg per h for 8 h, reached a similar concentration in CSF but caused a greater reduction (P < 0.01) in CSF bacteria, from 6.4 ± 0.36 to 1.3 ± 0.67 log10 colony-forming units per ml. Penicillin G, at 100 mg/kg per day intramuscularly for 5 days, cured 7 of 10 rabbits with pneumococcal meningitis. A higher dose, 300 mg/kg per day for 5 days, was no more efficacious: 11 of 14 rabbits were cured. Rosaramicin at 100 mg/kg per day intramuscularly for 5 days cured only 5 of 15 rabbits with meningitis, but a higher dosage regimen of that drug (250 mg/kg per day intramuscularly) produced acute, fulminant enterocecitis and death within 48 h in seven of eight rabbits. No cytotoxin was detected in the feces of one rabbit with acute enterocecitis. Thus the efficacy of rosaramicin in experimental pneumococcal meningitis, measured by bacterial clearance from CSF and by treatment outcome, was less than that of penicillin G. In addition, high-dose parenteral rosaramicin caused acute, fulminant enterocecitis in a high proportion of treated rabbits.
PMCID: PMC352952  PMID: 43705
22.  Effects of Interferon and Adenine Arabinoside Treatment of Hepatitis B Virus Infection on Cellular Immune Responses 
Fifteen patients with chronic hepatitis B were treated with adenine arabinoside (Ara-A) or human leukocyte interferon (HLI). Cellular immune response to hepatitis B virus surface antigen and antigens prepared from herpes simplex virus, varicella zoster virus, and cytomegalovirus was measured by a lymphocyte blast transformation assay and an assay for interferon production. Measurements were made before, during, and after antiviral treatment. Unlike patients convalescing from acute hepatitis B, only 2 of 15 patients with chronic hepatitis B had significant blast transformation to hepatitis B surface antigen. One such response occurred during the pretreatment period of HLI therapy, and the other was in a patient undergoing low-dose (<105 U/kg per day) HLI therapy. Mononuclear cell cultures were tested for interferon production in the presence of hepatitis B surface antigen. Cells from only 1 of 15 patients produced detectable levels of interferon. In contrast, all of these patients had normal cellular immune responses to herpesvirus antigens. Transformation responses to herpes antigens decreased three- to fivefold after patients were treated with >105 U of HLI per kg per day. Antiviral therapy with <105 U of HLI per kg per day or Ara-A did not produce a detectable depression of transformation response. Ara-A produced marked lymphocytopenia and a marked lymphocyte fragility after 5 or more days of therapy. In vitro Ara-A was toxic to lymphocytes at concentrations as low as 0.5 μg/ml. These changes in lymphocyte parameters may affect the outcome of antiviral therapy.
PMCID: PMC352953  PMID: 533259
23.  Bronchial Secretion Levels of Amikacin 
Amikacin was given to 14 noninfected men as three consecutive intramuscular injections (7.5 mg/kg) at 12-h intervals. Serum and bronchial secretion specimens were obtained at various times during flexible fiberoptic bronchoscopy after the final dose. Serum and bronchial secretion concentrations obtained between 1.5 and 2.0 h after the final dose ranged from 17 to 40 μg/ml and 2.3 to 8.4 μg/ml with a mean of 23.7 ± 2.9 and 5.23 ± 1.5 μg/ml, ±1 standard error of the mean, respectively. The highest bronchial secretion concentration in each subject correlated with the highest serum concentration (r = 0.83, P < 0.001), and all concurrent serum and bronchial secretion concentrations demonstrated a significant correlation (r = 0.82, P < 0.001). Clearance occurred at the same rate (half-life serum = 2.84 h; half-life of bronchial secretion = 2.60 h, P > 0.5). The mean bronchial secretion concentration of the 15 specimens obtained more than 7 h after the final dose was less than 1.0 μg/ml, with a range from 0.3 to 1.6 μg/ml. It is concluded that amikacin may achieve minimal inhibitory concentrations for many gram-negative bacteria in the bronchial secretions of noninfected patients 1 to 2 h after the final dose. However, levels fall below the reported minimal inhibitory concentrations against negative bacteria 6 to 7 h after the final dose. Furthermore, bronchial secretion levels may never reach the minimal inhibitory concentration against Pseudomonas aeruginosa.
PMCID: PMC352950  PMID: 533258
24.  Amikacin pharmacokinetics in pediatric patients with malignancy. 
The pharmacokinetics of amikacin were evaluated in 50 pediatric patients (1 to 17 years of age) with malignancies and normal renal function. Dosage regimens of 5 mg/kg per dose were administered intravenously (i) over 30 min every 8 h, (ii) over 60 min every 8 h, and (iii) over 60 min every 6 h. Administration of amikacin over 30 min produced concentrations in serum of 29.3 +/- 5.7 micrograms/ml at the end of the infusion and subtherapeutic concentrations 4 h after the infusion. The regimen of 20 mg/kg per 24 h, divided into doses given every 6 h infused over 60 min, achieved concentrations in serum at the end of the infusion of 17.2 +/- 1.7 micrograms/ml and at 6 h of 1.2 +/- 0.3 microgram/ml. The serum half-life was 1.24 +/- 0.09 h, volume of distribution was 0.26 +/- 0.02 liter/kg, and total body clearance rate was 131 +/- 10 ml/min per 1.73 m2. No accumulation of amikacin was noted, and no significant side effects could be attributed to the drug. This study suggests that the optimal initial dosage regimen of amikacin in children is 20 mg/kg per 24 h administered in equal doses every 6 h over 60 min; however, optimal therapy requires individualization of dosage based on measured serum concentrations and susceptibility data on bacterial pathogens isolated.
PMCID: PMC352961  PMID: 533263
25.  Fortimicin A: collaborative in vitro susceptibility. Comparison with amikacin and gentamicin against 11,840 clinical bacterial isolates. 
The susceptibility of 11,840 clinical bacterial isolates to fortimicin A was determined by agar dilution or broth microdilution methods and compared with their susceptibility to amikacin and gentamicin. In general, the in vitro activity of fortimicin A was essentially the same as that of amikacin. Significant exceptions were the increased effectiveness of fortimicin A against Serratia marcescens and the greater activity of amikacin against Pseudomonas and other nonfermentative gram-negative bacilli. On a weight-for-weight basis, gentamicin showed greater activity than the other two antimicrobial drugs against most species; S. Marcescens was the major exception. However, at concentrations equivalent to achievable nontoxic serum levels, the proportion of isolates inhibited by the three drugs was quite comparable. There were several strains with unusually high resistance to one or more of the tested antibiotics. These usually occurred in one of the six participating institutions and could be traced to specific enzyme-producing or permeability mutants endemic to that particular institution.
PMCID: PMC352960  PMID: 533262

Results 1-25 (336)