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D M Johnson

Publications and source records attributed to D M Johnson.

At least 55 records · Page 3Linked to original sources
PubMed1995

Progression and recapitulation of the chondrocyte differentiation program: cartilage matrix protein is a marker for cartilage maturation.

During endochondral bone formation, chondrocytes in the cartilaginous anlage of long bones progress through a spatially and temporally regulated differentiation program before being replaced by bone. To understand this process, we have characterized the differentiation program and analyzed the relationship between chondrocytes and their extracellular environment in the regulation of the program. Our results indicate that, within an epiphyseal growth plate, the zone of proliferating chondrocytes is not contiguous with the zone of hypertrophic chondrocytes identified by the transcription of the type X collagen gene. We find that the postproliferative chondrocytes which make up the zone between the zones of proliferation and hypertrophy specifically transcribe the gene for cartilage matrix protein (CMP). This zone has been termed the zone of maturation. The identification of this unique population of chondrocytes demonstrates that the chondrocyte differentiation program consists of at least three stages. CMP translation products are present in the matrix surrounding the nonproliferative chondrocytes of both the zones of maturation and hypertrophy. Thus, CMP is a marker for postmitotic chondrocytes. As a result of the changes in gene expression during the differentiation program, chondrocytes in each zone reside in an extracellular matrix with a unique macromolecular composition. Chondrocytes in primary cell culture can proceed through the same differentiation program as they do in the cartilaginous rudiments. In culture, a wave of differentiation begins in the center of a colony and spreads to its periphery. The cessation of proliferation coincides with the appearance of CMP and eventually the cells undergo hypertrophy and synthesize type X collagen. These results reveal distinct switches at the proliferative-maturation transition and at the maturation-hypertrophy transition during chondrocyte differentiation and indicate that chondrocytes synthesize new matrix molecules and thus modify their preexisting microenvironment as differentiation progresses. However, when "terminally" differentiated hypertrophic chondrocytes are released from their surrounding environment and incubated in pellet culture, they stop type X collagen synthesis, resume proliferation, and reinitiate aggrecan synthesis. Eventually they cease proliferation and reinitiate CMP synthesis and finally type X collagen. Thus they are capable of recapitulating all three stages of the differentiation program in vitro. The data suggest a high degree of plasticity in the chondrocyte differentiation program and demonstrate that the progression and maintenance of this program is regulated, at least in part, by the extracellular environment which surrounds a differentiating chondrocyte during endochondral bone formation.

Aggrecans↗
PubMed1995

Modifications for disk diffusion susceptibility testing criteria of clinafloxacin (CI-960, AM-1091, PD127371) and fleroxacin (Ro 23-6240, AM-833) following studies with a challenge panel of ciprofloxacin-resistant clinical isolates.

A collection of ciprofloxacin-resistant organisms (200 strains) was developed among 300 total test strains to "challenge" the initial interpretive criteria developed for clinafloxacin (formerly CI-960), fleroxacin (formerly Ro 23-6240, AM-833), and ciprofloxacin. Generated results indicate the necessity for modified criteria for disk diffusion tests (5-micrograms disks) as follows: for clinafloxacin, susceptible at > or = 21 mm ( < or = 1 microgram/ml) and resistant at < or = 17 mm ( > or = 4 micrograms/ml), or susceptible at > or = 19 mm ( < or = 2 micrograms/liter) and resistant at < or = 15 mm ( > or = 8 micrograms/ml); for fleroxacin, susceptible at > or = 16 mm ( < or = 2 micrograms/ml) and resistant at < or = 11 mm ( > or = 8 micrograms/ml); and for ciprofloxacin, resistant at < or = 17 mm > or = 4 micrograms/ml). These modifications maximize total absolute interpretive accuracy between the standardized test methods, especially minimizing the potential for false susceptibility (very major errors) when testing truly resistant isolates. The clinafloxacin spectrum was widest against these resistant isolates, and the other two tested fluoroquinolones (ciprofloxacin, fleroxacin) possessed comparable overall spectrums of activity, although ciprofloxacin was generally more active on a weight basis. We urge the rapid acceptance of these criteria to improve the accuracy of the widely used National Committee for Clinical Laboratory Standards method for disk diffusion tests.

Anti-Infective Agents↗
PubMed1995

Activity of two novel fluoroquinolones (DU-6859a and DV-7751a) tested against glycopeptide-resistant enterococcal isolates.

Two novel fluoroquinolones, DU-6859a and DV-7751a, were compared with three peer compounds (ciprofloxacin, levofloxacin, and ofloxacin) by testing 150 strains of enterococci that were resistant to vancomycin. Standardized methods recommended by the National Committee for Clinical Laboratory Standards were used for all minimum inhibitory concentration tests, and DU-6859a was additionally tested by the standardized disk diffusion procedure (5-mu g disks). The rank order of the fluoroquinolone spectrums against these Enterococcus spp. isolates was DU-6859a (71.3% of strains inhibited at < or = 2 mu g/ml) > DV-7751a (38.7%) > levofloxacin (33.3%) > ofloxacin (32.0%) > ciprofloxacin (3.3%). Using previously proposed break point zone diameters of > or = 16 mm (susceptible) and < or = 12 mm (resistant), the DU-6859a disk diffusion tests for these glycopeptide-resistant organisms were without false-susceptible or false-resistant error (81.3% absolute agreement). These results indicate that among the investigational and currently marketed fluoroquinolones, DU-6859a appears to have the greatest potential value in the therapy of Enterococcus spp. strains that are resistant to the glycopeptides and many other therapeutic agents.

Anti-Bacterial Agents↗
PubMed1995

Cartilage matrix protein forms a type II collagen-independent filamentous network: analysis in primary cell cultures with a retrovirus expression system.

Cartilage matrix protein (CMP) is expressed specifically in mature cartilage and consists of two von Willebrand factor A domains (CMP-A1 and CMP-A2) that are separated by an epidermal growth factor-like domain, and a coiled-coil tail domain at the carboxyl terminal end. We have shown previously that CMP interacts with type II collagen-containing fibrils in cartilage. In this study, we describe a type II collagen-independent CMP filament and we analyze the structural requirement for the formation of this type of filament. Recombinant wild-type CMP and two mutant forms were expressed in chick primary cell cultures using a retrovirus expression system. In chondrocytes, the wild-type virally encoded CMP is able to form disulfide bonded trimers and to assemble into filaments. Filaments also form with CMP whose Cys455 and Cys457 in the tail domain were mutagenized to prevent interchain disulfide bond formation. Therefore, intermolecular disulfide bonds are not necessary for the assembly of CMP into filaments. Both the wild-type and the double cysteine mutant also form filaments in fibroblasts, indicating that chondrocyte-specific factors are not required for filament formation. A truncated form of CMP that consists only of the CMP-A2 domain and the tail domain can form trimers but fails to form filaments, indicating that the deleted CMP-A1 domain and/or the epidermal growth factor domain are necessary for filament assembly but not for trimer formation. Furthermore, the expression of the virally encoded truncated CMP in chondrocyte culture disrupts endogenous CMP filament formation. Together these data suggest a role for CMP in cartilage matrix assembly by forming filamentous networks that require participation and coordination of individual domains of CMP.

Amino Acid Sequence↗
PubMed1995

The effect of indomethacin-induced gastric mucosal injury on 24-h intragastric acidity and plasma gastrin concentration in healthy volunteers.

AIMS: To determine the influences of prostaglandin inhibition by indomethacin on 24-h intragastric acidity and plasma gastrin concentration, related to gastric mucosal injury. METHODS: A pre- and post-treatment study design was employed in 10 Helicobacter pylori negative healthy male subjects. All subjects underwent upper gastrointestinal endoscopy at least 3 days before and after 7 days dosing with indomethacin 50 mg t.d.s. Mucosal damage was scored according to the Lanza method, and biopsies were taken for H. pylori status and assay of mucosal concentrations of prostaglandin (PG)E2 and leukotriene (LT)B4. Before and on the last day of dosing, intragastric acidity was measured by continuous 24-h pH monitoring, and plasma gastrin levels determined by radioimmunoassay in blood samples collected over the same period. RESULTS: All subjects completed the study and no serious adverse events were reported. The mucosal injury score increased significantly from 0 (0-2) to 3.4 (0-8) (mean and range of values, P < 0.05) after dosing with indomethacin. No differences were observed in 24-h mean pH or meal stimulated plasma gastrin concentrations. Mucosal PGE2 and LTB4 were unchanged 8-10 h after the last indomethacin dose. CONCLUSIONS: Endogenous prostaglandins do not appear to alter intragastric acidity or gastrin secretion, in contrast to the PGE analogues, whose effects must be more pharmacological than physiological.

Adult↗
PubMed1994

Interpretive criteria for DU-6859a disk diffusion tests using 5-micrograms disks.

In vitro disk diffusion test interpretive criteria were developed for DU-6859a, a new difluorinated quinolone, using a 5-micrograms disk. Included in the 494 organisms tested were 84 (17%) ciprofloxacin-resistant > or = 4 micrograms/ml) clinical isolates. The following interpretive criteria were proposed for two possible susceptible breakpoint minimum inhibitory concentrations: > or = 16 mm (< or = 2 micrograms/ml) = susceptible and < or = 12 mm (> or = 8 micrograms/ml) = resistant and; > or = 19 mm (< or = 1 microgram/ml) = susceptible and < or = 15 mm (> or = 4 micrograms/ml) = resistant. These criteria demonstrated > or = 97% absolute interpretive agreement between test methods with no major (false resistant) or very major (false susceptible) errors.

Anti-Infective Agents↗
PubMed1994

NK1 receptors mediated release of 6-keto-PGF1 alpha from the ex vivo perfused canine ileum.

The purpose of this study was to determine the effects of tachykinins on prostanoid production by the dog ileum and to characterize the tachykinin receptor(s) responsible for the principal eicosanoid shown to be released, 6-keto-PGF1 alpha. Substance P, the selective NK1 receptor agonist [Sar9,Met(O2)11]substance P and neurokinin A caused concentration-dependent production of 6-keto-PGF1 alpha; neurokinin A was least potent. The selective NK2 agonist [Nle10]neurokinin A(4-10) had no effect. The selective NK1 antagonist CP-96,345 (10(-7) M), blocked 6-keto-PGF1 alpha release from substance P (10(-7) M), [Sar9,Met(O2)11]substance P (10(-7) M) and neurokinin A (10(-7) M). Although the putative NK2 antagonist MEN 10207 (10(-7) M) partially blocked the 6-keto-PGF1 alpha release induced by neurokinin A (10(-7) M), we conclude that all these peptides acted primarily on NK1 receptors to induce 6-keto-PGF1 alpha. Additional experiments suggest that a major site of production of 6-keto-PGF1 alpha in the canine ileum may be the vasculature, but these experiments do not exclude other sources such as intestinal muscle for this prostanoid. Calcium-free Krebs' solution partially reduced the release of 6-keto-PGF1 alpha to substance P (10(-7) M), implying that extracellular calcium helps support tachykinin-induced production of 6-keto-PGF1 alpha. Blockade of synthesis of another vasoactive mediator, endothelium-derived relaxing factor (nitric oxide), by N omega-L-arginine methyl ester) did not alter substance P-induced release of 6-keto-PGF1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1994

FDA's requirements for in-vivo performance data for prosthetic heart valves.

The Food and Drug Administration (FDA) has recently revised its "Replacement Heart Valve Guidance". That document lists the data FDA deems necessary to support the approval of new prosthetic heart valves of all designs, and which should be contained in Premarket Approval Applications for these devices. The guidance covers detailed data requirements for in vitro, animal, and clinical data. This paper is intended to briefly summarize FDA's requirements for in vivo and clinical data. The clinical study must establish that the device is both safe and effective, as compared to currently marketed replacement heart valves. It is possible to achieve this goal using hypothesis testing to compare the results of an observational study against a set of Objective Performance Criteria (OPC) which have been established by the FDA. The establishment of the OPCs was facilitated by a standardized set of definitions of complications published by the American Association of Thoracic Surgery and Society of Thoracic Surgeons (AATS/STS) in 1987/1988. Papers published in peer reviewed journals have utilized this set of definitions for data analysis, providing an ample pool of data from which to establish OPCs. The number of patients required to establish the safety and efficacy of a replacement heart valve, using this approach, is 800 valve years, 400 in the aortic and 400 in the mitral position. Advantages of this approach are reduction in the number of patients and duration of the study.

Animals↗
PubMed1994

FDA's requirements for in-vitro performance data for prosthetic heart valves.

The Center for Devices and Radiological Health, Food and Drug Administration, has recently revised its "Replacement Heart Valve Guidance". That document lists the data FDA deems necessary to support the approval of new prosthetic heart valves of all designs, and which should be contained in Premarket Approval Applications for these devices. The Guidance covers detailed data requirements for in vitro, animal, and clinical data. This paper is intended to briefly summarize FDA's requirements for in vitro data, and, for those cases where it may not be obvious, to provide an overview of the significance of these data and how FDA interprets them in the approval decision process.

Biomechanical Phenomena↗
PubMed1994

Sample size requirements for evaluating heart valves with constant risk events.

A method is described for computing sample size requirements for a clinical study of a new heart valve, according to the guidance document recently revised by the FDA. The FDA requirements specify a one-sample hypothesis test in which the complication rates for the study valve are compared to fixed values determined from previous experience with approved devices. These values, which can differ for different complications and for mechanical or tissue valve types, are called OPC's (Objective Performance Criteria). The method described, using the Poisson distribution, provides a simple formula for computing the valve-years required corresponding to any OPC. At the OPC level required by the FDA guidelines (1.2%/year), the minimum follow-up necessary is about 800 valve-years.

Guidelines as Topic↗
PubMed1993

Effects of chronic NSAIDs on gastric mucosal injury related to mucosal prostanoids, and plasma drug concentrations in human volunteers.

The relationship between endoscopically observed gastric mucosal damage, elicited following repeated oral intake for 7 d of four NSAIDs, to their effects on antral and fundic production of PGE2, 6-keto-PGF1 alpha and TxB2 (assayed by GC-MS), mucosal histology and plasma concentration profiles was studied in 40 normal males. Subjects received azapropazone (APZ) 600 mg b.i.d., indomethacin (IND) 50 mg t.i.d., naproxen (NAP) 500 mg b.i.d., piroxicam (PIR) 20 mg qq.d., or one placebo capsule t.i.d. (N = 8/group). Plasma NSAIDs (HPLC) levelled at 7 d. Mucosal damage occurred in the antrum region with IND and NAP. APZ and PIR exhibited no differences compared to placebo. NAP and IND reduced all three prostanoids in the antrum while APZ and PIR were ineffective. Fundic PGE2 was reduced by IND, NAP and PIR; APZ had no effects. Thus, mucosal damage relates to effects on prostanoid production in the antrum but not in the fundus.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

In vitro antimicrobial activity of CP-99433 compared with other fluoroquinolones.

CP-99433 is a new C-7 diazabicyclofluoroquinolone with a broad spectrum of activity that includes Enterobacteriaceae, Gram-positive cocci, and nonenteric Gram-negative bacilli. Potent activity was demonstrated against Pseudomonas aeruginosa [minimum inhibitory concentration (MIC90, 0.5 microgram/ml), Xanthomonas maltophilia (MIC90, 1 microgram/ml), and all Streptococcus species (MIC90s, 0.25-1 microgram/ml). Only CP-99433 was active against Enterococcus faecium (MIC50, 2 micrograms/ml). CP-99433 also demonstrated activity against several ciprofloxacin-resistant staphylococci. Additional studies of CP-99433 activity appear indicated.

Anti-Infective Agents↗
PubMed1992

Antibacterial activity of the investigational oral and parenteral cephalosporin BK-218.

BK-218 is a novel cephalosporin with a dual route of administration and spectrum of activity most similar to that of second-generation cephalosporins. BK-218 was active against Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis but strains resistant to penicillins had higher MICs. BK-218 had greater activity (8-fold) than cefuroxime or cefaclor against oxacillin-susceptible Staphylococcus spp. Moderate BK-218 activity was observed against Neisseria gonorrhoeae and commonly isolated Enterobacteriaceae such as Escherichia coli (MIC90, 1 mg/l), Klebsiella spp. (MIC90, 2 mg/l), and Proteus mirabilis (MIC90, 2 mg/l). The following organisms were generally BK-218-resistant (MIC90, greater than 16 mg/l): Bacteroides fragilis, Pseudomonas spp., Acinetobacter spp., Xanthomonas maltophilia, Citrobacter spp., Enterobacter spp., indole-positive Proteus, Serratia spp., enterococci and oxacillin-resistant staphylococci.

Cefaclor↗
PubMed1992

Antimicrobial activity of ten macrolide, lincosamine and streptogramin drugs tested against Legionella species.

RP59500, a semisynthetic pristinamycin combination, and 14 other antimicrobial agents were tested against 108 Legionella strains. Of the ten macrolide, lincosamine and streptogramin agents tested, the new streptogramin RP59500 ranked seventh in order of activity against Legionella pneumophila on the basis of MIC90 results as follows: clarithromycin = 14-OH clarithromycin (MIC90 0.12 mg/l) > roxithromycin > erythromycin = tylosin = virginiamycin > RP59500 (MIC90 1 mg/l) = azithromycin > dirithromycin > clindamycin (MIC90 8 mg/l). Of all 14 drugs tested in this study, rifampicin was the most potent with an MIC90 of 0.008 mg/l. In this retrospective study of Legionella strains (1981-1990 isolates), we observed no trend toward resistance to the agents investigated.

Amino Sugars↗
PubMed1992

Antimicrobial activities of two investigational fluoroquinolones (CI-960 and E4695) against over 100 Legionella sp. isolates.

The antimicrobial activities of two investigational fluoroquinolones (CI-960 and E4695) were compared with those of five similar compounds and four comparison drugs against 103 strains of Legionella pneumophila and five other Legionella species type strains. When concentrations inhibiting 90% of strains tested (MIC90s) for L. pneumophila were determined, CI-960 and temafloxacin emerged as the most active (0.015 microgram/ml) and were followed in potency by E4695 (0.03 microgram/ml). This activity was two- to fourfold greater than that of the reference drug, ciprofloxacin, and approached that of rifampin (MIC90, 0.008 microgram/ml). All fluoroquinolones studied were more active than erythromycin (MIC90, 0.5 microgram/ml). These two investigational fluoroquinolones appear well suited for further in vivo study of legionellosis therapy.

Anti-Infective Agents↗
PubMed1991

Antimicrobial activity of isepamicin (SCH21420, 1-N-HAPA gentamicin B) combinations with cefotaxime, ceftazidime, ceftriaxone, ciprofloxacin, imipenem, mezlocillin and piperacillin tested against gentamicin-resistant and susceptible gram-negative bacilli and enterococci.

Isepamicin, formerly SCH21420 or 1-N-HAPA gentamicin B, is an aminoglycoside that was tested alone or in combination with one of seven broad spectrum drugs against 80 clinical isolates. Half of the strains were gentamicin-resistant but only one isolate (1.3%) was resistant to isepamicin. The broadest spectrum comparison drugs tested alone (ciprofloxacin at 3.8% resistance and imipenem at 5.0% resistance) were associated with the lowest synergy rates when combined with isepamicin. The rank order of synergy (complete or partial) was; cefotaxime = ceftazidime = ceftriaxone = mezlocillin = piperacillin (75% to 80%) greater than imipenem (66%) greater than ciprofloxacin (38%). Isepamicin/ampicillin combinations produced synergistic killing of those enterococci not having high-grade resistance to gentamicin or kanamycin. Enterococcus faecium strains were also refractory to isepamicin/ampicillin synergy. Isepamicin appears to be widely useable against gentamicin-resistant gram-negative bacilli either alone or combined with most commonly used broad spectrum beta-lactams.

Cefotaxime↗