In vitro susceptibility of common clinical anaerobic and aerobic isolates against josamycin. The in vitro susceptibility of 145 anaerobic clinical isolates and 96 gram-positive aerobic clinical isolates to josamycin, a new macrolide antibiotic, was studied using the agar dilution technique. Ninety-five of the aerobes were susceptible to 1.56 mug or less of josamycin per ml. The median minimal inhibitory concentration of these organisms was </=0.39 mug/ml. The in vitro activity of josamycin against the anaerobes was compared with that of erythromycin, clindamycin, penicillin, and chloramphenicol. At concentrations </=3.12 mug/ml, 100% of strains of Bacteroides species and Bacteroides fragilis were susceptible to josamycin. At low concentrations (</=0.39 mug/ml), clindamycin was more active than josamycin against the anaerobes. However, at concentrations </=3.12 mug/ml, the activities of josamycin and clindamycin were similar except against the Fusobacterium species, which was quite resistant to josamycin.


New plasmid-mediated nucleotidylation of aminoglycoside antibiotics in Staphlococcus aureus. A wild-type strain of Staphylococcus aureus, which inactivates a wide variety of aminoglycosides (except the gentamicin components), has been found to harbor a plasmid (RAp01) that mediates the biosynthesis of a nucleotidyltransferase. This enzyme modifies the 4'-hydroxy function of these antibiotics. The plasmid has been studied, the enzyme responsible for this resistance pattern has been isolated by affinity chromatography, and its kinetics and physicochemistry have been characterized. The target of this enzyme has also been located by demonstrating the structure of one inactivated compound, 4'-(O)-adenylyltobramycin.


Susceptibility of Streptococcus mutans to antimicrobial agents. Fifty strains of Streptococcus mutans, including defined strains and clinical isolates, were tested for susceptibility to 20 different antimicrobial agents. Minimal inhibitory concentrations were determined by a liquid microtiter procedure. Antibiotics that were most effective in concentrations below 0.1 mug/ml included penicillin, ampicillin, erythromycin, cephalothin, and methicillin. Antibiotics effective in concentrations between 0.1 mug and 10 mug/ml included rifampin, lincomycin, thiostrepton, spiromycin, vancomycin, streptolydigan, novobiocin, tetracycline, chloramphenicol, spectinomycin, and gentamicin. Antibiotics effective at higher concentrations ranging from 10 mug/ml to 400 mug/ml included the aminoglycosides kanamycin, neomycin, streptomycin, and kasugamycin. Although most antibiotics exhibited inhibitory effects in a narrow range of concentrations, antibiotics such as tetracycline, thiostrepton, and spiromycin had a 1,000-fold range from the lowest to highest concentrations required for growth inhibition.


Renal extraction of gentamicin in anesthetized dogs. The tubular handling of gentamicin (G) and its intrarenal distribution were determined to elucidate the mechanism of G accumulation in the kidney. At a serum level of 11.1 +/- 0.5 mug/ml (10 animals), as maintained by constant infusion for 5 h, serum Na(+) and K(+), arterial pressure, effective renal plasma flow and glomerular filtration rate remained undisturbed. The clearance values in milliliters per minute for G, inulin, and p-aminohippuric acid were 40.3 +/- 1.8, 49.9 +/- 2.8, and 132 +/- 14, respectively. The ratio of clearance of G to clearance of inulin was 0.82 +/- 0.04 (P < 0.005), suggesting net reabsorption of G by the renal tubules. The renal cortex/serum ratio for G was 11.9 +/- 2.1, and the medulla/serum ratio was 2.7 +/- 0.4, indicating greater uptake of G by the cortex. The extraction ratio of p-aminohippuric acid was 0.74 +/- 0.03. In contrast, the extraction ratio of G was 0.20 +/- 0.03, which was significantly lower than that of inulin (0.30 +/- 0.04). It is concluded that the accumulation of G in the cortex was due to tubular reabsorption. Probably some of the reabsorbed G became trapped in the epithelial cells after crossing the luminal membrane, whereas some returned to the circulation.


Pharmacokinetic interpretation of cephradine levels in serum after intravenous and extravascular administration in humans. Pharmacokinetic parameters were calculated from intravenous data based upon a two-compartment open model. These parameters were subsequently used to determine the absorption rates and bioavailability of cephradine administered intramuscularly and orally. The results indicate that cephradine obeys dose-independent kinetics and that biological availability is complete from all dosage forms.


In vitro evaluation of the new oral cephalosporin cefatrizine: comparison with other cephalosporins. Cefatrizine (BL-S640), a semisynthetic, orally administered cephalosporin, was found to have an in vitro spectrum of activity comparable to those of four other cephalosporins tested. It is as effective as cephalexin, the other orally administered cephalosporin evaluated, against most species, and it appears to be more effective than cephalexin against many Enterobacter, Haemophilus, and Proteus strains isolated in our hospital. It is not inactivated by the plasmid-determined beta-lactamases of 14 strains of ampicillin-resistant Salmonella typhimurium or the ampicillin resistance determinant of an H. influenza strain from the Center for Disease Control. No synergy was observed between cefatrizine and gentamicin, kanamycin, carbenicillin, or polymyxin when tested against selected strains.


Mode of action of a purified antitumor protein from the proteinaceous crystal of Baccillus thuringiensis subsp. thuringiensis on Yoshida ascites sarcoma cells. A purified antitumor protein from the proteinaceous crystal of Bacillus thuringiensis subsp. thuringiensis inhibits the growth of Yoshida ascites sarcoma both in vivo and in vitro. Exogenous respiration of the tumor cells was unaffected by the protein at a concentration as high as 500 mug/ml. The antitumor protein inhibits the uptake and incorporation of labeled precursors into macromolecules. However, the ratio of incorporation over uptake is not affected by the protein. Further, the protein brings about the leakage of 260-nm-absorbing material, proteins, and (32)P-labeled cellular constituents from the Yoshida ascites sarcoma cells. The results show that the action of the antitumor protein appears to alter the cellular permeability of the tumor cells.


Genetic basis of streptococcin A-FF22 production. Spontaneous, low-frequency loss of ability to produce streptococcin A-FF22 (SA) by group A streptococcus strain FF22 was observed. The proportion of non-SA-producing (SA(-)) derivatives occurring in strain FF22 cultures grown in Todd Hewitt broth supplemented with 1% of yeast extract (THBY) was increased on treatment with ethidium bromide, acriflavin, or rifampin. The highest incidence of SA(-) organisms, however, was found in untreated THBY cultures that had been aging by incubation at 37 degrees C for several months. The possibility of selective effects in these experiments, operating to enhance the apparent frequency of SA(-) bacteria, was discounted. The survival of SA(-) derivatives in association with populations of SA(+) bacteria was dependent upon the use of culture conditions inimical to SA activity, since a consistent finding was that the loss of ability to produce SA was associated with loss of immunity to the killing action of this bacteriocin. Whereas selective killing of SA(-) derivatives was evident in mixed cultures of SA(+) and SA(-) strains in tryptic soy broth, no such effect was demonstrable in THBY. In these experiments, elimination of SA(-) cells seemed directly related to the presence of active SA. Purified clones of SA(-) substrains did not seem revertible to SA production, either spontaneously or on treatment with nitrosoguanidine. It is suggested that the property of production of SA by group A streptococcus strain FF22, together with that of host cell immunity to the homologous bacteriocin, may be mediated by plasmid-borne genetic determinants.


Comparative pharmacokinetics and metabolism of cephapirin in laboratory animals and humans. Comparative drug disposition studies in mice, rats, dogs, and humans indicate that cephapirin, a new semisynthetic cephalosporin antibiotic that exhibits broad-spectrum antimicrobial activity, is metabolized to desacetylcephapirin in these species. Pharmacokinetic analyses of the concentrations of cephapirin and desacetylcephapirin in plasma and urine reveal that the rate and extent of deacetylation decreases from rodents to dogs to humans. The kinetic analyses also suggest that the kidney performs a role not only in the excretion but also in the metabolism of cephapirin to desacetylcephapirin.


Effect of gentamicin on growth of viral, chlamydial, and rickettsial agents in mice and embryonated eggs. Gentamicin, at concentrations up to 500 mug/ml, showed no effect on the replication, yield, or infectivity of seven viruses or on the agents of psittacosis and meningopneumonitis when grown in mice or embryonated eggs. At the 500 mug/ml level, lymphogranuloma venereum cultures had a slight reduction in infectivity. Rickettsia akari demonstrated susceptibility at the 5 mug/ml level, whereas R. rickettsii, R. mooseri, and R. canada grown in embryonated eggs were susceptible in varying degrees to gentamicin at or above the 50 mug/ml concentration.


Formation of methylated and phosphorylated metabolites during the fermentation process of verdamicin. In an attempt to understand the biosynthetic processes leading to the formation of verdamicin (end product), we have examined the patterns of the formation of methylated and phosphorylated metabolites, which resulted from either the addition of l-[methyl-(14)C]methionine or [(32)P]KH(2)PO(4) to the fermentation. Incorporation of label from l-[methyl-(14)C]methionine into the bioactive sisomicin, verdamicin, and the chromatographically polar components increased with the progression of time. Two methylated bioinactive metabolites were found in the culture broth after removal of the methylated bioactive metabolites. In contrast to the bioactive metabolites, incorporation of the methyl-(14)C label into the two methylated bioinactive metabolites decreased with the progression of time. A phosphorylated bioinactive metabolite (nonmethylated) was also found in the culture broth, fermented in the presence of [(32)P]KH(2)PO(4). The role of the phosphorylated metabolite in the biosynthesis of the bioactive metabolites cannot yet be explained.


In vitro susceptibility of pathogenic Naegleria and Acanthamoeba speicies to a variety of therapeutic agents. Six pathogenic strains of Naegleria fowleri, two of Acanthamoeba castellanii, and three of Acanthamoeba polyphaga were tested in vitro for susceptibility to a variety of potentially useful therapeutic agents. Minimal motility inhibitory concentrations and minimal inhibitory concentrations were determined by a technique of subculturing pure clones of amoebae in plastic tissue culture chamber slides containing liquid axenic media and serially diluted drug, incubating at 30 degrees C for Acanthamoeba and at 37 degrees C for Naegleria, and observing on an inverted microscope at 6 h for inhibition of motility and at 24 and 48 h for inhibition of growth. Drug concentrations were selected on the basis of fluid levels achievable in humans. Amphotericin B, clotrimazole, and miconazole were the most effective drugs against Naegleria, whereas polymyxin B sulfate and pentamidine isethionate were somewhat effective against pathogenic Acanthamoeba. Our results suggest that amphotericin B is the most effective agent against Naegleria, but few agents are effective against Acanthamoeba.


Change in susceptibility of group B streptococci to penicillin G from 1968 through 1975. This report describes a study of 212 isolates of group B streptococci from sore throats over an 8-year period. A small but increasing percentage showed increased resistance to penicillin G when tested in an in vitro system.


Comparison of activity of sisomicin and gentamicin in mouse protection tests with gram-negative bacilli. The efficacy of sisomicin and gentamicin was compared in mouse protection studies against strains of Escherichia coli, Klebsiella sp., Enterobacter aerogenes, Serratia marcescens, Proteus mirabilis, and Pseudomonas aeruginosa. There was no significant difference in mortality of the mice in any of the protocol groups when five different dosages of sisomicin and gentamicin given by three separate schedules were compared for each bacterial inoculum in each antibiotic protocol. The mean protective dose values of sisomicin were at least one-half those of gentamicin for each protocol against Pseudomonas aeruginosa.


Evolution of transferable antibiotic resistance in coliform bacteria from remote environments. The influence of a mission hospital on the evolution of antibiotic resistance in coliform bacteria from a remote antibiotic-free Xhosa community and environment is described.


Antimicrobiol susceptibility of Propinibacterium acnes and related microbial species. The minimal inhibitory concentrations of 32 antimicrobial agents were established for 73 strains of Propionibacterium acnes and four related species (P. granulosum, P. avidum, Corynebacterium minutissimum, and C. parvum). Most strains showed good susceptibility to those agents usually considered active against gram-positive organisms. With the exception of C. minutissimum, the strains tested revealed more or less identical susceptibility ranges. The lowest minimal inhibitory concentrations were observed with benzylpenicillin, ampicillin, cephalothin, rifampin, erythromycin, clindamycin, and minocycline. C. minutissimum was more susceptible to gentamicin, sisomicin, tobramycin, and fusidic acid but more resistant to most other drugs than were the other species examined.


Pharmacological study of cefazolin during intermittent and continuous infusion: a crossover investigation in humans. Levels of cefazolin were determined in plasma, urine, bile, and cerebrospinal fluid in humans after a bolus intravenous injection and during a controlled, continuous intravenous infusion. All the patients were studied in a steady-state and crossover fashion. In plasma, the mean peak level after bolus injection (1.5 g) studied in 12 patients was 206.5 mug/ml; during continuous infusion (6 g daily), the mean level remained stable at 52.6 mug/ml. With bolus injection and continuous infusion, respectively, 89.7 and 86.3% of the administered dose of cefazolin were excreted in the urine of nine patients over the 6-h period considered. The levels of cefazolin in common bile duct bile were studied in six cholecystectomized patients. In bile collected during the two 3-h periods of the experiment, the mean concentration of the drug in the bile after bolus injection was 66.9 and 22.0 mug/ml, respectively; during continuous infusion, the corresponding biliary levels were 50.7 and 51.3 mug/ml, respectively. In four neurosurgical patients with an intraventricular catheter, neither bolus injection nor continuous infusion resulted in a demonstrable concentration of cefazolin in the cerebrospinal fluid. The continuous intravenous administration of cefazolin might have some advantage over the intravenous bolus intermittent injections. In plasma, the area under the curve is greater with continuous infusion than with bolus injection. In bile, the levels of cefazolin are more sustained with continuous infusion than with bolus injection. This approach to intravenous administration of cefazolin deserves more pharmacological and clinical trials.


Comparative pharmacokinetics of cefamandole, cephapirin, and cephalothin in healthy subjects and effect of repeated dosing. Cefamandole nafate, cephapirin, and cephalothin were administered intravenously in crossover fashion to 12 volunteers, in dosages of 2 g every 6 h for 16 doses. Mean peak levels of cefamandole were approximately 50% higher than those of the other agents. The serum concentration curves appeared to decline bi-exponentially, suggesting that a two-compartment model was most applicable for pharmacokinetic analysis; accordingly, the t((1/2)) of cefamandole was significantly longer when the serum peak was omitted from the analysis (0.86 versus 0.73 h, P < 0.05). The half-lives of cephalothin and cephapirin, 0.34 and 0.36 h, respectively, were probably underestimates reflecting the inclusion of distribution-phase values in the calculation. Repeated dosing had no effect on the peak serum levels, half-life, serum clearance, or apparent volume of distribution with one exception: peak serum levels of cephapirin were significantly lower after the sixteenth than after the first dose. Marked variations within a given subject were noted in the half-life and apparent volume of distribution of cefamandole in several instances. Renal clearances of cefamandole exhibited saturation kinetics similar to those of penicillin G.


Laboratory evaluation of BL-S786, a cephalosporin with broad-spectrum antibacterial activity. Biological and physicochemical properties of BL-S786 were compared with those of cephalothin, cephaloridine, and cefazolin. With few exceptions, BL-S786 was more active than the reference compounds against major gram-negative pathogenic species and its antibacterial spectrum was broader than that of cephalosporins currently available for clinical use. Although BL-S786 was generally less active than the control cephalosporins against gram-positive pathogens, it inhibited their growth at concentrations that should readily be achieved in humans after standard parenteral dosage. Streptococcus faecalis, a species relatively unsusceptible to cephalosporins in general, was an exception. BL-S786 was an effective bactericidal agent for strains of various gram-negative organisms. After intramuscular administration to mice, BL-S786 achieved high concentrations in blood, and its biological half-life was longer than that of the other three cephalosporins.


Reversible thrombocytosis and anemia due to miconazole therapy. Miconazole was administered intravenously in six consecutive patients with, active coccidioidal infection. Such treatment was associated with progressive anemia and thrombocytosis. The hematological abnormalities appeared to be dose related and potentially reversible. Bone marrow studies demonstrated erythroid hypoplasia and increased or active platelet production in three subjects. No hemorrhagic or thrombotic episodes were identified. It is suggested that careful hematological monitoring be performed in subjects undergoing systemic miconazole therapy.


Comparative pharmacology of josamycin and erythromycin stearate. Two macrolide antibiotics, josamycin and erythromycin stearate, were administered orally to healthy, adult male volunteers for a comparative study of their pharmacological properties. In comparable doses, josamycin and erythromycin produced similar plasma concentrations, with similar half-lives and elimination constants. An initial loading dose of 1.5 g of josamycin produced greater peak concentrations of antibiotic throughout a 10-day period with a regimen of every 6 h. In addition, josamycin tended to reach higher peak and trough concentrations after regimens of every 6 or 8 h were maintained for 2 days. Josamycin penetrated into saliva, sweat, and tears, and it was better tolerated in fasting subjects than was erythromycin stearate.


Pharmacokinetics of cefamandole in patients undergoing hemodialysis and peritoneal dialysis. The pharmacokinetics of cefamandole nafate, a new parenteral cephalosporin derivative, were evaluated in 11 patients with chronic renal failure (creatinine clearance less than 5 ml/min), including five patients during hemodialysis, four patients during routine peritoneal dialysis, and two patients during the interdialytic period. Peak serum levels of cefamandole were comparable to those observed in patients with normal renal function. Clearance of the drug during the interdialytic period and during hemodialysis and peritoneal dialysis was minimal, with a resultant significant prolongation of serum half-life. The nondialyzability of cefamandole is in contrast with reported studies of cephalothin, where significant reduction of the serum half-life was achieved during hemodialysis but not peritoneal dialysis. The concentration of cefamandole in the peritoneal dialysate after parenteral administration was observed to be bactericidal for many gram-negative pathogens and, with the exception of Streptococcus faecalis, most gram-positive organisms found in bacterial peritonitis in patients with severe renal failure. The present data suggest that if stable bactericidal serum levels of cefamandole are to be maintained during hemodialysis and peritoneal dialysis, a parenteral loading dose must be administered followed by one-half the loading dose every half-life.


Concentrations of trimethoprim-sulfamethoxazole in blood after a single, large oral dose. Concentrations of trimethoprim (TMP) and sulfamethoxazole (SMZ) in blood were determined in seven healthy volunteers after ingestion of 720 mg of TMP and 3,600 mg of SMZ (nine tablets of TMP-SMZ, 1:5 ratio) as a single oral dose. The mean levels of drug in blood achieved during the first 8 h after drug administration ranged from 6.12 to 8.32 mug/ml for TMP and 98 to 120 mug/ml for SMZ. These concentrations easily exceeded the previously reported minimal inhibitory concentrations for clinical isolates of Neisseria gonorrhoeae. The combination of TMP-SMZ given as a single, large oral dose may be a useful therapeutic regimen for patients with uncomplicated gonorrhea and susceptible microorganisms.


Effect of renal failure and dialysis on the serum concentration of the aminoglycoside amikacin. Serum and dialysate levels of amikacin were determined at appropriate intervals after a 300-mg intravenous dose as a continuous infusion in six patients with end-stage renal failure undergoing hemodialysis and in three patients on peritoneal dialysis. The mean serum half-life of amikacin was 3.75 h during (or after) hemodialysis and 29 h during (or after) peritoneal dialysis. Although not on hemodialysis in the same six patients, the serum half-life was 28 h. The results indicate that the maintenance dose of amikacin should be markedly decreased in patients with severe renal failure even if they are treated with peritoneal dialysis, and that serial serum antibiotic concentrations are essential to prevent cumulative toxicity of the drug.


Substrate inhibition of beta-lactamases, a method for predicting enzymatic stability of cephalosporins. Selected cephalosporins, including cefamandole, cephaloridine, cephaloglycin, and cefoxitin, were examined for their ability to inhibit the enzymatic activity of and act as substrates for beta-lactamases produced by Enterobacter cloacae and Staphylococcus aureus. Enzyme inhibition was determined by Michaelis-Menten kinetic measurements and by a spot plate assay using a chromogenic substrate (Glaxo compound 87/312). These two methods provide comparable estimates of kinetic parameters. Inhibition of beta-lactamase, as measured by these two methods, was generally found to correlate with resistance to hydrolysis and is proposed as a preliminary method of assessing susceptibility of cephalosporins to beta-lactamase hydrolysis. Four 7-alphaOCH(3), 7-alphaH cephalosporin analogue pairs were also examined. The presence of the 7-alphaOCH(3) substituent invariably resulted in reduced susceptibility to enzymatic hydrolysis, regardless of the other C7 substituent. The 7-alphaOCH(3) compounds were also better inhibitors than were their 7-alphaH analogues, with the exception that 7-alphaOCH(3) compounds having C7 adipic acid substituents were less inhibitory to the S. aureus enzyme than were the corresponding 7-alphaH analogues. Response of these two enzymes to 7-alphaOCH(3) and 7-alphaH cephalosporins suggests that beta-lactamase hydrolysis of these compounds involves attack at the alpha side of the betalactam ring.


Pirbenicillin: pharmacokinetic parameters in mice. The rapid intravenous administration to mice of pirbenicillin, carbenicillin, and ampicillin produced biexponential blood concentration-time curves when assessed by frequent blood samplings at short intervals. The pharmacokinetic behavior of pirbenicillin and the other penicillins was analyzed by the two-compartment open model. This is thought to be the first study giving detailed pharmacokinetic values of penicillins in mice. Some significant differences were noted between the pharmacokinetic values of pirbenicillin, ampicillin, and carbenicillin. These values suggest that the interchange of pirbenicillin between the central and peripheral body compartments of the mouse was slower than that of either carbenicillin or ampicillin and indicated that a greater fraction of the pirbenicillin than the ampicillin dose reached the peripheral compartment.


Chemical nature of agrocin 84 and its effect on a virulent strain of Agrobacterium tumefaciens. Agrocin 84, produced by Agrobacterium radiobacter K84, inhibited ribonucleic acid, deoxyribonucleic acid, and protein synthesis and amino acid transport in a susceptible, virulent strain of A. tumefaciens H-38-9. Cell motility was immediately stopped by action of the agrocin, 50% of the cells were killed within 15 min of contact, and the remainder were inhibited. Agrocin 84 is trypsin and pepsin resistant, but chemical analysis indicated a small peptide with a molecular weight of 2,500 containing six different amino acids, including nine molecules of glutamine or glutamic acid and seven molecules of serine.


Comparison of the in vitro activity of several cephalosporin antibiotics against gram-negative and gram-positive bacteria resistant to cephaloridine. The in vitro activity of each of two oral [cefatrizine (BL-S640), cephalexin] and three parenteral (cefamandole, cefazolin, cephapirin) cephalosporin antibiotics was compared with that of cephalothin against 168 clinical isolates of gram-negative and gram-positive bacteria selected as resistant to 20 mug of cephaloridine per ml on the basis of agar dilution susceptibility test data. Each of the five other cephalosporins inhibited a greater percentage of gram-negative bacillary isolates than did cephalothin or cephaloridine, with minimal inhibitory concentration values ranging 2- to 50-fold lower. Significant differences between minimal inhibitory concentrations of the compounds tested were also observed in tests against strains of Streptococcus faecalis and of methicillin-resistant Staphylococcus aureus. Potential advantages of including more than a single cephalosporin antibiotic in the panel of antibiotics used for routine susceptibility testing, suggested by these observations, are discussed.


Selection and characterization of strains of Staphylococcus aureus displaying unusual resistance to aminoglycosides. Susceptibility tests with aminoglycosides against Staphylococcus aureus have revealed discrepancies between the minimal inhibitory concentrations and the minimal bactericidal concentrations. To further evaluate these discrepancies, kill curves were performed against a susceptible strain of S. aureus with five different aminoglycosides (amikacin, kanamycin, tobramycin, gentamicin, sisomicin) at concentrations up to 16-fold above the minimal inhibitory concentration. Results revealed the presence of small subpopulations of cells capable of growth within 24 h in concentrations of aminoglycoside up to eightfold above the minimal inhibitory concentration for the parent strain. These subpopulations occurred at a frequency of >/=10(-7) parent cells, were not physiologically different from the susceptible parent strains, and were present in approximately one-half of 30 strains of S. aureus tested. The resistance of these subpopulations was approximately eightfold higher than that of the parent for all five aminoglycosides and was independent of concentration or type of aminoglycoside used to select them. This resistance was not due to extracellular degradation of drug and was stable over eight transfers in drug-free medium, except when selected by gentamicin or sisomicin.


Synergy of mecillinam, a beta-amidinopenicillanic acid derivative, combined with beta-lactam antibiotics. Mecillinam, a beta-amidinopenicillanic acid derivative, was combined with ampicillin, amoxicillin, carbenicillin, cephalothin, cefamandole, and cefoxitin and tested against most members of the Enterobacteriaceae and Pseudomonas. Synergy was demonstrated with selected isolates of most of the organisms tested. Isolates highly susceptible to mecillinam (minimum inhibitory concentration, <0.8 mug/ml) were not synergistically inhibited by addition of another beta-lactam antibiotic. Synergy of mecillinam and a beta-lactamase-resistant penicillin, cloxacillin, was demonstrated. In media of osmolality >10 mOsm or of conductivity >6 mS, mecillinam and beta-lactam antibiotics showed synergy in most instances, whereas at low osmolality and conductivity the activity of mecillinam is so great that synergy cannot be demonstrated. The proportion of mecillinam to beta-lactam antibiotic that will be synergistic ranged from 100:1 to 1:1 to 1:100. Mecillinam did not increase the activity, minimum inhibitory concentration or minimum bactericidal concentration values, of beta-lactam compounds against streptococci, staphylococci, clostridia, listeria, or bacteroides. Synergy was not demonstrated with combinations of mecillinam and aminoglycosides (kanamycin, gentamicin, tobramycin, amikacin), chloramphenicol, tetracycline, or polymyxins.


Therapeutic effects of ribavirin given by the intraperitoneal or aerosol route against influenza virus infections in mice. Ribavirin (1-beta-d-ribofuranosyl-1,2,4-triazole-3-carboxamide) is an effective antiviral agent against type A influenza infection of mice. Therapy was most effective when administered as a small-particle aerosol early in the infection. Treatment was also effective by either the intraperitoneal or aerosol route in mice with histological evidence of pneumonia. Ribavirin increased the percent survival, lowered lung virus titers, and decreased the development of lung pathology when therapy was initiated at 6 h as a small-particle aerosol. There was no evidence of pulmonary toxicity or immunosuppressive effects.


Inhibition of antibiotic activity in vitro by synthetic melanin. Synthetic melanin (100 to 1,000 mug/ml) markedly inhibited the in vitro activity of aminoglycosides and tetracyclines but did not affect the activity of betalactam antibiotics, erythromycin, or clindamycin.


Antiviral effects of virazole in chronic hepatitis B surface antigen-seropositive chimpanzees. Virazole (Ribavirin, ICN 1229), a broad-spectrum, antiviral chemotherapeutic agent was used to treat two adult chronically hepatitis B surface antigen (HB(s) Ag)-seropositive chimpanzees. No significant change in serum hepatitis B surface antigen was noted and no adverse reactions were observed. The role of viral replication in the chronic carrier state of hepatitis B is discussed.


Pharmacokinetics of cefamandole in the presence of renal failure in patients undergoing hemodialysis. The pharmacology of cefamandole in seven patients with stable renal insufficiency and in eight patients undergoing hemodialysis was determined. All patients had creatinine clearances less than 5 ml/min. The half-life of cefamandole in those patients with stable chronic renal failure was 7.7 +/- 2.2 h. The mean venous level 1 h after intravenous injection of a 1-g dose was 85.3 +/- 32.0 mug/ml. The mean venous half-life of cefamandole during hemodialysis was 6.1 h. The venous serum level after 5.5 of hemodialysis was 50.4 +/- 20.8 mug/ml. The mean coefficient of extraction was 0.155, and the mean clearance was 34.7 ml/min. The time interval between doses of cefamandole administered intravenously should be lengthened to 24 h in the presence of stable renal failure. No major change in dosage schedule is necessary for patients undergoing dialysis.


Metabolism of (14C) cefaclor, a cephalosporin antibiotic, in three species of laboratory animals. The metabolic fate of the orally effective cephalosporin antibiotic cefaclor (Lilly 99638) has been studied in rats, mice, and dogs. Cefaclor is efficiently absorbed from the gastrointestinal tract as the intact antibiotic. In rats and mice, cefaclor, for the most part, escapes metabolism in the body and is eliminated unchanged as unaltered antibiotic, primarily by renal excretion. In dogs, however, cefaclor is more labile to metabolism and only a portion of the administered antibiotic is eliminated unchanged via the kidney.


Comparison of the antibacterial activity of nine cephalosporins against Enterobacteriaceae and nonfermentative gram-negative bacilli. The in vitro antibacterial activity of nine cephalosporins (cephalothin, cephaloridine, cephalexin, cefazolin, cefamandole, cefuroxime, cefatrizine, cefoxitin, and cefazaflur) was determined against 344 strains of Enterobacteriaceae and 99 nonfermentative gram-negative bacilli. Cefamandole, cefazaflur, and cefuroxime were the most active cephalosporins against the Enterobacteriaceae (with the exception of Serratia marcescens). However, cefoxitin was the only cephalosporin that inhibited all 30 S. marcescens strains in a concentration of 16 mug/ml and was by far the most active compound against selected cephalothin-resistant strains of Escherichia coli, Klebsiella, and Proteus mirabilis. Acinetobacter spp. were inhibited best by cefuroxime, but none of the cephalosporins had appreciable activity against the Pseudomonas spp.


Enzymatic adenylylation by aminoglycoside 4'-adenylytransferase and 2"-adenylyltransferase as a means of determining concentrations of aminoglycoside antibiotics in serum. A fast and accurate enzymatic estimation of the concentration of aminoglycoside antiobiotics in serum is given by aminoglycoside 4'-adenylyltransferase (synonym: tobramycin adenylyltransferase), a new enzyme recently found in tobramycin-resistant staphylococci (P. Santanam and F. H. Kayser, J. Infect. Dis. [Suppl.], in press). This enzyme is useful in assaying the kanamycins, the butirosins, amikacin, ribostamycin and, if required, the neomycins, tobramycin, and paromomycin. In combination with the assay using aminoglycoside 2''-adenylyltransferase (synonym: gentamicin adenylyltransferase) to determine the level of gentamicin, sisomicin, and tobramycin, a convenient method to estimate a wide range of aminoglycoside antibiotics in patients' sera is described.


Comparative toxicological studies of amphotericin B methyl ester and amphotericin B in mice, rats, and dogs. In acute and subacute toxicological studies, amphotericin B methyl ester was shown to be much less toxic than the parent antibiotic. As a single intravenous dose in mice, the methyl ester was approximately 20 times less toxic than amphotericin B. Also, the acute toxicity of the methyl ester in mice was not enhanced by the presence of chemically induced hepatic or renal damage or by the concurrent administration of amphotericin B or flucytosine. In a 1-month intraperitoneal study in rats, the methyl ester was about one-fourth as nephrotoxic as amphotericin B. In a 1-month intravenous study in dogs, the methyl ester was about one-eighth as nephrotoxic and one-fourth to one-half as hepatotoxic as the parent compound. In addition, the methyl ester, unlike amphotericin B, produced minimal renal effects, which did not increase in severity with increasing dosage. Based on the results of these studies, it is concluded that amphotericin B methyl ester has the potential for an improved therapeutic ratio in the treatment of systemic mycoses.


Variation in the susceptibility of strains of Staphylococcus aureus to oxacillin, cephalothin, and gentamicin. Three cases of staphylococcal bacteremia caused by organisms that were inhibited by low concentrations of oxacillin, but were resistant to the killing effects of oxacillin, stimulated us to screen 60 clinical isolates of Staphylococcus aureus for their susceptibility to oxacillin, cephalothin, and gentamicin. All 60 strains were inhibited by low concentrations of the antibiotics. The antibiotics were bactericidal against 27 of the 60 strains and only bacteriostatic against the other 33 after 24 h of incubation. However, after 48 h of incubation, the antibiotics were also bactericidal against the latter group.


Susceptibility of respiratory tract anaerobes to orally administered penicillins and cephalosporins. Anaerobic bacteria recovered from airway-related infections were tested by agar dilution against selected penicillins and cephalosporins available for oral administration. Against 136 isolates, penicillins G and V showed comparable activity, particularly when pharmacological differences were considered. Although many isolates were exquisitely susceptible to the penicillins, only 55% of the Bacteroides species and 72% of all isolates were inhibited at 0.5 mug of penicillin G per ml. Results for penicillin V at 1 mug/ml were similar (59 and 73%). The two cephalosporins were more active at achievable levels, inhibiting 94 to 95% of Bacteroides and 95 to 96% of all isolates at 8 mug/ml. These levels represent approximately 50% of the reported peak serum levels after oral administration of 625 mg of the penicillins and 500 mg of the cephalosporins. Dicloxacillin and nafcillin were tested against 50 isolates. The two were comparably active on a weight basis; dicloxacillin was more active when pharmacological differences were considered, but did not match the other penicillins or the cephalosporins.


Antimicrobial susceptibility testing of yeasts: a turbidimetric technique independent of inoculum size. The current development of potent antifungal drugs necessitates reliable methods of in vitro susceptibility testing of clinical isolates. Other laboratories have noted with some antimicrobials that conventional tube dilution visual end points for determining minimal inhibitory concentrations (MIC) vary markedly with the inoculum. With seven isolates (four species) we compared the conventional method with one developed with a spectrophotometer. Yeasts were diluted to inocula of 10(2) to 10(5) cells/ml and incubated at 37 degrees C with 5-fluorocytosine or miconazole or without drug in a synthetic defined medium. At frequent intervals MICs were determined by the lowest drug concentration without visible turbidity. Concurrently, the percent transmission of each tube was measured and an inhibitory concentration (IC((1/2))) was calculated from the turbidimetric measurements. MICs of both drugs for all strains varied with the inoculum. Intrastrain differences averaged 128-fold for miconazole and greater than 8-fold with 5-fluorocytosine. This variability in MIC occurred when readings were made after 12 to 48 h of incubation. In contrast, IC((1/2)) values of all isolates varied less than two-fold with the same range of inocula. Most isolates showed this independence when measured at 48 h. Fast-growing yeasts showed greater IC((1/2)) variability unless the turbidimetric measurements were taken earlier while the drug-free growth was still in a rapid growth phase. This method is reproducible, inoculum independent, rapid, free from subjectivity and observer variability, and suitable for adaptation to a clinical setting.


Aerobically incubated thioglycolate broth disk method for antibiotic susceptibility testing of anaerobes. The anaerobic broth disk (AnBD) method of Wilkins and Thiel and a new modification, designated the thioglycolate broth disk method, were compared with an agar dilution technique. The thioglycolate broth disk method was incubated aerobically (AeTBD) or anaerobically (AnTBD). One hundred anaerobic bacteria representing 15 species were tested with clindamycin, chloramphenicol, erythromycin, penicillin, and tetracycline. Agreement of results by the two methods with minimal inhibitory concentration determinations were: AnBD, 95.2%; AnTBD, 91.5%; AeTBD, 94.5%. With clindamycin, chloramphenicol, and penicillin, the agreement of the AeTBD and agar dilution results was 100%, 100%, and 95%, respectively. Using the AeTBD method, only 1.1% of all tests gave false susceptible readings, whereas 4.4% gave false resistant readings. All susceptibility testing errors occurred with tetracycline, erythromycin, and, to a lesser extent, penicillin. For each method, the changes in designation of bacteria as being susceptible or resistant to an antibiotic between trials primarily involved strains with minimal inhibitory concentrations which were +/- one dilution of the respective breakpoint value. The same situation was true for most bacteria that yielded false resistant readings within each trial. False resistant readings with tetracycline were determined to be unrelated to excess cation content of test media. These results reaffirm the reliability of the AnBD method and indicate that the AeTBD modification is equally reliable. The greater convenience and lower cost of the AeTBD method should make possible more widespread performance of susceptibility testing for anaerobic bacteria in hospital laboratories.


Concentration of cefamandole in serum interstitial fluid, bile, and urine. Cefamandole readily diffuses from the serum into soft tissue interstitial fluid. The rate of diffusion differs little from that of cephalothin. The concentrations of antibiotic were greater in bile and urine during the entire period of study than is necessary to kill susceptible pathogenic bacteria present in these fluids.


Susceptibility of anaerobic bacteria to 23 antimicrobial agents. The antimicrobial susceptibility of 492 anaerobic bacteria, the majority of which were recent clinical isolates, was determined by the agar dilution technique. Penicillin G was active against most of the strains tested at 32 U or less/ml, but only 72% of Bacteroides fragilis strains were susceptible at this level and 9% required 256 U or more/ml. Ampicillin was effective against most of the strains except B. fragilis at 16 mug or less/ml. Amoxicillin was active against only 31% of B. fragilis, 76% of other Bacteroides species, and 67% of Fusobacterium species at 8 mug/ml. Two new penicillins, mezlocillin and azlocillin, were similar to ampicillin in their activity. Carbenicillin and ticarcillin inhibited all but a few strains at 128 mug or less/ml. BLP 1654 was somewhat more active than penicillin G against B. fragilis but had similar activity against other anaerobes. Cephalothin was inactive against B. fragilis, and only 65% of other Bacteroides species were inhibited by 32 mug or less/ml. It was effective against all other anaerobes at that level. Cefamandole showed somewhat greater activity than cephalothin against B. fragilis but generally less activity against gram-positive organisms. Cefazaflur (SKF 59962) was comparable to cephalothin against B. fragilis. Cefoxitin was distinctly more active than cephalothin against B. fragilis. These latter two agents were less active than cephalothin against the gram-positive anaerobes. Chloramphenicol remains active against anaerobic bacteria at 16 mug or less/ml, with rare exceptions. Thiamphenicol was similar to chloramphenicol in its activity. Clindamycin was very active against most of the anaerobes at 8 mug or less/ml. Erythromycin and josamycin were also tested, with josamycin showing greater activity against B. fragilis than either erythromycin or clindamycin. A new oligosaccharide, everninomicin B, was less active than clindamycin against B. fragilis but more active against clostridia and some of the other strains tested. Most of the groups of bacteria tested demonstrated a trend toward resistance to tetracycline. Doxycycline and minocycline were somewhat more active than was tetracycline. Metronidazole was active against the majority of the anaerobes tested; resistance ws demonstrated by some of the gram-positive cocci and gram-positive, non-sporeforming bacilli.


Inhibition of bacteriophage lambda, T1, and T7 development by R plasmids of the H incompatibility group. R plasmids from chloramphenicol-resistant salmonella from Ontario are shown to belong to the H(2) incompatibility subgroup and to mediate a broad-spectrum, phage inhibition function.


Josamycin and rosamicin: in vitro comparisons with erythromycin and clindamycin. The macrolide antibiotics josamycin and rosamicin were compared in vitro with erythromycin for activity against Staphylococcus aureus, S. epidermidis, and enterococci and with clindamycin for activity against a variety of anaerobic organisms. Rosamicin and erythromycin were similar in activity and superior to josamycin against aerobic cocci. Most isolates of S. aureus (96%), S. epidermidis (79%), and the enterococci (87%) were inhibited by 1.56 mug of either of the new macrolide compounds per ml. Clindamycin was the most active compound against the anaerobic organisms.


Inactivation of Semliki Forest Virus in aerosols. Purified Semliki forest virus in aerosols is inactivated rapidly at 40% and above 70% relative humidity. At all humidities tested the decay of virus infectivity runs parallel with the decrease in hemagglutination activity, whereas the biological integrity of the virus ribonucleic acid is preserved. Also, free infectious ribonucleic acid is stable after spraying at all relative humidities. Evidence is presented for the hypothesis that above 20% relative humidity, virus inactivation in aersols is mainly due to surface-dependent factors, damaging the virus coat.


An obligate osmophilic yeast from honey. An obligate osmophilic yeast that requires high sugar concentrations (10 to 20% glucose) for growth was identified as Saccharomyces bisporus var. mellis. Optimum growth for this strain was at 60% glucose. Several non-assimilable compounds permitted growth at glucose concentrations below the minimum requirement and stimulated growth at glucose concentrations above the minimum. No correlation existed between growth stimulation and spheroplast stabilization capacities of the compounds examined.


Inhibition of aflatoxin formation by 2-mercaptoethanol. 2-Mercaptoethanol inhibits growth of Aspergillus parasiticus NRRL 3240 and aflatoxin formation by the fungus. When added to the resuspended medium, 2-mercaptoethanol inhibited [1-14C]acetate incorporation into both aflatoxins and neutral lipids, thereby showing that it acts at an early stage of aflatoxin biosynthesis. The inhibition is probably due to its chelating action on zinc, which is essential for aflatoxin production. It is proposed that any chelating agent that selectively binds to zinc will inhibit aflatoxin formation.


Recovery of Yersinia enterocolitica from streams and lakes of California. Stream and lake water from the Mammoth Lakes region of California was sampled for Yersinia enterocolitica. From 10 of the 34 sites examined, organisms were isolated that were biochemically identified as Y. enterocolitica. Only one of the ten strains could be serologically confirmed. This strain was identified as Y. enterocolitica serotype 16. Although an outbreak of enteritis in the area prompted this study, no correlation with gastrointestinal disease could be established since the majority of the strains were untypeable.


Use of activated charcoal for the removal of patulin from cider. Penicillium urticae (NRRL 2159A) was grown in culture broth containing 1 muCi of [1-14C-A1acetate to produce [14C]patulin. [14C]patulin was purified from the broth and added to apple cider. After the patulin concentration of the cider was adjusted to 30 mug/ml with unlabeled patulin, the cider was subjected to various charcoal treatments. [14C]patulin was completely removed by shaking the cider with 20 mg of activated charcoal per ml and by eluting the cider through a 40- to 60-mesh charcoal column. Activated charcola at 5 mg/ml reduced patulin in naturally contaminated cider to nondetectable levels.


Screeing of toxic isolates of Fusarium poae and Fusarium sporotrichiodes involved in causing alimentary toxic aleukia. A total of 131 isolates of Fusarium poae and F. sporotrichioides from overwintered cereals, which were associated with the alimentary toxic aleukia toxicoses in the Soviet Union, were tested for their ability to produce T-2 toxin [4 beta, 15 diacetoxy-8alpha-(3-methylbutyryloxy)-12,13-epoxytrichothec-9-en 3alpha-ol]. The presence of T-2 toxin was determined by thin-layer chromatography, gas-liquid chromatography, spectroscopic analyses, and the rabbit skin test. A good correlation was demonstrated between T-2 toxin dectetion by thin-layer chromatography and inflammatory skin reactions of rabbits.


Use of hydroxyapatite-coasted glass beads for preclinical testing of potential antiplaque agents. Methods for rapid preclinical testing of antiplaque agents in vitro using hydroxyapatite (HT)-coated glass beads are described. The assays developed could reliably detect (i) prevention of growth in the culture fluid or on the HT surfaces, (ii) the effect of transient exposure of a bactericidal agent on the viability of cells in a preformed bacterial mat, (iii) reversible adsorption of a bactericidal agent on an HT surface, and (iv) the ability of an agent to inhibit adsorption of Streptococcus sanguis to an HT surface or to salivary proteins adsorbed to an HT surface.


Protoplasts of Cosmarium as a potential protein source. Cosmarium turpinii, a fast-growing desmid alga, transforms into protoplasts in 4 h when incubated in a mineral medium + 0.4 M mannitol + 0.5% Cellulysin.


Tremorgenic mycotoxin from Penicillium paraherquei. A tremorgenic mycotoxin was isolated from Penicillium paraherquei Abe ex G. Smith and identified as verruculogen. It was produced at the rate of approximately 1 mg/g of the dried fungal mycelium cultured on peptone-enriched Czapek-Dox medium at 28 degrees C.


Comparison of various brands of membrane filters for their ability to recover fungi from water. Five brands of ethylene oxide- and autoclave-sterilized membrane filters were examined for their ability to recover fungi from natural waters. Results showed that the recovery on Gelman membranes was consistently higher than on the other brands tested.


Analysis of the exudate produced by Streptococcus mutans SL-1 colonies of sucrose-containing agar media. The watery exudate produced by Streptococcus mutans SL-1 colonies on sucrose-containing agar media was found to contain about 7% (wt/vol) of a water-soluble, branched dextran, 4% sucrose, and smaller (less than 1%) amounts of fructose, Folin-phenol-positive material, and lactic acid.


Computer-assisted analysis of adenosine triphosphate data. A computer program has been written to assist in the analysis of adenosine 5'-triphosphate data. The program is designed to calculate a dilution curve and to correct sample and adenosine 5'-triphosphate standard data for background and dilution effects. In addition, basic statistical parameters and estimates of biomass carbon are also calculated for each group of samples and printed in a convenient format. The versatility of the program to analyze data from both qauatic and terrestrial samples is noted as well as its potential use with various types of instrumentation and extraction techniques.


Comparison of different purification procedure for extraction of staphylococcal enterotoxin A from foods. Different procedures commonly used for extraction, purification, and concentration of staphylococcal enterotoxins from foods were investigated with 131I- and 125I-labeled staphylococcal enterotoxin A. Loss of labeled enterotoxin A was compared with loss of total nitrogen. The results showed that in most of the common procedures, such as gel filtration, ion exchange, and heat treatment, the percentage of loss of labeled enterotoxin A was greater than the loss of total nitrogen. Chloroform extraction and acid precipitation with hydrochloric acid had nearly the same effect on the purification of both labeled enterotoxin A and total nitrogen. Ammonium sulfate precipitation proved to be practical and was successfully used for purification of enterotoxin A from sausage extract. Simultaneous use of trypsin and Pseudomonas peptidase for treatment of food extracts considerably reduced food proteins capable of interfering with serological detection of enterotoxins but did not essentailly influence the loss of enterotoxin A.


Presence of bifidobacteria in the rumen of calves fed different rations. A study was made on the numbers and species of bifidobacteria present in the rumen of calves fed high-roughage and high-concentrate diets. With the roughage ration the bifidobacteria were not detectable in a 10(-3) dilution, whereas with the concentrate ration their number was high, usually in the order of 10(8) to 10(9)/ml of rumen fluid. The species most represented, identified by means of deoxyribonucleic acid-deoxyribonucleic acid hybridization tests, included Bifidobacterium ruminale, Bifidobacterium globosum, and an apparently new species.


Regulation of nitrogen fixation in Rhizobium sp. Regulation of nitrogen fixation by ammonium and glutamate was examined in Rhizobium sp. 32H1 growing in defined liquid media. Whereas nitrogenase synthesis in Klebsiella pneunoniae is normally completely repressed during growth on NH4+, nitrogenase activity was detected in cultures of Rhizobium sp. grown with excess NH4+. However, an "ammonium effect" on activity was invariably observed in cultures grown on NH4+ as sole nitrogen source; the nitrogenase activity was, depending on conditions, 14 to 36% of that of comparable glutamate-grown cultures. Glutamate inhibited utilization of exogenous NH4+ and, in one of two procedures described, glutamate partially alleviated the ammonium effect on nitrogenase activity. NH4+, apparently produced from N2, was excreted into the culture medium when growth was initiated on glutamate, but not when NH4+ was thesole source of fixed nitrogen for growth. These findings are discussed in relation to nitrogen fixation by Rhizobium bacteroids.


Studies on glucose isomerase from a Streptomyces species. Production and properties of glucose isomerase from a Co2+-sensitive Streptomyces species were studied. After 4 days of shaking cultivation at 30 degrees C and 200 rpm, a maximum of 1.1 enzyme units per ml of broth was obtained. Cell-free glucose isomerase, obtained from mycelia heat-treated in the presence of 0.5 mM Co2+, showed a 3.5-fold increase in specific activity over enzyme obtained from untreated mycelia. The optimum pH and temperature for the glucose isomerase were 7 to 8 and 80 degrees C, respectively. The Michaelis constant for fructose was 0.40 M. Mg2+ was found to enhance the glucose isomerase activity, whereas the effect of Co2+ on enzyme activity depended on the manner in which the enzyme was prepared. This glucose isomerase was quite heat stable, with a half-life of 120 h at 70 degrees C.


Commercial formulations of Bacillus thuringiensis for control of Indian meal moth. Doses of four commercial formulations and one experimental formulation of Bacillus thuringiensis Berliner were mixed with the diet used to rear colonies of the Indian meal moth Plodia interpunctella (Hübner). Indian meal moth eggs were introduced to the treated diet, and the resultant adult emergence was tabulated. The experimental formulations ranked as follows in efficacy in controlling the Indian meal moth: Dipel (50% lethal concentration [LC50], 25 mg/kg) greater than Bactospeine WP (LC50, 100 mg/kg) greater than Thuricide (LC50, 150 mg/kg) greater than IMC 90007 (LC30, 180 mg/kg) greater than Bactospeine Flowable (LC50, 440 mg/kg).


Natural occurrence of Fusarium toxins in feedstuff. The mycotoxins diacetoxyscirpenol, deoxynivalenol, and zearalenone, produced by Fusarium roseum, were found naturally occuring in mixed feed samples. In all cases analyzed, deoxynivalenol occurred together with zearalenone. The natural occurrence of zearalenone in sesame seed is reported for the first time. Strains of F. roseum isolated in various parts of the world form feed implicated in animal mycotoxicosis produced monoacetoxyscirpenol, diacetoxyscirpenol, deoxynivalenol, and zearalenone.


Biodegradability of [14C]methylcellulose by activated sludge. Three Methocel methylcellulose ethers of 1.9 degree of substitution with [14C]methyl labels were shown to be biodegradable using batch-type activated sludge tests. The maximum rate for conversion to 14CO2, attained after 1 week, was only 0.62 mg of methylcellulose/g of mixed liquor volatile solids per day. In 20 days, 55 to 73% of the radioactivity had been removed from solution as 14CO2, and the suspended solids contained 12 to 15% of the original radioactivity. Only 4% of the original methylcellulose appeared to be polymeric after the 20-day period. Thin-layer chromatography of supernatant liquid indicated at least two degradation products.


Quantitative requirements for exponential growth of Alcaligenes eutrophus. Quantitative nutrient requirements for unrestricted autotrophic growth of Alcaligenes eutrophus were determined. Minimum saturating concentrations of Mg2+, SO42-, PO43-, Fe3+, and Na2+ for an optical density increase of 2 were 10(-4) M 8 X10(-5) M, 5 X 10(-4) to 6 X 10(-4) M, 10(-5) M, and 10(-7) to 2 X 10(-7) M, respectively. Trace metal requirements for cobalt, chromium, and copper were also demonstrated, but minimum concentrations could not be determined because other reagents contributed a high background of these metals. Under certain conditions an apparent response to zinc was observed, although other experiments suggest the zinc salt contained another metal that was required for growth. Poly-beta-hydroxybutyrate biosynthesis was shown to be initiated by a magnesium or sulfate deficiency as well as by a nitrogen or phosphate deficiency.


Desulfovibrio of the sheep rumen.

Desulfovibrio of the sheep rumen. A sulfate-reducing bacterium has been isolated in pure culture from sheep rumen contents. Its properties agree in all respects tested with those ascribed to Desulfovibrio desulfuricans. The populations observed (about 10(8)/ml) are sufficient to account for published rates of ruminal sulfide production.


Morphological characterization of small cells resulting from nutrient starvation of a psychrophilic marine vibrio. Upon starvation, Ant-300, a psychrophilic marine vibrio, was observed to decrease in size and change in shape from a rod to a coccus. After 3 weeks of starvation 50% of the starved population was able to pass through a filter with a pore size of 0.4 mum. Electron microscopy of thin sections of the small cells revealed normal cell structure except for an enlarged periplasmic space. When inoculated into a fresh medium, starved cells growth without a significant lag and regained "normal" size and shape within 48 h.


Morphological and physiological characteristics of Gemmiger formicilis isolated from chicken ceca. Morphological and physiological studies were made on chicken cecal isolates of the strictly anaerobic bacterial species Gemmiger formicilis. Structural features (phase-contrast and electron microscopy) of these microorganisms indicate they (i) are highly pleomorphic, (ii) possess a trilaminar cell wall like gram-negative bacteria, (iii) exhibit an unusual growth process characterized by polar swelling (resembling budding bacteria), and (iv) grow into elongated cells when exposed to a subinhibitory concentration of penicillin. The morphological data presented suggest that this species has a rod-shaped structure. These bacteria ferment a variety of sugars to produce formic, butyric, and lactic acids. There appear to be two groups of Gemmiger, one producing primarily lactate and the other producing formate as major fermentation metabolites. Growth of six strains in a basal medium, consisting of Trypticase, minerals, carbohydrate, Na2CO3 buffer, and cysteine as reducing agent, was stimulated by rumen fluid and yeast extract. Volatile fatty acids partially replaced the requirement for rumen fluid with some strains. Single deletions of vitamins (from a defined vitamin mixture) indicated that pantothenate, riboflavin, and thiamine were highly stimulatory to growth of the organism in a medium containing rumen fluid and Trypticase as source of vitamins. Other vitamin requirements were not studied.


Electrochemical sterilization of beer.

Electrochemical sterilization of beer. Electrochemical inactivation of microorganisms was not achieved in beer but was achieved in physiological saline. Addition of carbohydrates or proteins to physiological saline prevented inactivation in this medium.


Autoflora in the upper respiratory tract of Apollo astronauts. The typical microbial inhabitants of the oral and nasal cavities of Apollo astronauts were identified before space flight and generally found to be similar to those previously reported for healthy male adults. Additional analyses of samples collected immediately after return of the Apollo 13, 14, 15, and 16 crew members to earth were performed to evaluate the effects of space travel on the microbial bioburden of the upper respiratory tract. In-flight cross-contamination and buildup of pathogens such as Staphylococcus aureus were noted, although significant increases in nonpathogenic species were absent. Other proposed alterations, such as dysbacteriosis (flooding of the mouth with a single species) and simplification of the autoflora, did not occur. Generally, the incidence and quantitation of each species after flight was within the preflight range, although the number of viable Haemophilus cells recovered from the mouth decreased significantly after space flight. Except for those minor alterations listed above, the aerobic and anaerobic bacterial components of the upper respiratory autoflora of Apollo astronauts was found to be stable after space flight of up to 295 h.


Membrane filter procedure for enumeration of Vibrio parahaemolyticus. A membrane filtration procedure has been developed for the enumeration of Vibrio parahaemolyticus in marine waters. Background microbial growth on the primary medium was decreased through the use of sodium cholate and copper sulfate, high pH, 3% NaCl, and an elevated incubation temperature. A series of in situ tests was employed to obviate the picking of colonies for identification; thereby, the enumeration of V. parahaemolyticus was accomplished within 30 h. Confirmation of typical colonies approached 95%. Relative to immediate plating on brain heart infusion agar spread plates, the recovery of V. parahaemolyticus cells suspended in phosphate-buffered saline or in seawater held for 24 h at 4 to 6 degrees C was about 90%. Assay variability did not exceed that expected by chance. Recoveries of V. parahaemolyticus from coastal and estuarine surface waters exceeded those obtainable by other methods examined.


Inactivation of Clostridium botulinum toxin by ruminal microbes from cattle and sheep. Toxin from Clostridium botulinum type C was rapidly inactivated during incubation in vitro with ruminal contents from either a cow or a sheep. Fractions of ruminal contents from which cells had been removed by high-speed centrifugation did not inactivate toxin. Inactivation was associated with fractions containing bacteria, whereas fractions containing protozoa and relatively few bacteria were much less active. This activity may help explain the relatively greater tolerance by ruminants to oral doses of botulinum toxin than to toxin administered by other routes. The results are also pertinent to assays for botulinum toxin from gastrointestinal samples obtained postmortem.


Bacteria within ovules and seeds.

Bacteria within ovules and seeds. Surface-sterilized ovules and seeds of 27 species of plants were cultured in the water of syneresis of a nutrient medium low in agar content. Bacteria were obtained from 30% of the ovules, 15% of the seeds of herbaceous plants, 16% of the seeds of woody plants, 5.4% of the overwintered noncereal seeds, and 13.5% of overwintered cereal seeds. In no instance did every ovule or seed of a plant species contain bacteria. No bacteria were obtained from the hard, waxy seeds of mimosa or yellowwood. They were not obtained from ovules with unbroken coats or from seeds with coats that were not ruptured during the swelling of the seed. Only one species of bacteria was recovered in 93% of the instances in which bacteria were obtained. Bacteria were obtained from seeds that were embedded in the acidic parenchyma of the lemon or surrounded by the thickened flesh of the cucurbits. The bacteria were distributed among 19 genera and 46 species. The species isolated in greatest numbers were Bacillus megaterium, B. cereus, Erwinia herbicola, Flavobacterium devorans, and Pseudomonas fluorescens. Bacteria recovered less frequently were in the genera Achromobacter, Acinetobacter, Alcaligenes, Brevibacterium, Corynebacterium, Cytophaga, Leuconostoc, Micrococcus, Nocardia, Proteus, Streptococcus, Streptomyces, and Xanthomonas. Members of 11 genera and 15 species of bacteria were isolated once.


Ultrastructural examination of Aeromonas cultured in the presence of organic lead. Aeromonas sp. will methylate trimethyl lead acetate (Me3PbOAc) to volatile tetramethyl lead (Me4Pb). Examination of cultures grown in the presence of Me3PbOAc revealed no major irregularities between cells of the treated and untreated cultures. Some cells, however, showed evidence that intracytoplasmic materials had been leached from the cells. The lead-treated cells were interpreted to contain lead ions on the basis of energy-dispersive X-ray analysis.


Microbiological hydroxylation of carbons 18 and 19 in 9-oxo-13(cis and trans)-prostenoic acids. dl-9-Oxo-13 (cis and trans)-prostenoic acids were converted in high yields into their 18- and 19-hydroxy derivatives by cultures of Microascus trigonosporus. The structure elucidation of the microbial products is described.


Photochemotherapy of vitiligo. Use of orally administered psoralens and a high-intensity long-wave ultraviolet light system. A new light source that provides high-intensity ultraviolet light (UVA) (300 to 400 nm) to the entire body surface makes orally administered psoralen treatment of vitilligo with an artificial light practical. In the 26 patients studied, the degree of repigmentation with either trioxsalen (TMP) or methoxsalen (8-MOP) and high intensity UVA was at least as great as that with the same oral agents and sunlight. With artificial UVA and similar treatment conditions, the two psoralen derivatives were compared in the treatment of vitiligo; TMP stimulated repigmentation as well as 8-MOP and caused fewer side effects.


Dermatologic manifestations of Schistosomiasis mansoni. Schistosomiasis mansoni, a potentially severe disease that victimizes an appreciable number of US citizens in this hemisphere, shows cutaneous changes corresponding to various stages in the life cycle of the causative parasite within its definitive host. A transient pruritus or dermatitis, probably irritative, characterizes the stage of cercarial penetration. Urticaria, periorbital edema, and rarely a purpuric eruption may occur four to six weeks later, shortly after oviposition by adult worms, probably as an expression of hypersensitivity to ova and their products. Papulonodular lesions, similar to but not as devasting as those developing internally, may rarely appear months later at the perineum or distant cutaneous sites as a manifestation of granulomatous hypersensitivity to eggs and, very rarely, worms, accidentally carried there through collateral and anastomosing vascular pathways.


Skin capillary changes in early systemic scleroderma. Electron microscopy and "in vitro" autoradiography with tritiated thymidine. Skin biopsy specimens obtained from involved and noninvolved areas in a patient with early diffuse systemic scleroderma were processed for histology, electron microscopy, and "in vitro" autoradiography with tritiated thymidine. The affected area revealed cellular infiltrates around the eccrine sweat glands, consisting of plasma cells and lymphocytes. The capillaries showed thickening of the basement lamina, damage of endothelial cells, and obstruction of their lumens. However, in some vessels, endothelial cells were preserved and appeared in prophase. Autoradiography with tritiated thymidine showed a marked increase in endothelial and periendothelial cell labeling. Blood immunological studies revealed an increase in B-lymphocytes, IgG, and IgA and the presence of antinuclear and antismooth muscle antibodies.


Pacinian neurofibroma.

Pacinian neurofibroma. A 40-year-old woman developed a tender, greyish-white nodule of the index finger. Histologic examination disclosed mature and immature pacinian corpuscles.


Induction of glycosuria and hyperglycemia by topical corticosteroid therapy. A patient with psoriasis is described who had an abnormal response to the glucose tolerance test without other evidence of diabetes and then developed postprandial hyperglycemia and glycosuria during a period of topical administration of a corticosteroid cream, halcinonide cream 0.1%, under occlusion. A second patient with a similar glucose tolerance test result showed postprandial hyperglycemia when treated similarly with betamethasone valerate cream 0.1%. Two additional patients with midly abnormal responses to glucose tolerance tests showed no evidence of altered glucose metabolism when treated with halcinonide cream in a similar manner.


Malignant angioendothelioma.

Malignant angioendothelioma. We have seen six cases of malignant angioendothelioma of face and scalp. This condition occurs most commonly in older individuals and is rapidly progressing. Large areas of infiltration of the skin appear showing purpura and foci of superficial erosions. Internal metastasis and death may occur within three months to two years.


Coexistence of benign familial pemphigus and psoriasis vulgaris. The treatment of psoriasis vulgaris in a 67-year-old woman was complicated by the presence of an acantholytic diathesis. The clinical and histologic evidence showed that the patient had an atypical phenotype of familial benign chronic pemphigus (FBCP) as well as psoriasis. Consideration of the possible effects of psoriasis and FBCP on each other may help explain some of the typical features noted in this patient.


Disseminated granuloma faciale.

Disseminated granuloma faciale. Granuloma faciale is a well-defined entity that almost exclusively involves the face, although it has been reported in extrafacial locations. The infrequent reports of extrafacial lesions may reflect the inconspicuous nature of extrafacial lesions or a failure to specifically examine the patient for such lesions.


Disorders of phagocyte function.

Disorders of phagocyte function. An increasing number of phagocytic defects with cutaneous manifestations and signs in humans are being reported. With the increasing availability of phagocyte assays, detection of phagocyte defects will allow us to dissect the component events and more clearly understand the central role of the phagocytic leukocyte in host defenses of the skin.


Isolation and physicochemical characterisation of the DNA from normal human skin and psoriatic scales. In psoriatic parakeratosis preserved nuclei are found in the epidermal horny layer. The question arises, whether the components of the nuclei remain unchanged. Thus we isolated and purified the DNA of psoriatic scales and normal skin. Comparing the melting points and circular dichroism of both DNAs no significant difference could be detected. These data indicate the same guanine-cytosine content as well as comparabel helical compositions of the isolated DNAs.


Influences of retinoic acid and retinoid on skin metabolism. Investigations of oxygen consumption and enzymatic activities of human skin. All-trans retinoic acid and its derivative retinoid, two new compounds with expanding therapeutic spectrum in dermatology, were investigated in biochemical assays. Both substances provoke an increase in oxygen consumption of rat skin whereas in human skin only retinoid was found active in this respect. In resting yeast cells, both substances failed to exert any significant influence on oxygen consumption.--Pure G-6-PDH was inhibited by retinoic acid and retinoid in concentrations as low as 5 mug/ml. In human skin homogenates, LDH-, GAPDH-, and G-6-PDH-activities were inhibited by retinoic acid whereas GOT-, LAP-, and ALD-activites remained practically unchanged following an incubation with retinoic acid in concentrations between 1 and 100 mug/ml for 60 min.--The data collected in this study were briefly discussed with regard to the use of retinoic acid and its derivatives in psoriasis.


Measurement of dermal thickness with the Harpenden skinfold caliper. A simple method of determining skin thickness using the Harpenden Skinfold Caliper is described. Using this technique the atrophy caused by the topical application of Fluocinolone acetonide in normal volunteers has been detected. As a comparison the skin thickness was also measured in the same individuals by an established x-ray technique. Not only was a similar degree of atrophy observed but also a high degree of correlation (r=0.82, n=32, P less than 0.001) was found between the values obtained with both techniques.


Metabolism of testosterone 4-14C in skin of castrated rats. Testosterone metabolism was studied in the skin and preputial glands of normal and prepuberally castrated male rats during the 2nd hair cycle. In catagen-telogen the 17-beta-OHSDH of dorsal skin was higher in castrated than in control animals; 5-alpha-reductase instead, remained unchanged through out the hair cycle. Also in the preputial glands of castrated rats 17-beta-OHSDH was higher than in normal rats. So was 5-alpha-reductase. A possible direct control of a substrate, like Testosterone, and/or of a hypophyseal tropin, like prolactin, on enzymes that direct the metabolism of steroids in target tissues is conceivable.


Studies on rat hair cultures. IV. The effects of testosterone and dihydrotestosterone. By means of two different quantification techniques the Authors were able to show that the addition of increasing concentrations of testosterone to the medium of hair-cultures simultaneously provokes an increased volume of epidermis as well as of hair-follicles and a better differentiation of hair follicles. The addition of dihydrotestosterone, on the contrary, does not induce any change.


[Erythropoietic protoporphyria: porphyrin content of a gall-stone (author's transl)]. In the case of a 48 year old woman with characteristic signs of erythropoetic protoporphyria, a solitary gall-stone which had persisted over a period of 10 years was removed. Porphyrin-concentration of this gall-stone was found to be 22.6 mcg/g, which is almost twenty times the concentration of other cholestrol-stones. Besides protoporphyrin, porphyrins with a higher degree of carboxylation were discovered in four different samples by thin layer chromatography. It is postulated that the increased bile-concentration of protoporphyrin in the liver causes the cristallisation of cholestrol and the formation and growth of gall-stones. The biochemical finding of porphyrins with a higher degree of carboxylation indicates that the porphyrins of the gall-stone may not only come from hemolysed erythrocytes but possibly also from metabolites of disturbed hepatic porphyrin biosynthesis.


Langerhans cells in human apocrine ducts. Electron microscopic observations revealed for the first time a few number of Langerhans cells within the intradermal apocrine duct of the normal human axillary skin. In many respects the fine structural features of Langerhans cells were noted to be identical with those described in the epidermis. Our present results suggest that Langerhans cells could be a stable and constant cellular constituent for the normal apocrine ducts. The significance of this presence of Langerhans cells remains to be investigated.


The effect of X-ray irradiation upon the epithelial melanin unit of the hair bulb in hooded rat. A marked increase in the quantity of pigment in the upper bulb, penetration of melanosomes into the papillae and vacuolisation of the bulb keratinocytes occurred as early as 4--6 h after irradiation with a dose 600--1200 R. Afterwards considerable hyperpigmentations appeared in the proximal segments of dystrophic and catagen hairs and melanin was found in the catagen columns and beyond them. In most animals within 4--6 h after irradiation occurred a distinct vacuolisation of the Malpighian layer and the granular layer became more prominent.


Adenyl-cyclase activity in rat-hair-cycle. In the skin of rat, during telogen phase, a high adenyl-cyclase activity coincides with maximal catecholamines content, minimal histamine level and blocking of mitoses in epithelial cells. These events suggest that in telogen the control of mitotic activity in rat hair follicles may operate through a block of G1 cells as already suggested for epidermal cells.


Vascular changes of chronic lupus erythematosus. Electron microscopic studies. Vascular changes in the course of chronic lupus erythematosus were mainly characterized by a large, yet varying degree of proliferation of endothelial cells. In all cases examined the presence of tubular forms similar to paramyxoviruses was noted. The vascular basal membrane was noted to be either widened, segmentally separated or absent in places. Collagen fibres in these cases adhered directly to the endothelial cells. In the nuclei of endothelial cells of the infiltrate, "nuclear bodies" could be observed. In area surrounding capillaries oval concentrations of fibrilles 80 A in diameter were noticed.


Scleroderma in childhood.

Scleroderma in childhood. Scleroderma in childhood is a rare but confusing disorder. Systemic and diffuse disease do occur but are uncommon. Much more common are local lesions of different types which can be multiple; these are often associated with joint symptoms and the development of joint contractures and tendon contractures due to nodule formation. In such circumstances the condition mimics juvenile chronic polyarthritis (Still's disease). A third, rare variant, sclerodermatous fasciitis, has also been described in one young patient.


Review of septic arthritis throughout the antibiotic era. 134 patients with septic arthritis who have been treated at the Nuffield Orthopaedic Centre during a 30-year period have been reviewed. There has been little change in the overall incidence during the last 20 years, but recently the disease has become more common among the elderly and patients tend to be less ill on presentation. The problems and necessity of rapidly establishing a diagnosis are stressed. Overall, 70% attained a good result though infection in infants' hips and all joints in the elderly carried a poor prognosis. Once a good result was achieved the joint did not deteriorate with the passage of time.


Psoriatic arthritis. Follow-up study.

Psoriatic arthritis. Follow-up study. 227 patients with psoriasis and various forms of arthritis have been kept under review. Psoriasis and inflammatory arthropathy was present in 168 patients, of whom 94 have been followed up for more than 10 years. An arthritis indistinguishable from rheumatoid disease was present in 78%, distal joint arthritis in 16-6%, and deforming arthritis in 4-8%. There was a female predominance in the sex ratio of patients, although males predominated in the distal joint group (male:female 1-5:1). The peak age of onset was between 36 and 45 years, although in the deforming group the arthritis began before the age of 20 three times as commonly as it did in the indistinguishable group. Onset was acute in nearly half of the patients. At onset the distal joints were affected in one-third of the distal joint group. A synchronous onset of skin and joint changes was uncommon. Skin lesions usually preceded the arthritis but occurred after onset in 16%. Apart from in the deforming group, the arthritis was mild, judged by the number of admissions to hospital for treatment of the joint disease, and the time off work. Deterioration clinically and radiographically occurred in only a small portion of the distal joint and indistinguishable groups. Antimalarial drugs have been used in 7 patients, with deterioration of the skin condition in 4. Uveitis occurred particularly in the men of all three groups, but was most frequent in those with deforming arthritis. A family history of psoriasis was obtained in 26% of first-degree relatives and 13% of second-degree relatives. A history of polyarthritis was most common in patients in the deforming group. The sheep cell agglutination test was negative in the majority, but was positive in 16% of the indistinguishable group, fluctuating in a further 10%. A small number of joints only deteriorated radiographically (10% of the distal and indistinguishable groups). The men in the distal group showed greater radiographic changes and more deterioration in the terminal interphalangeal joints of the fingers than the women. Similarly they showed more deterioration of the metatarsophalangeal joints than the women. 18 patients died, one with gastric haemorrhage resulting from treatment of exfoliative psoriasis with immunosuppressive therapy, and 2 from bronchopneumonia thought to be related to immobility caused by the arthritis.


Periarthritis of the shoulder. I. Aetiological considerations with particular reference to personality factors. 186 patients with periarthritis of the shoulder have been studied. The sex ratio was female:male, 1-52:1. The peak age of onset was 54-59 years in both sexes. Over 40% of the patients were referred to the clinic after 6 months had elapsed from the time of onset of the disease. The right shoulder was more frequently involved than the left, particularly in the men. One shoulder only was affected in 75% of patients. There was frequently a previous history of 'rheumatism' before the episode of periarthritis. In one-third of the women 'nonspecific rheumatism' had occurred. Cervicobrachial pain and a previous episode of shoulder pain had occurred more often in the women. There were a number of associated diseases, ischaemic heart disease, thyroid disease among women, diabetes among women, hemiplegia, pulmonary tuberculosis, chronic bronchitis, and epilepsy. Acute trauma was rarely a precipitating factor. Manual workers were more frequently seen than sedentary workers in the sample, and there were more in the sample than in the general population of Leeds. The general psychological background was no different from a control group. The Maudsley Personality Inventory gave no different results among patients with periarthritis of the shoulder than among a control group and among the general population. It is suggested that there is no evidence in this study for a 'periarthritic personality'. It is suggested that the cause of periarthritis of the shoulder is likely to be related to chronic trauma occurring in an age range when changes in connective tissue are occurring. Certain associated diseases may predispose the patient to this disorder.


Periarthritis of the shoulder. II. Radiological features. A group of 113 women and 73 men with periarthritis of the shoulder have been studied in detail. Electromyography showed 4 patients with neuralgic amyotrophy who had been referred for the shoulder study but were excluded on this basis. Nerve conduction studies showed little difference between the periarthritic group and a control group, apart from some reduction in amplitude and potential, and in women a suggestion of an increased latency. Duration of the action potential was equal. 6 patients had an undoubtedly long latency compatible with median nerve compression. Degenerative changes were found in the glenohumeral joints in 6-9%. Degenerative changes were found at the acromioclavicular joints in 31% of the men and 44% of the women. Calcification was found around 11 of the shoulder joints. There was frequently a previous history of 'rheumatism' before the episode of periarthritis. In one-third of the women 'nonspecific rheumatism' had occurred. Cervicobrachial pain and a previous episode of shoulder pain had occurred more often in the women. Arthrography was performed in 7 patients and there was a reduction in volume of material that could be injected in only one patient. There was obliteration of the axillary fold in that patient, and a torn capsule in a patient who had previously been manipulated. Lateral cervical spine x-rays were compared with films from an epidemiological survey. The disc space/vertebral body height ratio was taken, overcoming the magnification effects shown by technical alterations in the method of taking films. Good intra- and interobserver correlation was found for this ratio, but not for the width of the canal. There was no difference in the disc/body ratio between the periarthritic and control group in the upper cervical region. In the C5/6 and C6/7 intervertebral discs there was evidence of more disc degeneration in the periarthritic group. The differences from the control group were not great because of the high incidence of disc space narrowing and osteophytosis after the age of 45 years in the general population.


Avascular necrosis in SLE. An apparent predilection for young patients. Recent reports of avascular necrosis (AN) in systemic lupus erythematosus (SLE) have suggested that its occurrence may be most frequent in young patients. In our population of 99 patients with SLE, 7 young patients have developed AN. Patterns of prednisone therapy had no apparent relationship to the development of AN. AN may become apparent in patients who have relatively inactive lupus, when increased physical activity precipitates articular collapse. A diagnosis of AN should be considered in young patients with localized joint pain.


Detection of IgG rheumatoid factor by concanavalin A treatment and complement fixation with IgG rheumatoid factor. Concanavalin A (Con A) froms precipitates with carbohydrate-rich protein such as IgM, IgD, IgE, and IgA. Since IgG contains little carbohydrate and does not react with Con A, the activity of IgG-rheumatoid factor (RF) can be measured in the supernate of the Con A-treated serum. When the latex fixation test (LFT) and the sensitized sheep cell agglutination test (SSCA) were perfromed in the supernate for the detection of IgG-RF, LFT was positive in 32-1% of sera, out of 137 sera originally positive for LFT, and SSCA was positive in 18-5% of sera, out of 119 sera originally positive for SSCA. IgG-RF exhibited lower complement fixing ability than IgM-RF and correlated with agglutination titres of IgG-RF, while the CH50 of the original serum did not correlate with haemolytic activities of either IgM-RF or IgG-RF.


Serum immunoreactive gastrin in rheumatoid arthritis. Further observations on its identity, clinical specificity, and relationship to gastric function. Serum immunoreactive gastrin is raised in some patients with rheumatoid arthritis (RA). In this paper paired samples taken within 30 minutes of each other show that this phenomenon is reproducible. Dilution curves show identity between gastrin from RA patients and from patients with no RA, and the raised immunoreactive gastrin concentration is demonstrable in patients who do not have chronic atrophic gastritis and in whom both basal and stimulated acid output concentrations are normal. Samples of gastric mucous membrane obtained from the body of the stomach and gastroscopy under direct vision in 18 patients with raised serum immunoreactive gastrin concentrations were normal.


Seropositive rheumatoid arthritis associated with decreased diffusion capacity of the lung. Sixty-two patients with classical or definite rheumatoid arthritis were subjected to lung function analysis. The various parameters--spirography, plethysmography, blood gas analysis, measurement of lung compliance, and diffusion capacity--were correlated with duration and stage of disease, and with rheumatoid factor titres. A statistically significant correlation was found to exist between Rose-Waaler titre and specific diffusion capacity. Similar results between Rose-Waaler titre and lung compliance, however, were not statistically significant.


Clinical diagnosis of ankylosing spondylitis in women and relation to presence of HLA-B27. Thirty-nine Caucasian women with definite or probable ankylosing spondylitis were tissue typed and the radiographic and clinical features were correlated with the presence of B27 (formerly W27). This investigation showed that the same strong positive correlation observed in men obtains in women between B27 and unequivocal radiographic changes. As such changes develop slowly in women, clinical and laboratory features were identified which were sufficiently characteristic to enable the diagnosis to be reached in advance of decreased spinal mobility. Immobility pain and stiffness and bilateral sacroiliac pain are the most characteristic features, but additional support is provided by the presence of any of the following: onset by age 30, a raised sedimentation rate, peripheral joint involvement, circumthoracic pain, family history, and iritis.


HLA frequencies in less common arthropathies. There was no increased incidence of HLA-B27 in patients suffering from rubella arthropathy, when compared to both the Westminster controls and a group of patients with arthritis secondary to dysentery who nearly all possessed this allele.


Osteoarthrosis in a rural South African Negro population. The prevalence and distribution of osteoarthrosis has been studied in a South African Negro population. One or more joints were affected in 60% of the males and 48% of the females, compared with a prevalence of 55% in males and 63% in females in a comparable English population. Multiple osteoarthrosis was significantly less common in the African than in the English population, the difference here being greatest in females. Clinical Heberden's nodes were also very infrequent in the African population. However, the Tswana males had significantly more osteoarthrosis of the metacarpophalangeal and proximal interphalangeal joints than was encountered in English males. This is attributed to the traumatic effect of hard manual work which is carried on into old age among most African populations.


Familial Felty's syndrome.

Familial Felty's syndrome. A family is described in which the mother and 2 of the 5 children had Felty's syndrome, a pattern of inheritance suggesting a dominant defect and one which has not previously been reported. The family is also of interest in that the other sib had rheumatoid arthritis.


Measurement of circumference of the knee with ordinary tape measure. The circumference of the knees and thighs at three locations was measured in 10 patients on two consecutive occasions by three observers. Analysis of the results for interobserver, intraobserver and among-patient variation established that a change in circumference noted by different observers on two different days is significant if it exceeds 1-5 cm at the midpatella, 2-7 cm at 7 cm above, and 3-5 cm at 15 cm above the patella. If a single observer performs both measurements, the change need exceed only 1-0, 2-0, and 2-7 cm, respectively, to be significant.


The accuracy of predicting lymph nodes metastases in malignant melanoma by clinical examination and microstaging. Since 1971, a prospective treatment regimen for primary cutaneous malignant melanoma performed by a single clinician has revealed the following early observations: 1) A significantly higher number of females with level II disease; 2) No recurrences or metastases to date in 29 patients with level II lesions treated by appropriate surgery; 3) The apparent clinical predictability of lymph node metastases in the group microstaged at level III. 4) An inability to predict lymph node metastases (or their delayed development) in patients with level IV disease; 5) A correlation between lymph node metastases and the development of disseminated disease.


Changing clinical, pathologic, therapeutic, and survival patterns in differentiated thyroid carcinoma. Records of 792 patients with differentiated thyroid carcinoma seen at the Lahey Clinic Foundation over a 40-year period were analyzed; 631 patients had a minimum followup period of 15 years. Differentiated types currently constitute nearly 90% of thyroid carcinomas. The clinical presentation has improved substantially through the years, and the results of treatment generally have improved. The per cent of patients with primarily incurable and locally unresectable disease or distant metastases has decreased from 7% before 1950 to 1% currently, and this group resulted in almost one third of the total fatalities and one half of fatalities within the first 5 years after treatment. Clear relationships were demonstrated between older age, men, extraglandular extension, blood vessel invasion, major capsular involvement, multifocal disease, and higher mortality rates. Lymph node metastases were found to exert a protective effect in all categories of disease analyzed, and this effect was directly related to the number of lymph node metastases present such that no deaths occurred in those patients who had more than 10 node metastases. Surgical treatment recommended is subtotal thyroidectomy for patients at high risk of death from disease as defined by combinations of age, sex, and extraglandular extension. Patients at low risk or with small carcinomas can be treated satisfactorily by lobectomy. Lymph node resections should be of a limited type or a modified neck dissection and should be performed only therapeutically. No improvement, as judged by mortality or recurrence rates, could be demonstrated by the use of radio therapy after surgery, and its use should be discouraged. Thyroid hormone administered for suppression of endogenous thyroid-stimulating hormone production improved mortality rates significantly in patients with papillary and mixed forms of carcinoma in all age groups but did not affect survival in patients with follicular carcinoma of the thyroid.20


Operative correction of pectus excavatum: an evolving perspective. From 1949 to 1975, 220 children have undergone surgical reconstruction of pectus excavatum using a variety of operations on our Pediatric Surgical Service. The first 183 were previously reported and have had subsequent, careful followup evaluation. From 1970 to 1975, an identifiable group of 45 children had a standard operation, a modified Ravitch repair, with the addition of a three-point or tripod internal fixation technique for support of the sternum. These children have all obtained satisfactory reconstruction without prosthetic support of any kind. We have thus avoided the possible danger of foreign material within the chest and have obviated the need for another procedure to remove a supporting stent. The two groups have been analyzed and compared with respect to age distribution, postoperative complications and end results to see if we could detect any trends in the evolving management of children with this condition. The main indications for surgical correction remain cosmetic and postural. Specific trends which have emerged from our experience include an increased percentage of patients between 3 and 8 years of age (average 5.8 years); a decreased need for blood transfusion (10%); a near resolution of postoperative seromas with the use of substernal and subcutaneous suction drains; and in the last 45 children, a 100% excellent or acceptable result to date. We feel that age selection is an important factor in the improved operative result and in the emotional impact on these young patients. Eighty per cent of the children in the recent series were between 3 and 8 years of age at the time of repair. On the basis of this experience, we now feel confident in recommending our standardized operation for pectus excavatum at an elective age of 4 to 6 years.


Craniofacial surgery: present and future. The possibilities for radical craniofacial restructuring have increased dramatically in the past 6 years with the development of craniofacial surgery. The field developed from a background of patients with major craniofacial birth defects allowing orderly planning and expansion to correction of a multitude of other craniofacial structural problems. The procedures concentrate upon changing the skeletal structures using extensive subperiostial dissection of soft tissue, and adding bone to fill in areas of deficiency. There are three grades of complexity in craniofacial procedures. After extensive soft tissue sub-periostial stripping about the orbits and upper face, the simplest form consists of onlay bone grafts. The next most complicated involves osteotomies to shift the face into a more normal position. In its most complicated form, abnormal proportions of bone are removed and the orbits or cranium are shifted into a new or normal position. We have had experience with 69 patients since September, 1972. Thirty-six have had intracranial procedures. Infection has been the most serious problem, and there have been no instances of death or blindness. A number of lesser problems occur. Future applications of craniofacial surgery are appearing with great frequency as more experience is gained with its uses. It has particular application in acute and late reconstruction of patients with traumatic defects about the face. Preventive osteotomies are an area with great potential, by releasing stenotic areas of bone and allowing the developing brain to mold the upper face and orbits. There is also applicability in surgery of tumors about the craniofacial structure and in cosmetic surgery.


Further experience with peritoneo-venous shunt for ascites. A specially devised pressure-sensitive valve forms the basis for a new peritoneo-venous shunt operation which delivers ascitic fluid continuously into the venous system. It is effective in ascites attributed to different causes. The procedure is simple and brings a long lasting relief with recovery in strength and nutrition and improved kidney function. Hepatorenal syndrome in ascites is reversed.