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Biomedical subjects

M H Miller

Publications and source records attributed to M H Miller.

At least 19 recordsLinked to original sources
PubMed2002

Iris configuration in accommodation in pigment dispersion syndrome.

PURPOSE: This study was conducted in order to investigate the effect of accommodation on the iris morphology and iridolenticular contact, in eyes with Pigment Dispersion Syndrome and Pigmentary Glaucoma, using high-resolution ultrasound. METHODS: We performed a prospective observational study, examining a group of 30 Pigment Dispersion Syndrome and Pigmentary Glaucoma patients (49 eyes) and a smaller group of eight 'normals' non-Pigment Dispersion Syndrome patients (8 eyes). All patients underwent ultrasound biomicroscopy, before and during accommodation. RESULTS: The iris profile before accommodation was found convex in 48.5%, flat in 19.7% and concave in 31.8%. Following accommodation the iris configuration remained unchanged in 66.2%, increased in concavity in 20.3% and decreased in concavity in 13.5%. CONCLUSIONS: The effect of accommodation on iris configuration and accommodation is highly variable. From our experience the measurement of iris configuration using ultrasound biomicroscopy may not be a useful method of evaluating the effect of different treatments on iris configuration.

Accommodation, Ocular↗
PubMed2002

Intraobserver and interobserver reliability of the R/D score for evaluation of iris configuration by ultrasound biomicroscopy, in patients with pigment dispersion syndrome.

UNLABELLED: The work has been presented at The Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, Fort Lauterdale, Florida, May 1999. PURPOSE: To evaluate inter- and intraobserver variability of the R/D score in assessing the iris configuration in Pigment Dispersion Syndrome patients. METHODS: Fifty-seven high-resolution ultrasound biomicroscopy images were obtained by a single ophthalmologist. All images were examined twice by each of three ophthalmologists, the second assessment being at least 2 weeks after the first. Each observer was masked to their colleagues' and their previous measurements. R/D scores were calculated at each examination. Agreement between and amongst observers was assessed using Bland-Altman plots. In addition, the R/D scores were categorised and reassessed using the Kappa statistic. RESULTS: Intraobserver variability was small, the average differences between first and second scores of each observer being less than 0.01 units. Agreement within observers was 89% or higher, with Kappa values of 0.8 or higher, indicating almost perfect agreement. Interobserver variability was, however, greater. Although there was substantial agreement between two of the observers (87% agreement, first assessment; 80%, second assessment with respective kappa statistics of 0.78 and 0.66), they only moderately agreed with the other observer (kappa statistics between 0.55 and 0.68). CONCLUSIONS: This study suggests that when using R/D scores to demonstrate changes in iris configuration, assessments should preferably be made by the same observer.

Exfoliation Syndrome↗
PubMed2001

Impact of the order of initiation of fluconazole and amphotericin B in sequential or combination therapy on killing of Candida albicans in vitro and in a rabbit model of endocarditis and pyelonephritis.

In vitro time-kill studies and a rabbit model of endocarditis and pyelonephritis were used to define the impact that the order of exposure of Candida albicans to fluconazole (FLC) and amphotericin B (AMB), as sequential and combination therapies, had on the susceptibility of C. albicans to AMB and on the outcome. The contribution of FLC-induced resistance to AMB for C. albicans also was assessed. In vitro, AMB monotherapy rapidly killed each of four C. albicans strains; FLC alone was fungistatic. Preincubation of these fungi with FLC for 18 h prior to exposure to AMB decreased their susceptibilities to AMB for 8 to >40 h. Induced resistance to AMB was transient, but the duration of resistance increased with the length of FLC preincubation. Yeast sequentially incubated with FLC followed by AMB plus FLC (FLC-->AMB+FLC) showed fungistatic growth kinetics similar to that of fungi that were exposed to FLC alone. This antagonistic effect persisted for at least 24 h. Simultaneous exposure of C. albicans to AMB and FLC [AMB+FLC(simult)] demonstrated activity similar to that with AMB alone for AMB concentrations of > or =1 microg/ml; antagonism was seen using an AMB concentration of 0.5 microg/ml. The in vitro findings accurately predicted outcomes in our rabbit infection model. In vivo, AMB monotherapy and treatment with AMB for 24 h followed by AMB plus FLC (AMB-->AMB+FLC) rapidly sterilized kidneys and cardiac vegetations. AMB+FLC(simult) and FLC-->AMB treatments were slower in clearing fungi from infected tissues. FLC monotherapy and FLC-->AMB+FLC were both fungistatic and were the least active regimens. No adverse interaction was observed between AMB and FLC for the AMB-->FLC regimen. However, FLC-->AMB treatment was slower than AMB alone in clearing fungi from tissues. Thus, our in vitro and in vivo studies both demonstrate that preexposure of C. albicans to FLC reduces fungal susceptibility to AMB. The length of FLC preexposure and whether AMB is subsequently used alone or in combination with FLC determine the duration of induced resistance to AMB.

Amphotericin B↗
PubMed2001

Pharmacodynamics of daptomycin in a murine thigh model of Staphylococcus aureus infection.

Daptomycin is a lipopeptide antibiotic with activity against gram-positive bacteria, including Staphylococcus aureus. We defined the pharmacodynamic parameters that determine the activity of daptomycin for S. aureus using in vitro methods and the Craig (W. A. Craig, J. Redington, and S. C. Ebert, J. Antimicrob. Chemother. 27[Suppl. C]:29--40, 1991) neutropenic mouse thigh infection model. In Mueller-Hinton broth, the MICs for three S. aureus isolates were 0.1 to 0.2 microg/ml. In mouse serum, the MICs were 1.0 microg/ml. The protein binding of daptomycin was 90 to 92.5% in mouse serum. Single-dose intraperitoneal (i.p.) pharmacokinetic studies with infected mice showed a linear relationship between dose versus the maximum concentration of drug in serum and dose versus the area under the concentration-time curve (AUC). The serum half-life of daptomycin in infected mice was approximately 1.8 h. In single-dose, dose-ranging studies using mice, daptomycin showed a dose-response effect described by an inhibitory sigmoid E(max) (maximum effect) curve (r = 0.974; P << 0.001). The density of S. aureus in untreated controls was 8.26 log(10) CFU/g, and the E(max) was 3.97 log(10) CFU/g. The 50% effective dose (ED(50)) was 3.7 mg/kg of body weight i.p. and the stasis dose was 7.1 mg/kg. Dose fractionation studies at schedules of Q6h, Q12h, and Q24h, for total 24-h ED(30), ED(60), and ED(80) doses of 2.5, 5.6, and 15 mg/kg i.p., showed no difference in effect at each total 24-h dose level by schedule, indicating that the AUC/MIC ratio is the dynamically linked variable.

Animals↗
PubMed2000

Longterm methotrexate use in rheumatoid arthritis: 12 year followup of 460 patients treated in community practice.

OBJECTIVE: To extend our observations on the longterm tolerability of methotrexate (MTX) and reasons for discontinuation in a cohort of 460 patients with rheumatoid arthritis (RA). METHODS: We studied all patients with RA who started MTX before June 1986 and attended the community based private practices of 6 rheumatologists in Melbourne. Information to at least April 1, 1995, or within one year of death was updated from the patient's medical records to include MTX discontinuation and reasons for discontinuation. Addition of disease modifying antirheumatic drugs (DMARD) concomitant with MTX was noted. Survival analyses based upon life table methods were used with MTX discontinuation as the observable endpoint. Three different definitions of MTX discontinuation were used (1) according to whether the patient was taking the drug at last followup irrespective of any periods of temporary discontinuation; (2) MTX discontinuation for > 3 months considered to be a treatment endpoint; and (3) addition of concomitant DMARD considered to be only partial success of MTX (as a need for additional therapy to meet treatment goals). RESULTS: At 12 years, 53% of patients were continuing to take MTX (irrespective of any periods of temporary discontinuation). If discontinuation of the drug for 3 or more months was considered a treatment termination then 38% were still taking the drug at 12 years, and if addition of concomitant DMARD was regarded as a treatment endpoint only 17% of patients were continuing MTX at 12 years. Withdrawal for gastrointestinal toxicity declined over time but the risk of other adverse effects appeared to persist over time. CONCLUSION: MTX in RA is well tolerated over the longer term, with > 50% of patients starting MTX in a community based rheumatology private practice continuing to take it 12 years later. However, a substantial number of patients had 2nd line therapies added over this time. Monitoring for toxicity should continue throughout the course of therapy.

Antirheumatic Agents↗
PubMed1999

Efficacies of high-dose fluconazole plus amphotericin B and high-dose fluconazole plus 5-fluorocytosine versus amphotericin B, fluconazole, and 5-fluorocytosine monotherapies in treatment of experimental endocarditis, endophthalmitis, and pyelonephritis due to Candida albicans.

We compared the efficacies of fluconazole (Flu), amphotericin B (AmB), and 5-fluorocytosine (5FC) monotherapies with the combination of Flu plus 5FC and Flu plus AmB in a rabbit model of Candida albicans endocarditis, endophthalmitis, and pyelonephritis. The dose of Flu used was that which resulted in an area under the concentration-time curve in rabbits equivalent to that seen in humans who receive Flu at 1,600 mg/day, the highest dose not associated with central nervous system toxicity in humans. Quantitative cultures of heart valve vegetations, the choroid-retina, vitreous humor, and kidney were conducted after 1, 5, 14, and 21 days of therapy. All untreated controls died within 6 days of infection; animals treated with 5FC monotherapy all died within 18 days. In contrast, 93% of animals in the other treatment groups appeared well and survived until they were sacrificed. At day 5, the relative decreases in CFU per gram in the vitreous humor were greater in groups that received Flu alone and in combination with 5FC or AmB than in groups receiving AmB or 5FC monotherapies (P < 0. 005) but were similar thereafter. In the choroid-retina, 5FC was the least-active drug. However, there were no differences in choroidal fungal densities between the other treatment groups. On days 5 and 14 of therapy, fungal densities in kidneys of AmB recipients were lower than those resulting from the other therapies (P < 0.001 and P < or = 0.038, respectively) and AmB-plus-Flu therapy was antagonistic; however, all therapies for fungal pyelonephritis were similar by treatment day 21. While fungal counts in cardiac valves of Flu recipients were similar to those of controls on day 5 of therapy and did not change from days 1 to 21, AmB therapy significantly decreased valvular CFUs versus Flu at days 5, 14, and 21 (P < 0.005 at each time point). 5FC plus Flu demonstrated enhanced killing in cardiac vegetations compared with Flu or 5FC as monotherapies (P < 0. 03). Similarly, the combination of AmB and Flu was more active than Flu in reducing the fungal density in cardiac vegetations (P < 0.03). However, as in the kidney, AmB plus Flu demonstrated antagonism versus AmB monotherapy in the treatment of C. albicans endocarditis (P < 0.05, P = 0.036, and P < 0.008 on days 5, 14, and 21, respectively).

Amphotericin B↗
PubMed1999

Interaction between fluconazole and amphotericin B in mice with systemic infection due to fluconazole-susceptible or -resistant strains of Candida albicans.

The interaction between fluconazole (Flu) and amphotericin B (AmB) was evaluated in a murine model of systemic candidiasis for one Flu-susceptible strain (MIC, 0.5 microg/ml), two strains with intermediate Flu resistance (Flu mid-resistant strains) (MIC, 64 and 128 microg/ml), and one highly Flu-resistant strain (MIC, 512 microg/ml) of Candida albicans. Differences in fungal densities in kidneys of infected mice after 24 h of therapy and in survival rates at 62 days of mice treated with an antifungal drug or a combination of antifungal drugs for 4 days were compared. For the Flu-susceptible and Flu mid-resistant strains, the combination of Flu and AmB was antagonistic, as shown by both quantitative culture results and survival. The interaction was additive for the highly Flu-resistant strain. These results suggest that the combination of Flu and AmB should be used with caution in infections due to fungi that are usually susceptible to both antifungal agents and as empirical antifungal drug therapy.

Amphotericin B↗
PubMed1999

Differential attrition rates and active parental consent.

Active parental consent in survey research poses ethical and practical concerns. One common argument against the requirement of active consent procedures is its effect on participation rates. There is additional concern that higher risk groups may be underrepresented in the final sample. Empirical support of differential attrition, however, is lacking. In the current multisite longitudinal study, passive consent procedures were approved for the collection of pretest data. For subsequent years of data collection, active parental consent procedures were required. In this article, we use the pretest data to examine demographic, attitudinal, and behavioral differences between those students for whom active consent was provided and those for whom active consent was either denied or for whom no response was received. The results indicate that active consent procedures produce deleterious effects on participation rates and lead to an underrepresentation of at-risk youth in the sample.

Adolescent↗
PubMed1999

Prevalence of leg wound complications after coronary artery bypass grafting: determination of risk factors.

BACKGROUND: The reported prevalence of leg wound complications after coronary artery bypass grafting is 2% to 24%. Decreased length of hospital stay for patients who have this surgical procedure poses new care requirements in both acute care and community settings. OBJECTIVE: To determine the prevalence of postoperative leg wound complications in patients undergoing coronary artery bypass grafting and the risk factors associated with these complications. METHOD: In this prospective, observational study, 547 consecutive patients who had coronary artery bypass grafting alone or in combination with other cardiac surgical procedures were examined for evidence of leg wound complications each day after surgery during hospitalization. After discharge, problems were detected by home care nurses. RESULTS: The prevalence of leg wound complications was 6.8%. Factors significant by multiple logistic regression included preoperative hospitalization, use of an Ace elastic bandage in the operating room, the length of time the leg incision remained open in the operating room, and administration of nicardipine intravenously in the intensive care unit. Odds ratios were calculated for each variable. Premorbid factors such as diabetes or peripheral vascular disease were not predictive of complications. On average, most problems occurred on postoperative day 10, when many patients were at home. CONCLUSIONS: The results highlight the need to detect complications early, in both the hospital and the community settings. The determination of factors related to poor outcomes may assist clinicians in improving healthcare delivery.

Aged↗
PubMed1998

Comparison of fluconazole pharmacokinetics in serum, aqueous humor, vitreous humor, and cerebrospinal fluid following a single dose and at steady state.

The objective of this study was to characterize the pharmacokinetic parameters and penetration of fluconazole following a single dose in the serum, aqueous humor, vitreous humor and cerebrospinal fluid (CSF) of non pigmented rabbits using serial sampling techniques and to determine if the pharmacokinetic parameters in the eye and CSF are similar. Twenty healthy male rabbits received intravenous fluconazole 20 mg/kg as a single dose or 20 mg/kg every 12 hours for 4 doses. Serum, aqueous humor, vitreous humor and CSF samples were taken 15 minutes after the initial intravenous injection and hourly thereafter for six hours. Fluconazole concentrations were determined by microbiological assay. Pharmacokinetic analyses were performed using a nonlinear least-square regression program. Fluconazole's penetration in all anatomical compartments was > 70% than in the serum. Similar elimination half-lives and time to reach maximum concentrations were noted in all compartments. While mean concentrations in each anatomical compartment were similar in animals receiving a single dose or among those at serum steady state, the mean concentrations achieved in the serum, aqueous and vitreous humors and CSF were between 1.82 and 2.17 times higher at serum steady state than following a single dose. At serum concentrations that are comparable to those in humans, the penetration of fluconazole into the noninflamed aqueous and vitreous humors and CSF were > or = 70%. The CSF and ocular pharmacokinetic parameters closely resembled each other, so that either could be used as a surrogate for the other.

Animals↗
PubMed1998

Pharmacodynamics of fluconazole in a murine model of systemic candidiasis.

In this study we defined the pharmacodynamic parameter that optimizes outcome in deep-seated Candida albicans infections treated with fluconazole. Using a murine model of systemic candidiasis, we conducted single-dose dose-ranging studies with fluconazole to determine the dosage of this drug that resulted in a 50% reduction in fungal densities (50% effective dose [ED50]) in kidneys versus the fungal densities in the kidneys of untreated controls. We found that the ED50 of fluconazole given intraperitoneally was 4.56 mg/kg of body weight/day (95% confidence interval, 3.60 to 5.53 mg/kg/day), and the dose-response relationship was best described by an inhibitory sigmoid maximal effect (Emax) curve. To define the pharmacodynamics of fluconazole, we gave dosages lower than, approximating, and higher than the ED50 of fluconazole (range, 3.5 to 5.5 mg/kg/day, equivalent to the ED16 to the ED75) to various groups of infected animals using three dose-fractionation schedules. For each total dose of fluconazole examined, the dose-fractionation schedules optimized the ratio of the area under the concentration-time curve (AUC) to the MIC (the AUC/MIC ratio), the ratio of the maximum concentration of drug in serum (Cmax) to the MIC, and the time that the drug remained above the MIC for the infecting C. albicans isolate. Similar reductions in fungal densities in kidneys were seen between groups that received the same total dose of fluconazole in one, two, or four equally divided doses. Thus, dose-fractionation studies demonstrated that the pharmacodynamic parameter of fluconazole that best predicted outcome was the AUC/MIC ratio.

Animals↗
PubMed1998

Pharmacokinetics of sparfloxacin in the serum and vitreous humor of rabbits: physicochemical properties that regulate penetration of quinolone antimicrobials.

We have used a recently described animal model to characterize the ocular pharmacokinetics of sparfloxacin in vitreous humor of uninfected albino rabbits following systemic administration and direct intraocular injection. The relationships of lipophilicity, protein binding, and molecular weight to the penetration and elimination of sparfloxacin were compared to those of ciprofloxacin, fleroxacin, and ofloxacin. To determine whether elimination was active, elimination rates following direct injection with and without probenecid or heat-killed bacteria were compared. Sparfloxacin concentrations were measured in the serum and vitreous humor by a biological assay. Protein binding and lipophilicity were determined, respectively, by ultrafiltration and oil-water partitioning. Pharmacokinetic parameters were characterized with RSTRIP, an iterative, nonlinear, weighted, least-squares-regression program. The relationship between each independent variable and mean quinolone concentration or elimination rate in the vitreous humor was determined by multiple linear regression. The mean concentration of sparfloxacin in the vitreous humor was 59.4% +/- 12.2% of that in serum. Penetration of sparfloxacin, ciprofloxacin, fleroxacin, and ofloxacin into, and elimination from, the vitreous humor correlated with lipophilicity (r2 > 0.999). The linear-regression equation describing this relationship was not improved by including the inverse of the square root of the molecular weight and/or the degree of protein binding. Elimination rates for each quinolone were decreased by the intraocular administration of probenecid. Heat-killed Staphylococcus epidermidis decreased the rate of elimination of fleroxacin. Penetration of sparfloxacin into the noninflamed vitreous humor was greater than that of any quinolone previously examined. There was an excellent correlation between lipophilicity and vitreous entry or elimination for sparfloxacin as well as ciprofloxacin, fleroxacin, and ofloxacin. There are two modes of quinolone translocation into and out of the vitreous humor: diffusion into the eye and both diffusion and carrier-mediated elimination out of the vitreous humor.

Animals↗
PubMed1998

Pharmacokinetic studies of fluconazole in rabbits characterizing doses which achieve peak levels in serum and area under the concentration-time curve values which mimic those of high-dose fluconazole in humans.

We conducted steady-state pharmacokinetic studies with high-dose fluconazole with rabbits and human volunteers. We then derived mathematical equations that predict the doses of fluconazole that should be given to rabbits to produce 24-h area under the concentration-time curve values and maximum concentrations in serum that are similar to those measured for humans given 800 to 2,000 mg of fluconazole per day. These equations provide a rational basis for designing future efficacy studies with rabbits and in evaluating the strength with which results of previously conducted studies using rabbit infection models can be extrapolated to the clinic.

Animals↗
PubMed1997

"Cyclodiode". Trans-scleral diode laser cyclophotocoagulation in the treatment of advanced refractory glaucoma.

PURPOSE: To analyze the results of intraocular pressure (IOP) reduction by diode laser contact cyclophotocoagulation ("cyclodiode") in cases of advanced glaucoma refractory to alternative treatments. METHODS: Two hundred and ten eyes of 195 patients, ages 1 to 89 years (mean, 51 years) were followed for 3 to 30 months (mean, 10 months) after cyclodiode treatment. RESULTS: More than one treatment was given in 102 eyes (49%), and the overall mean number of treatments given per eye was 1.75 (range, 2-5). Mean pretreatment IOP was 34.1 mmHg (+/-10.6 mmHg). At last follow-up, mean IOP was 20.1 mmHg (+/-9.3 mmHg), and mean total medications was reduced from 2.3 to 1.7. Mean final IOP was lowest in patients with silicone oil glaucoma (17.3 mmHg), and the mean reduction in IOP was greatest in patients with neovascular glaucoma (23.9 mmHg). At last follow-up, visual acuity was worse than before treatment in 29% of eyes, unchanged in 60%, and better in 11%. Overall success rate (IOP < 22 mmHg) was 66% at a mean follow-up of 10 months. Phthisis occurred in one eye (0.5%), and chronic hypotony (0 mmHg < IOP < 5 mmHg for > 3 months) in a further two eyes (1%). Corneal graft decompensation followed treatment in two eyes, macular pucker occurred in one eye, and combined hyphema/vitreous hemorrhage in one patient. CONCLUSIONS: Diode laser cycloablation is relatively safe and effective at controlling IOP in eyes with advanced refractory glaucoma in the short and medium term. With the treatment parameters used, multiple applications may be needed.

Adolescent↗