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Biomedical subjects

J M Andrews

Publications and source records attributed to J M Andrews.

At least 19 recordsLinked to original sources
PubMed1997

In vitro activity of BAY 12-8039, a new fluoroquinolone.

The in vitro activity of BAY 12-8039, a new fluoroquinolone, was studied in comparison with those of ciprofloxacin, trovafloxacin (CP 99,219), cefpodoxime, and amoxicillin-clavulanate against gram-negative, gram-positive, and anaerobic bacteria. Its activity against mycobacteria and chlamydia was also investigated. BAY 12-8039 was active against members of the family Enterobacteriaceae (MIC at which 90% of strains tested were inhibited [MIC90S] < or = 1 microgram/ml, except for Serratia spp. MIC90 2 microgram/ml), Neisseria spp. (MIC90S, 0.015 microgram/ml), Haemophilus influenzae (MIC90, 0.03 microgram/ml), and Moraxella catarrhalis (MIC90, 0.12 micrgram/ml), and these results were comparable to those obtained for ciprofloxacin and trovafloxacin. Against Pseudomonas aeruginosa, the quinolones were more active than the beta-lactam agents but BAY 12-8039 was less active than ciprofloxacin. Strains of Stenotrophomonas maltophilia were fourfold more susceptible to BAY 12-8039 and trovafloxacin (MIC90S, 2 micrograms/ml) than to ciprofloxacin. BAY 12-8039 was as active as trovafloxacin but more active than ciprofloxacin against Streptococcus pneumoniae (MIC90, 0.25 microgram/ml) and methicillin-susceptible Staphylococcus auerus (MIC90S, 0.12 micrograms/ml). The activity of BAY 12-8039 against methicillin-resistant S. aureus (MIC90, 2 micrograms/ml) was lower than that against methicillin-susceptible strains. BAY 12-8039 was active against anaerobes (MIC90S < or = 2 micrograms/ml), being three- to fourfold more active against Bacteroides fragilis, Prevotella spp., and Clostridium difficile than was ciprofloxacin. Against Mycobacterium tuberculosis, BAY 12-8039 exhibited activity comparable to that of rifampin (MICs < or = 0.5 micrograms/ml). Against Chlamydia trachomatis and Chlamydia pneumoniae BAY 12-8039 was more active (MICs < or = 0.12 microgram/ml) than either ciprofloxacin or erythromycin and exhibited a greater lethal effect than either to these two agents. The protein binding of BAY 12-8039 was determined at 1 and 5 micrograms/ml as 30 and 26.4%, respectively. The presence of human serum (at 20 or 70%) had no marked effect on the in vitro activity of BAY 12-8039.

Anti-Infective Agents↗
PubMed1997

The cellular stress response enhances human T-cell lymphotropic virus type 1 basal gene expression through the core promoter region of the long terminal repeat.

Viral protein expression is postulated to play a critical role in the pathogenesis of human T-cell lymphotropic virus type 1 (HTLV-1)-associated diseases. Therefore, knowledge of the cellular events which initiate or enhance viral gene expression is important in understanding the mechanism of HTLV-1-induced disease. In this report, we examined the modulation of transcription of the HTLV-1 long terminal repeat (LTR) following induction of the cellular stress response. We demonstrate by both in vitro transcription assays and transient transfections that induction of the stress response increases basal transcription from the LTR. Transient cotransfection assays indicate that stress induction of viral transcription is Tax independent. In addition, we provide evidence that the sequences responsible for the enhanced transcription are -52 through +157 of the U3/R region of the HTLV-1 LTR. Finally, our data suggest that the increase in transcription is mediated through an intermediate polymerase II/polymerase III transcriptional complex, demonstrated by the inability to abolish the effect with low concentrations of alpha-amanitin.

Amanitins↗
PubMed1996

Stimulation of the CD2 receptor pathway induces apoptosis in human T lymphotropic virus type I-infected cell lines.

We demonstrate that CD2 receptor engagement, but not CD3 crosslinking, induces apoptosis in lymphocytes transformed by human T-cell lymphotrophic virus type I (HTLV-I). Mitogenic pairs of anti-CD2 monoclonal antibodies inhibited [3H]thymidine incorporation from 25 to 62% in CD2+ HTLV-I-infected lymphocytes. This inhibition was associated with a 20-40% reduction in cell number and viability over a 3-day period, morphologic evidence of apoptosis, and irreversible DNA fragmentation. While cyclosporin A abrogated CD2-mediated proliferation in peripheral blood mononuclear cells, it had no effect on CD2-induced apoptosis in the HTLV-I-infected cell lines. Since HTLV-I is mitogenic to resting lymphocytes through CD2 activation pathways, these results suggest that HTLV-I-infected lymphocytes are primed for apoptosis following additional CD2 stimulation. This CD2-mediated apoptosis might be a factor in immune regulation of HTLV-I-associated diseases or might offer a novel adjunctive approach to treatment.

Antigens, CD↗
PubMed1996

Distribution of cefdinir, a third generation cephalosporin antibiotic, in serum and pulmonary compartments.

The distribution of a new cephalosporin, cefdinir, in serum, epithelial lining fluid (ELF), bronchial mucosa and alveolar macrophages was studied in 17 adults following a single oral dose of 300 or 600 mg of cefdinir; tissue samples being obtained by diagnostic bronchoscopy approximately 4 h after this dose. Mucosal biopsies were taken, alveolar macrophages harvested by lavage, and ELF volume derived from urea concentrations in bronchial lavage fluid and blood. A microbiological assay for cefdinir was performed in serum, bronchial mucosa, ELF and alveolar macrophages. In patients taking 300 mg of cefdinir, the median concentrations of cefdinir were 2.00 mg/L (range 1.40-8.00) in serum, 0.78 mg/L (range 0-1.33) in bronchial mucosa, and 0.29 mg/L (range 0-4.73) in ELF. In patients taking 600 mg, the median concentrations were 4.20 mg/L (range 3.05-6.40) in serum, 1.14 mg/L (range 0-1.92) in bronchial mucosa, and 0.49 mg/L (range 0-0.59) in ELF. Cefdinir did not penetrate macrophages.

Administration, Oral↗
PubMed1996

Pharmacokinetics and penetration into inflammatory fluid of trovafloxacin (CP-99,219).

A single 200-mg oral dose of trovafloxacin (CP-99,219) was given to each of eight healthy male volunteers, and the concentrations of the drug were measured in plasma, cantharides-induced inflammatory fluid, and urine over the subsequent 36 h. The mean maximum concentration observed in plasma was 2.9 micrograms/ml at a mean time of 0.75 h postdose. The mean maximum concentration observed in inflammatory fluid was 1.2 micrograms/ml at 4.0 h postdose. The mean elimination half-life in plasma was 7.8 h. The overall penetration into inflammatory fluid was 64%, as assessed by determining the ratio of the area under the concentration-time curves. Recovery of the dose in urine within the first 36 h postdose was 5.0% of the administered dose. Our results indicate that trovafloxacin, at a dosage of 200 mg once or twice daily, should be adequate for the treatment of systemic infections caused by most common bacterial pathogens.

Adolescent↗
PubMed1996

In vitro activity of the tricyclic beta-lactam GV104326.

GV104326 is a novel tricyclic beta-lactam (a trinem or, formerly, tribactam). The in vitro activity of GV104326 was compared with those of cefuroxime, cefixime, amoxicillin, amoxicillin-clavulanic acid, cefpirome, and ciprofloxacin. GV104326 had in vitro activity generally similar to that of cefixime against members of the family Enterobacteriaceae (MIC at which 90% of the isolates are inhibited [MIC90], < or = 2 micrograms/ml), with cefuroxime and amoxicillin-clavulanic acid being 8- to 32-fold less active and with cefpirome being 4- to 8-fold more active against members of this family. The trinem had no activity against Pseudomonas aeruginosa or Stenotrophomonas maltophilia (MIC90, > 128 micrograms/ml) but was the most active agent against Acinetobacter calcoaceticus. GV104326 was particularly active against gram-positive cocci. Ninety percent of methicillin-susceptible Staphylococcus aureus strains were susceptible to 0.03 microgram of GV104326 per ml, making it the most active agent studied. Enterococci and Lancefield group A and B streptococci were generally equally or somewhat more susceptible to GV104326 than they were to amoxicillin. Streptococcus pneumoniae strains were highly susceptible to GV104326, and those strains which showed decreased susceptibility to penicillin were generally twofold more susceptible to the trinem than to amoxicillin. Haemophilus influenzae and Moraxella catarrhalis were highly susceptible to GV104326 (MIC90s, 0.12 and 0.03 microgram/ml, respectively). The anaerobes Clostridium perfringens, Bacteroides fragilis, and Peptostreptococcus spp. were more susceptible to the trinems (formerly tribactams) than to the other agents studied.

Amoxicillin↗
PubMed1996

Human T-cell lymphotropic virus type 1 Tax mediates enhanced transcription in CD4+ T lymphocytes.

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma and is associated with a variety of immunoregulatory disorders. HTLV-1 has been shown to bind to and infect a variety of hematopoietic and nonhematopoietic cells. However, both in vivo and in vitro, the provirus is mostly detected in and preferentially transforms CD4+ T cells. The molecular mechanism that determines the CD4+ T-cell tropism of HTLV-1 has not been determined. Using cocultures of purified CD4+ and CD8+ T cells with an HTLV-1 producing cell line, we measured viral transcription by using Northern (RNA) blot analysis, protein production by using a p24 antigen capture assay and flow cytometric analysis for viral envelope, and proviral integration by using DNA slot blot analysis. We further measured HTLV-1 long terminal repeat-directed transcription in purified CD4+ and CD8+ T cells by using transient transfection assays and in vitro transcription. We demonstrate a higher rate of viral transcription in primary CD4+ T cells than in CD8+ T cells. HTLV-1 protein production was 5- to 25-fold greater in CD4+ cocultures and mRNA levels were 5-fold greater in these cultures than in the CD8+ cocultures. Transient transfection and in vitro transcription indicated a modest increase in basal transcription in CD4+ T cells, whereas there was a 20-fold increase in reporter gene activity in CD4+ T cells cotransfected with tax. These data suggest that unique or activated transcription factors, particularly Tax-responsive factors in CD4+ T cells, recognize regulatory sequences within the HTLV-1 long terminal repeat, and this mediates the observed enhanced viral transcription and ultimately the cell tropism and leukemogenic potential of the virus.

Animals↗
PubMed1996

Influence of methylprednisolone acetate on osteochondral healing in exercised tarsocrural joints of horses.

OBJECTIVE: To evaluate joint function and healing of surgically created full-thickness articular cartilage defects in exercised horses after intra-articular administration of methylprednisolone acetate (MPA; 120 mg) and sterile saline solution in the contralateral limb. DESIGN: Experimental investigation. SAMPLE POPULATION: 12 healthy, sound, radiographically normal horses with induced full-thickness osteochondral lesions on the medial and lateral trochlear ridges of the tali. PROCEDURE: Two 8.4-mm-diameter full-thickness articular cartilage lesions were created in each tarsocrural joint (12 horses [24 tarsocrural joints]); 1 was in a weight-bearing (WB) position and the other in a less weight-bearing (LWB) position. Each horse was maintained on a standardized exercise protocol (stall rest, days 0-6; walking, days 7-12; and treadmill, days 13-42) and evaluated throughout the study for changes in joint circumferences, synovial fluid, radiographs, lameness, and scintigraphy. 6 horses were euthanatized on day 42, and 6 on day 180. Gross morphometric assessment was performed, using an image analysis system on a projected color slide of the defect. The type of repair tissue, based on gross appearance, was expressed as a percentage of the total defect for each osteochondral defect. Histochemical assessment was performed, using safranin-O staining for proteoglycans and an image analysis system to express the area of stain uptake. Histomorphometric assessment was performed on H&E-stained sections, using an image analysis system. The repair tissue filling the defect was categorized as to tissue type and expressed as a percentage of the total defect area. Synovial membrane specimens were assessed semiquantitatively on H&E-stained sections for changes in character. Significance was established at P < 0.05. RESULTS: Joint circumference was significantly increased in the saline, compared with the MPA-treated, limbs on days 7, 12, and 42. Synovial fluid WBC counts were significantly increased in the MPA-treated limbs on day 42. Gross osteochondral defects had a greater percentage of mature repair tissue in saline-treated joints (30.8% LWB, 23% WB), compared with MPA-treated joints (0% LWB, 0% WB) at 42 days Histomorphometric assessment of the repair tissue indicated significant differences with regard to the quality of repair in the saline-treated (34% fibrous tissue LWB, 19.4% fibrous tissue WB) versus MPA-treated (2.5% fibrous tissue in LWB and WB) joints at 42 days. Microscopically, the percentage of fibrocartilage in the LWB (MPA, 23.7%; saline, 24.8%) was significantly greater than that in the WB (MPA, 14.6%; saline, 15.4%) site at day 180. The MPA-treated limbs had greater villous hyperplasia, edema, and extent of inflammation within the synovial membrane than did saline-treated limbs (days 42 and 180). CONCLUSION: MPA inhibits the development and maturation of repair tissue at 42 days and incites potential long-term (180 days) detrimental synovial membrane inflammation. Furthermore, a single dose of MPA does not cause long-term detrimental effects (180 days) in quality of repair-tissue.

Animals↗
PubMed1995

Inflammatory bowel disease: a retrospective review of a specialist-based cohort.

OBJECTIVE: To study the morbidity and mortality of inflammatory bowel disease in Australia and whether it decreases life expectancy. DESIGN: A retrospective review of patient case notes from two Sydney teaching hospitals and the consulting rooms of the 17 gastroenterologists appointed to these hospitals, examining all presentations with a diagnosis of inflammatory bowel disease from January 1977 to September 1992. RESULTS: 997 cases were identified: 533 with ulcerative colitis, 417 with Crohn's disease, and 47 with indeterminate colitis. In patients diagnosed from 1977 onwards (n = 730), no difference in survival was demonstrated for inflammatory bowel disease overall, or any subgroup, or in males or females, as compared with an age- and sex-matched control population. Gastrointestinal malignancies occurred in 19 cases (18 colorectal carcinoma and one cholangiocarcinoma). The most commonly encountered problems were the use of immunosuppressants and the need for surgery. Inflammatory bowel disease, particularly Crohn's disease, entails appreciable morbidity. CONCLUSION: Since 1977, despite a significant requirement for medical and surgical treatment in patients with inflammatory bowel disease, there has been no adverse effect on survival in a specialist-referred cohort as compared with the general population.

Australia↗
PubMed1995

Enhanced human T-cell lymphotropic virus type I expression following induction of the cellular stress response.

Human T-cell lymphotropic virus type I (HTLV-I) infection is typically associated with long incubation periods between virus exposure and disease manifestation. Although viral protein expression is considered to play an important role in the pathogenesis of HTLV-I-associated diseases, limited information is known regarding host cell mechanisms that control viral gene expression. This study was designed to evaluate modulation of HTLV-I gene expression following induction of the cellular stress response in HTLV-I-infected lymphocytes. The cellular stress response was elicited by treatment with either Na arsenite or thermal stress and was monitored by demonstrating increased expression of the 72-kDa heat shock protein. Induction of the cellular stress response in HTLV-I-infected lymphocytes resulted in significantly increased HTLV-I-mediated syncytia formation due to enhanced HTLV-I envelope (gp46) expression. Intracellular viral proteins and released p24 capsid protein were increased in stressed infected lymphocytes as compared to nonstressed infected lymphocytes. Furthermore, HTLV-I-LTR reporter gene constructs had increased activity (three- to sixfold) in a transiently transfected, uninfected lymphocyte cell line following induction of the cellular stress response. Quantitation of HTLV-I RNA expression by slot blot analysis of infected lymphocytes suggested variable increases in RNA accumulation. Northern blot analysis demonstrated no qualitative changes in expression of RNA species. These data suggest a relationship between modulation of viral replication and a basic cellular response to stress and have important implications for understanding host cell control mechanisms of HTLV-I expression.

Arsenites↗
PubMed1995

Systemic Mycobacterium smegmatis infection in a dog.

A 3-year-old female Basset Hound was examined because of fever and lameness of 2 months' duration. Physical examination revealed a small cranial abdominal mass, which had an ultrasonographic appearance of a large abdominal lymph node. Cytologic examination of an ultrasound-guided fine-needle aspirate of the mass revealed a few macrophages that contained numerous linear unstained structures consistent with mycobacteria. Intracellular acid-fast bacilli were identified in an aspirate that was stained with modified Ziehl-Neelsen. Exploratory laparotomy revealed wide-spread abdominal lymphadenopathy. Histologic examination of hepatic and lymph node biopsy specimens revealed chronic granulomatous hepatitis and lymphadenitis. Acid-fast organisms isolated after bacteriologic culturing of a mesenteric lymph node specimen were identified as Mycobacterium smegmatis. Because the prognosis was poor, the dog was euthanatized.

Animals↗
PubMed1995

Concentrations of OPC-17116, a new fluoroquinolone antibacterial, in serum and lung compartments.

The efficacy of an antibiotic is usually predicted from serum concentration and MICs for likely pathogens, but in the lung, tissue concentrations may be more relevant. This study compares concentrations of a new fluoroquinolone, OPC-17116, in serum, epithelial lining fluid (ELF), alveolar macrophages and bronchial mucosa, in 24 adults. OPC-17116 400 mg was given daily for 4 days, and diagnostic bronchoscopy was performed up to 13 h after the final dose. Mucosal biopsies were taken from macroscopically normal sites, alveolar macrophages were harvested by lavage, and ELF volume was derived from urea concentrations in bronchial lavage fluid and blood. A microbiological assay, using Escherichia coli, was used to assay OPC-17116 concentration in serum, bronchial mucosa, ELF and alveolar macrophages. The mean concentration of OPC-17116 in serum was 1.2 mg/L. Serum concentrations were significantly exceeded in bronchial mucosa (mean ratio 3.13) in ELF (mean ratio 12.21) and in macrophages (mean ratio 194.52). Penetrations of these compartments considerably exceeded those reported for other fluoroquinolones, and concentrations in all tissues were substantially higher than previously reported MIC90 levels for a variety of bacteria, including Streptococcus pneumoniae. A clinical role for OPC-17116 is suggested in a wide range of respiratory infections, including those due to intracellular bacteria.

Adult↗
PubMed1995

In-vitro activity of two glycylcyclines against enterococci resistant to other agents.

Two new glycylcyclines, CL 329,998 and CL 331,002, were tested for in-vitro activity against 178 clinical strains of enterococci which were resistant to one or more of the commonly used agents (ampicillin, high level gentamicin, vancomycin and teicoplanin). Both glycylcyclines demonstrated good activity (MICs < or = 0.5 mg/L) against all isolates tested, including those strains which demonstrated multiple resistance. As resistant enterococci are increasing in importance, new agents with activity against these strains are urgently required. Glycylcyclines have in-vitro activity which suggests they may be useful agents for treatment of infections caused by these organisms.

Anti-Bacterial Agents↗
PubMed1995

Total reconstruction of the alar cartilage en bloc using the ear cartilage: a study in cadavers.

To determine whether the lamina tragi, isthmus, and cavum conchae are a donor area for reconstruction of the alar cartilage with all its elements (medial crus, junction of the medial and lateral crura, and lateral crus), with the same dimension and en bloc, 40 alar cartilages and 40 lower parts of ear cartilages of 20 cadavers were dissected. Several measurements were taken in the alar cartilages, such as distance, thickness, and angle. Then they were compared with the measurements performed in the ear cartilages and segments removed from the lamina tragi, isthmus, and cavum conchae. This study, done with cadavers, shows that from the lamina tragi, isthmus, and cavum conchae, en bloc resection is possible with characteristics of form and dimension similar to those of the homolateral alar cartilage. The segment removed en bloc from the intermediate part of the lamina tragi, isthmus, and cavum conchae replaces, respectively, the medial crus, junction of the medial and lateral crura, and lateral crus.

Adult↗