17ß-Estradiol (E-2) administration to male (NZB × SWR)F1 mice results in increased Id(LN)F1-reactive memory T-lymphocytes and accelerated glomerulonephritis.

While it has been shown that estradiol treatment accelerates the onset of lupus nephritis with autoantibody production and kidney damage in both male and female lupus-prone mice, the specific mechanism(s) involved are unknown. Our previous work has shown that alterations in Id(LN)F(1)-reactive T cells and Id(LN)F(1)+ antibodies correlated closely with the onset of autoimmune nephritis in female F(1) progeny of SWR and NZB (SNF(1)) mice, supporting a critical role for the Id(LN)F(1) idiotype in the development of disease. Since male SNF(1) mice normally do not develop nephritis, we tested whether administration of 17ß-estradiol (E-2) to male SNF(1) mice would increase Id(LN)F(1) IgG levels and autoreactive T cells, and further, induce nephritis. We found that E-2-treated male SNF(1) mice developed nephritis with the same time course and mean survival as normal female SNF(1) mice. Moreover, it appeared that the mechanism involved increased serum Id(LN)F(1)(+)IgG and its deposition in kidney glomeruli, preceded by a striking twofold increase in T-lymphocytes expressing the memory phenotype (CD44(+)CD45RB(lo)) predominantly in the Id(LN)F(1)-reactive T-cell population. In addition, we noted that cells with this phenotype were increased in the nephritic kidneys of treated mice, suggesting a direct involvement of those cells in the renal pathology. E-2 treatment also induced increased numbers of pathogenic Id(LN)F(1)+ antibody-producing B cells and elevated presentation of pathogenic Id(LN)F(1)+ peptide. Taken together, these results suggest a mechanism of E-2-induced acceleration of autoimmune disease in lupus-prone mice may involve expansion of autoreactive idiotypic T and B-cell populations.

Effects of valproic acid on organic acid metabolism in children: a metabolic profiling study.

Young children are at increased risk for valproic acid (VPA) hepatotoxicity. Urinary organic acid profiles, as a surrogate of mitochondrial function, were obtained in children 1.9 to 17.3 years of age (n = 52) who were undergoing treatment with VPA for seizure disorders. Age-matched patients receiving treatment with carbamazepine (CBZ; n = 50) and healthy children not undergoing treatment (n = 22) served as controls. Age-related changes in organic acid profiles were observed in all three groups. Although the untreated and CBZ control groups were indistinguishable from each other with respect to the principal-component analysis (PCA) score plots of the subjects, a distinct boundary was apparent between the VPA and each of the control groups. Interindividual variability was observed in the VPA-induced alterations in endogenous pathways corresponding to branched-chain amino acid metabolism and oxidative stress. The data suggest that more detailed metabolomic analysis may provide novel insights into biological mechanisms and predictive biomarkers for children at highest risk for serious toxicity.

The potential for discovery and development of improved aminoglycosides.

Following the development of amikacin, pharmaceutical companies made intensive efforts to find even more potent and broader-spectrum aminoglycosides. This effort was justifiable in view of the fact that over the preceding decade, these agents, because of their unique properties, had proven to be the primary weapons in the therapeutic armamentarium for the treatment of seriously ill patients. Since the toxicities associated with the aminoglycosides were beginning to limit their use in general medicine, researchers ultimately shifted their emphasis from probing for higher-potency, broader-spectrum agents to finding those with a reduced potential for toxicity. This article addresses the issue of whether superior aminoglycoside derivatives will reach the marketplace in the future. A comparison is made of several key properties of virtually all aminoglycosides that have reached an advanced preclinical development stage, gone into the clinic, or been registered for commercial use over the past 10 years. The following parameters are used for comparisons with already marketed aminoglycosides: antibacterial potency, as measured by relative minimum inhibitory concentrations for 50 percent of the strains tested, against wild-type Pseudomonas aeruginosa; degree of resistance to inactivation by microbial enzymes; and potential for toxicity utilizing comparative acute intravenous lethal doses for 50 percent of the population in mice, values that appear to predict the maximum recommended daily doses in man. An assessment of a number of compounds, including three structurally related to gentamicin, two to sisomicin, two to kanamycin A, three to kanamycin B, and two to fortimicin, revealed that none had overall properties superior to those already being utilized commercially. In no case did a compound prove to be less toxic, and in many instances, the antibacterial potency of the newer agents was lower than that exhibited by the older aminoglycosides. Some increase in resistance to inactivating enzymes was seen, but only BB-K 311 proved refractory to more enzymes than did amikacin. In view of this and the fact that no new agents of promise have moved into the development stage during the past five years, it seems safe to say that the current armamentarium of aminoglycosides is all that will be available for use in the foreseeable future.

Structural analysis of natural textures.

Many textures can be described structurally, in terms of the individual textural elements and their spatial relationships. This paper describes a system to generate useful descriptions of natural textures in these terms. The basic approach is to determine an initial, partial description of the elements using edge features. This description controls the extraction of the texture elements. The elements are grouped by type, and spatial relationships between elements are computed. The descriptions are shown to be useful for recognition of the textures, and for reconstruction of periodic textures.

Antibacterial activity of phosphanilic acid, alone and in combination with trimethoprim.

We explored the antibacterial activity of phosphanilic acid (P), an analog of sulfanilic acid, alone and in combination with trimethoprim (T; TP, 1:5) with sulfamethoxazole (S) and co-trimoxazole, the combination of this sulfonamide with trimethoprim (TS, 1:5) as the reference. P resembled S in spectrum but, in addition, had significant activity against Pseudomonas aeruginosa. The overall frequency and degree of synergism with TP were lower than with co-trimoxazole. P, like S, was strongly affected by changes in inoculum size and was not bactericidal. P was well absorbed parenterally but not orally in mice. Despite low (but prolonged) blood levels, P, given orally to mice, was effective in treating infections caused by P. aeruginosa. However, against most experimental infections the therapeutic effectiveness of P, as well as that of TP, administered either intramuscularly or orally was unimpressive. Based on in vivo data, the therapeutic application of P or TP would appear to be limited.

Mutational resistance as the mechanism of acquired drug resistance to aminoglycosides and antibacterial agents in Mycobacterium fortuitum and Mycobacterium chelonei. Evidence is based on plasmid analysis, mutational frequencies, and aminoglycoside-modifying enzyme assays.

Possible mechanisms of drug resistance of Mycobacterium fortuitum and Mycobacterium chelonei to antibacterial agents were investigated. Single-step mutational frequencies were low (generally less than or equal to 10(-7] for cefoxitin, doxycycline, erythromycin, and sulfamethoxazole and relatively high (10(-4) to 10(-7] for kanamycin and amikacin. Aminoglycoside-susceptible strains of both species contained an aminoglycoside acetyltransferase (3)-III or IV. No additional enzymes were seen with laboratory or clinically acquired aminoglycoside resistance. Plasmids of several sizes were present in some susceptible isolates of both species, but acquired resistance was not associated with a change in the apparent size or number of these plasmids. Isolates with acquired resistance to amikacin were resistant to the other 2-deoxystreptamine aminoglycosides but showed little or no change in minimal inhibitory concentrations to streptomycin, suggesting either a difference in cellular uptake between the 2 groups of drugs or, more likely, different binding sites on the ribosome. In 59 patients treated with 63 courses of therapy with a single agent for 1 month or longer, the development of resistance was observed only twice (3%). Both isolates had high mutational frequencies (10(-4) and 10(-5]. These studies support mutational resistance as the mechanism of acquired resistance to antibacterial agents in M. fortuitum and M. chelonei.

Comparison of a new cephalosporin, BMY 28142, with other broad-spectrum beta-lactam antibiotics.

BMY 28142, a new broad-spectrum semisynthetic cephalosporin, was evaluated in vitro and in vivo in comparison with ceftazidime, cefotaxime, moxalactam, and cefoperazone. The activity of BMY 28142 compared favorably with the activities of the other compounds against both Pseudomonas aeruginosa and Staphylococcus aureus and was somewhat greater against members of the family Enterobacteriaceae. The influence of inoculum size on MICs of BMY 28142 was small for most of the isolates tested, except Enterobacter species. With Enterobacter strains, a marked inoculum effect was found with all of the compounds, and the effect was more pronounced in broth than agar. Still, MICs of BMY 28142 in broth did not exceed 16 micrograms/ml. Of 37 Enterobacteriaceae strains resistant to one or more of the comparison beta-lactams, none were resistant, at a low inoculum size (10(4) CFU), to BMY 28142, compared with 3 for moxalactam, 18 for ceftazidime, 23 for cefotaxime, and 34 for cefoperazone; at an inoculum size of 10(6) CFU, the number of resistant strains was 12, 17, 25, 34, and 37, respectively. Binding to human serum proteins approximated 19%. Recovery of 73% of the drug in mouse urine indicated good bioavailability. The in vitro profile was sustained in vivo by the results obtained with experimental infections in mice. BMY 28142 was as effective as ceftazidime against systemic infection with P. aeruginosa and as effective as cefotaxime against systemic infection with S. aureus. Overall, infections with 18 of 20 strains representing nine genera were responsive to BMY 28142 at doses equivalent to or lower than those of the most effective of the comparison compounds.

Relaxation matching techniques-a comparison.

Many different relaxation schemes have been proposed for image analysis tasks. We have developed a general matching procedure for comparing semantic network descriptions of images, and we have implemented a variety of relaxation techniques. An automatic segmentation and description system is used to produce the image representations so that the matching procedures must cope with variations in feature values, missing objects, and possible multiple matches. This environment is used to test different relaxation matching schemes under a variety of conditions. The best performance (of those we compared), in terms of the number of iterations and the number of errors, is for the gradient-based optimization approach of Faugeras and Price. The related optimization approach of Hummel and Zucker performed almost as well, with differences primarily in difficult matches (i.e., where much of the evidence is against the match, for instance, poor segmentations). The product combination rule proposed by Peleg was extremely fast, indeed, too fast to work when global context is needed. The classical Rosenfeld, Hummel, and Zucker method is included for historical comparisons and performed only adequately, producing fewer correct matches and taking more iterations.

Presence of aminoglycoside acetyltransferase and plasmids in Mycobacterium fortuitum. Lack of correlation with intrinsic aminoglycoside resistance.

Isolates of the 3 biovariants of Mycobacterium fortuitum exhibited 3 patterns of resistance when tested against 9 aminoglycosides. Examination of cell lysates from the 3 groups revealed 15/15 isolates to contain an aminoglycoside acetyltransferase (AAC) resembling AAC (3)-III or (3)-IV found in bacterial species. The enzyme did not appear to confer resistance, as its activity did not correlate with any pattern of resistance. The DNA extraction revealed plasmids in only 2 of 8 isolates tested, suggesting no relationship of plasmids to intrinsic aminoglycoside resistance or the presence of the AAC. These studies, combined with current knowledge of ribosomal resistance, suggest altered cellular transport or permeability as the mechanism of intrinsic aminoglycoside resistance in this species, although the patterns of resistance are different from those observed in other bacteria with nonenzymatic aminoglycoside resistance. This is the first demonstration of specific aminoglycoside-modifying enzymes among mycobacterial species and the first report of plasmids in M. fortuitum.

Basic design of beta-lactam antibiotics--cephalosporins.

Since the introduction of cephaloglycin and cephalothin as the first commercially available cephalosporin C derivatives, there has been a proliferation of new agents, predominantly injectables. These have provided compounds with increased potency, improved spectrum, and/or pharmacokinetic advantages. The nature of the modifications producing these changes is the subject of the present report. The pathway generally followed by chemists working on a nucleus suitable for modification is initially a combination of trial and error and application of analogies from related areas. Once a moiety conferring a desirable effect has been identified, it or its analogs will be widely utilized in an effort to achieve further improvements. The choice of derivatives to be made is appreciably influenced by potential patentability and the feasibility of synthesis. For oral cephalosporins, to achieve adequate intrinsic bioavailability, the 7 beta-side chain has almost invariably been found to require a primary amino group on the alpha-carbon (D-configuration). This has limited potential changes at the 7 beta-position and leaves the 3-position as the major site for introducing novel substituents. Among thousands of derivatives prepared, only a few have actually been developed for clinical use. For injectables, where oral absorption is not a factor, there are no such specific preferred entities for either the 3- or 7 beta-position. Because of this, cephalosporin derivatives containing a large and diverse group of substituents at these positions have been prepared. In addition, another substitution site was identified upon discovery of the cephamycins, antibiotics which differ from cephalosporins by the presence of a methoxy group at the 7 alpha-position. Substitution at this site confers remarkable beta-lactamase stability, but only methoxy has given acceptable potency. First generation injectables which have in the 3-position the naturally occurring acetoxymethyl group or other relatively simply substituents are very active against Gram-positive organisms and a few species of Gram-negatives. As new 3- and 7 beta-side chain moieties were studied, appropriate combinations yielded compounds active vs. a broader spectrum of Enterobacteriaceae and/or Pseudomonas aeruginosa or Bacteroides fragilis. Furthermore, dramatic changes in pharmacokinetics (longer half-lives) were achieved by both 3- and 7 beta-side chain modifications.(ABSTRACT TRUNCATED AT 400 WORDS)

Evidence for a chromosomal site specifying amikacin resistance in multiresistant Serratia marcescens.

We studied 21 strains of amikacin-resistant Serratia marcescens from three different U.S. cities, Twenty of the 21 strains contained conjugative R plasmids mediating gentamicin and tobramycin resistance. Amikacin-resistant S. marcescens from two cities predominated in protracted outbreaks. Conversely, the amikacin-resistant Charleston strain (serotype 02/03:nonmotile) was isolated from only four patients during an outbreak of gentamicin- and tobramycin resistant, amikacin-susceptible S. marcescens (serotype O19:O17). Five different representative amikacin-resistant S. marcescens, each containing a single conjugative plasmid, elaborated a nontransferable aminoglycoside (6')-N-acetyltransferase [AAC(6')] with similar substrate profiles in addition to other transferable aminoglycoside-modifying enzymes. One amikacin-resistant S. marcescens cured of its plasmid and another naturally occurring plasmid-free amikacin-resistant S. marcescens elaborated only AAC(6')-1. These data support the concept of a chromosomal locus in S. marcescens for AAC(6')-1 which commonly coexists with plasmid-mediated genes for aminoglycoside-modifying enzymes.

Locating structures in aerial images.

A technique for locating desired structures utilizing user specified information about properties of these structures and their relationships with other more easily extracted objects is described. An edge-based and region-based technique is used for scene segmentation. Experimental results of the processing of aerial pictures are presented.

Semantic description of aerial images using stochastic labeling.

This paper discusses the application of stochastic labeling to a general symbolic image description problem. A method used to compute initial likelihoods and compatibilities is described. It was derived from an earlier symbolic matching procedure, but was modified to provide the data needed for application of the labeling method. This labeling procedure differs from simpler ones, in that it minimizes a global criterion at each iteration. This technique is compared to other matching methods, and results on two scenes are presented.

Bactericidal activity of cefadroxil, cephalexin, and cephradine in an in vitro pharmacokinetic model.

Cefadroxil (Duricef, Mead Johnson and Company), resembles cephalexin and cephradine in spectrum of antibacterial activity but differs in human pharmacokinetic properties. Whether the latter are likely to affect activity in vivo was assessed by determining bactericidal activity against clinical isolates under conditions simulating the variation of drug concentration in the blood stream after an oral dose of 500 mg to adults. In this kinetic model, cefadroxil was more active than cephalexin or cephradine against Staphylococcus aureus, Streptococcus pneumoniae, Klebsiella pneumoniae, Proteus mirabilis, Haemophilus influenzae and one of two strains of Escherichia coli. The other strain of E. coli was virtually unaffected by the cephalosporins. S. pyogenes was equally susceptible to all three cephalosporins. Analysis of the results suggest that the pharmocokinetic properties of an antibiotic affect its activity in the blood stream, provided the susceptibility of the infecting organism is concentration-dependent within the range of drug concentration occurring in serum.

Comparative bactericidal effect of ceforanide (BL-S 786) and five other cephalosporins in an in vitro pharmacokinetic model.

The bactericidal activity of ceforanide was compared, in an in vitro kinetic model, with that of five other cephalosproins: cephalothin, cefazolin, cefamandole, cefuroxime, and cefoxitin. Cultures of various pathogens in 95% human serum were incubated for 12 hours in the presence of the cephalosporins whose concentrations were modified periodically-by addition of a concentrated solution of drug or dilution with unmedicated serum-in order to simulate the variation of antibiotic concentration in human blood after one-gram intramuscular dose. One Gram-positive strain and six Gram-negative strains were used. Bactericidal activity was assessed by monitoring changes in the number of colony-forming units. Tests showed that against Klebsiella pneumoniae, ceforanide was the most active of the six cephalosporins. Proteus mirabilis was more susceptible to ceforanide and cefuroxime than to the other compounds; Enterobacter cloacae to ceforanide, cefuroxime, and cefamandole; Escherichia coli to ceforanide, cefuroxime, cefamandole, and cefazolin. The number of viable cells of Staphylococcus aureus was reduced below detectable levels by all cephalosporins except cefoxitin. On the other hand, Providencia stuartii was virtually unaffected by all of the cephalosporins except cefoxitin.

Cefadroxil, a new broad-spectrum cephalosporin.

Cefadroxil is a new semisynthetic cephalosporin with a broad antibacterial spectrum and a high chemotherapeutic potential when administered orally. The inhibitory activity of this compound was similar to that of cephalexin and cephradine when tested against 602 clinical isolates on Mueller-Hinton medium. In the oral treatment of experimental infections of mice, cefadroxil was more effective than cephalexin against Streptococcus pyogenes, and comparably effective against Streptococcus pneumoniae, Staphylococcus aureus, and several gram-negative species. Administered orally to mice, at doses ranging from 25 to 100 mg/kg, cefadroxil attained peak concentrations in the blood similar to those of cephalexin. At a dose of 200 mg/kg, however, higher peak levels were noted with cefadroxil than with cephalexin. In regard to other properties which were investigated, the behavior of cefadroxil compared favorably to that of cephalexin.

Amikacin, an aminoglycoside with marked activity against antibiotic-resistant clinical isolates.

A total of 319 clinical isolates known to be resistant to one or more aminoglycoside antibiotics were tested for their susceptibility to 10 aminoglycosides. The percentages of isolates found by an agar dilution method to be susceptible were: amikacin, 83.7%; tobramycin, 41.4%; butirosin A, 33.2%; dideoxykanamycin B, 32.6%; gentamicin C, 27.3%; lividomycin A, 17.6%; neomycin B, 10.7%; paromomycin, 10.3%; kanamycin A, 10.0%; and ribostamycin, 7.2%. The effectiveness of the antibiotics was related to their degree of resistance to bacterial enzymes; e.g., of the nine enzymes known to inactivate antibiotics containing 2-deoxystreptamine, amikacin was affected by one enzyme, tobramycin by five, and gentamicin and kanamycin by six. Examination of cell-free extracts from the 52 strains resistant to amikacin revealed that only four contained the amikacin-inactivating enzyme aminoglycoside-6'-acetyltransferase, a finding indicating that this mechanism of resistance is rare. Other experiments suggest that most amikacin-resistant strains, which are almost invariably resistant to all aminoglycosides, lack the ability to accumulate effectively either amikacin or presumably the other antibiotics intracellularly.

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.