Data Linkages for Wildfire Exposures and Human Health Studies: A Scoping Review.

Wildfires are increasing in frequency and intensity, with significant consequences that impact human health. A scoping review was conducted to: (a) understand wildfire-related health effects, (b) identify and describe environmental exposure and health outcome data sources used to research the impacts of wildfire exposures on health, and (c) identify gaps and opportunities to leverage exposure and health data to advance research. A literature search was conducted in PubMed and a sample of 83 articles met inclusion criteria. A majority of studies focused on respiratory and cardiovascular outcomes. Hospital administrative data was the most common health data source, followed by government data sources and health surveys. Wildfire smoke, specifically fine particulate matter (PM2.5), was the most common exposure measure and was predominantly estimated from monitoring networks and satellite data. Health data were not available in real-time, and they lacked spatial and temporal coverage to study health outcomes with longer latency periods. Exposure data were often available in real-time and provided better temporal and spatial coverage but did not capture the complex mixture of hazardous wildfire smoke pollutants nor exposures associated with non-air pathways such as soil, household dust, food, and water. This scoping review of the specific health and exposure data sources used to underpin these studies provides a framework for the research community to understand: (a) the use and value of various environmental and health data sources, and (b) the opportunities for improving data collection, integration, and accessibility to help inform our understanding of wildfires and other environmental exposures.

Gut and intestinal passage time in the Rainbow Skink (Trachylepis margaritifer): implications for stress measures using faecal analysis.

Stress levels in organisms provide a rapid measure for assessing population health. Handling and capture stress, however, cause error in blood measures, so this method is rapidly being replaced by assessing levels of stress metabolites in faeces. This eliminates the source of error because there is a lag period between stress perception and the resultant stress metabolite accumulation within faeces. This lag period is correlated with specific intestinal passage time, a measure that can vary greatly between taxa, particularly amongst ectotherms. Due to two deleterious consequences associated with extended exposure of the metabolites to the intestinal environment, species that exhibit long and variable intestinal passage times are not good candidates for metabolite studies. We measured gut and intestinal passage times in Trachylepis margaritifer to ascertain whether it would be an appropriate candidate for stress metabolite studies. We first tested if barium sulphate in the meal had an effect on gut passage time at three ambient temperatures (25, 27 and 32 °C). Barium sulphate had no effect; however, temperature had a significant effect with an unexpected pattern: gut passage time was fastest at 32 °C but was slower at 27 °C than at 25 °C. We then used X-ray technology and barium sulphate-loaded meals to measure gut and intestinal passage times at 25 and 27 °C. This allowed us to observe which parts of the digestive process were responsible for increased passage times at 27 °C: the faster passage time at 25 °C was due to faster intestinal passage time; there was no difference in gastric emptying time. We assess the species to be a suitable candidate for studies using faeces to measure stress. It is imperative however, that the effect of temperature on passage rates is known and taken into account in such studies.

Phosphonomycin, a new antibiotic produced by strains of streptomyces.

Phosphonomycin is a newly discovered antibiotic produced by streptomycetes. It is effective, when administered by the oral route, to mice infected with Gram-positive or Gram-negative microorganisms. The antibiotic is bactericidal and inhibits cell-wall synthesis.

Effects of total plasma concentration and age on tolbutamide plasma protein binding.

Tolbutamide plasma protein binding at different total tolbutamide concentrations was determined in 44 healthy, nonsmoking, drug-free men from 23 to 87 yr old. The data showed that unbound drug increased with total tolbutamide plasma concentration and with age, but that neither the binding equilibrium constant nor the number of binding sites correlated with age. The increase in unbound fraction with age could be partially explained by the decrease in albumin concentration in elderly subjects. Results of multiple linear regression analysis indicated that, although age had a considerably greater influence than albumin concentration, total tolbutamide concentration was the most important determinant of the unbound fraction. Thus, both age and total plasma concentration may affect tolbutamide kinetics.

Rosiglitazone does not affect the steady-state pharmacokinetics of digoxin.

Rosiglitazone is a potent insulin-sensitizing oral hypoglycemic agent of the thiazolidinedione class that works through activation of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) nuclear receptor and improves glycemic control in patients with non-insulin-dependent diabetes mellitus. The potential for a drug-drug interaction with oral digoxin was investigated. Subjects received both of the study regimens in a random sequence: digoxin 0.375 mg plus matching placebo for rosiglitazone orally each morning for 14 days or digoxin 0.375 mg plus 8 mg rosiglitazone orally each morning for 14 days. There was a 14-day washout period between sessions. Blood and urine were collected over 24 hours beginning on the morning of day 14 for measurement of digoxin concentrations. An equivalence statistical approach was used, with rosiglitazone considered to have no effect on the pharmacokinetics of digoxin if the 90% confidence interval (CI) for the ratio of digoxin plus rosiglitazone relative to digoxin plus placebo was completely contained within the range (0.80, 1.25) for the primary end points, AUC(0-24), and C24. Digoxin AUC(0-24) and C24 values were similar for digoxin 0.375 mg plus matching placebo (18.5 ng.h/mL and 0.579 ng/mL, respectively) and digoxin 0.375 mg plus rosiglitazone (19.1 ng.h/mL and 0.594 ng/mL, respectively). Point estimates were 1.05 (90% CI: 1.01, 1.10) for AUC(0-24) and 1.04 (90% CI: 0.98, 1.11) for C24. Oral and renal clearance were also similar between regimens. Digoxin alone or in combination with rosiglitazone was safe and well tolerated. The most common adverse experience was headache. Coadministration of digoxin with rosiglitazone had no significant effect on the safety or steady-state pharmacokinetics of digoxin.

Lack of effect of rosiglitazone on the pharmacokinetics of oral contraceptives in healthy female volunteers.

The effect of rosiglitazone (Avandia [BRL 49653C]) on the pharmacokinetics of ethinylestradiol and norethindrone was evaluated after repeat dosing of rosiglitazone with an oral contraceptive (OC; Ortho-Novum 1/35 containing norethindrone 1 mg and ethinylestradiol 0.035 mg) in a randomized, double-blind, placebo-controlled crossover study. Thirty-four healthy female volunteers received oral rosiglitazone (RSG) 8 mg + OC or matched placebo (P) + OC daily on days 1 to 14 of a 28-day OC dosing cycle; the alternate regimen was administered during a second cycle. Ethinylestradiol and norethindrone pharmacokinetics were determined from plasma concentrations on day 14. Lack of pharmacokinetic effect was prospectively defined as 90% CI for the point estimate (PE) of the ratio (RSG + OC):(P + OC) contained within a 20% equivalence range for both ethinylestradiol and norethindrone (analyzed by ANOVA). For RSG + OC and P + OC, respectively, mean ethinylestradiol AUC(0-24) was 1126 and 1208 pg.h/mL (PE: 0.92; 90% CI: 0.88-0.97), and mean norethindrone AUC(0-24) was 178 and 171 ng.h/mL (PE: 1.04; 90% CI: 1.00-1.07). Thus, rosiglitazone had no significant effects on the pharmacokinetics of ethinylestradiol or norethindrone. Coadministration of rosiglitazone with OCs does not induce metabolism of these synthetic sex steroids and is not expected to impair the efficacy of OCs or hormone replacement therapy.

Rosiglitazone has no clinically significant effect on nifedipine pharmacokinetics.

To examine the effects of repeat oral dosing of rosiglitazone on the pharmacokinetics of nifedipine, a prototype CYP3A4 substrate, a randomized, open-label, crossover study was performed with two treatment phases separated by a washout period of at least 14 days. Twenty-eight healthy male volunteers received either a single 20 mg oral nifedipine dose or rosiglitazone 8 mg orally once daily for 14 days with a single 20 mg oral nifedipine dose administered on day 14. Plasma nifedipine concentrations were determined over the 24-hour period following administration of the nifedipine doses. Lack of effect was defined as the demonstration that the 90% CI was contained entirely within a symmetrical 30% range either side of unity on the loge-scale. Following rosiglitazone + nifedipine administration, the area under the nifedipine concentration-time curve from time zero to infinity (AUC(0-infinity)) was 13% lower than that after administration of nifedipine alone. This difference in nifedipine AUC(0-infinity) was not deemed to be clinically significant since the 90% CI was contained within the protocol-defined 30% range (point estimate for ratio of geometric means 0.87; 90% CI: 0.79, 0.96). Rosiglitazone had no marked effect on nifedipine peak plasma concentration (point estimate: 0.99; 90% CI: 0.73, 1.34) or time to peak concentration compared with nifedipine alone. Rosiglitazone coadministration produced a small decrease in the mean nifedipine half-life (point estimate: -0.77; 90% CI: mean difference -1.29 h, -0.25 h). Both treatment regimens were well tolerated and associated with a favorable safety profile. Rosiglitazone, at the highest dose used in clinical studies, produced a small, clinically insignificant decrease in nifedipine exposure. The very small effect on nifedipine pharmacokinetics suggests that rosiglitazone is an extremely weak inducer of CYP3A4, a characteristic that distinguishes rosiglitazone from troglitazone.

The effect of low-dose cimetidine (200 mg twice daily) on the pharmacokinetics of theophylline.

The potential for nonprescription cimetidine (200 mg twice daily) to affect the pharmacokinetics of sustained-release (SR) theophylline was assessed in 26 male subjects, 13 smokers and 13 nonsmokers. This was a concentration-controlled drug interaction study in which the subjects were administered a dose of SR theophylline every 12 hours to provide a mean steady-state concentration between 8 and 15 micrograms/ml. To determine individual theophylline dose, a test dose of aminophylline was administered, and baseline theophylline pharmacokinetics were determined. Subjects remained on SR theophylline for 23 days and were treated in the following sequence: run-in phase (4 days), treatment 1 (7 days), washout (5 days), and treatment 2 (7 days). During the treatment phases, subjects received cimetidine (200 mg at approximately 08:00 and 12:00) or placebo for 7 days in a randomized crossover fashion. Theophylline pharmacokinetics were determined on days 1, 4, and 7 of both treatment phases. A large day-to-day variability in the oral clearance of theophylline was evident for the theophylline-placebo treatment and the theophylline-cimetidine treatment. Nonprescription strength cimetidine resulted in a mean 5% decrease in theophylline oral clearance on day 1 and a mean 12% decrease on days 4 and 7 combined. There were no significant differences in the cimetidine-theophylline interaction between smokers and nonsmokers. Oral clearance during the nighttime dosing interval was 13% greater than the daytime oral clearance for nonsmokers and 22% greater for smokers, showing a greater circadian rhythm for smokers. In summary, nonprescription doses of cimetidine (400 mg/day) have the potential to produce small changes in theophylline concentrations during steady-state dosing with SR theophylline; however, this effect appears less than changes that occur as a consequence of theophylline's intrasubject variability.

Using the Quantimet 720 image analyzing computer to count nucleolated neurones in the human brain.

An approach to the automatic counting of neurones in the human hippocampus is described which uses a modified Quantimet 720 image analyzing computer. Previous work with this and similar machines has attempted to use size alone to discriminate between the various types of cell which are present in any section of central nervous system tissue. Serious errors may then result since agglomerates of small cells and cell fragments can bae confused with single large cells. Instead, 2 electron devices have been designed and built which allow nucleolated neurones, defined as those objects having a grey phase and a black phase both within designated area limits, to be distinguished from all other cells. The mean values for absolute cell numbers and for cell density were within 5% of those obtained by traditional manual methods. The operation of both electronic devices is described and circuit diagrams given for one of them. The other is beyond the scope of this paper, but has been fully reported elsewhere.

Reduction of paraphimosis with hyaluronidase.

The use of hyaluronidase facilitates reduction of paraphimosis. It acts by dispersing extracellular edema, permitting easy reduction of the foreskin. Its use is applicable both in the hospital and outpatient setting. Hyaluronidase is widely available and keeps well if refrigerated. It is effective for children and adults.

Response of spinal cord blood flow to the nitric oxide inhibitor nitroarginine.

OBJECTIVE: The extent to which nitric oxide (NO) is involved in the modulation of spinal cord blood flow (SCBF) in the uninjured and injured cord is unknown. To elucidate these questions, the following experiments in anesthetized rats were conducted. METHODS: Because NO is an unstable free radical with a half-life of seconds, its role can be understood through the study of the NO synthase inhibitor L-NG-nitroarginine (L-NOARG). L-NOARG was administered intravenously for 30 minutes at a dose of 100 or 500 micrograms/kg/min in 12 and 10 uninjured animals, respectively. SCBF fluctuations at C7-T1 were measured using laser doppler flowmetry. In a second set of 12 rats, L-NOARG (500 micrograms/kg/min) was administered 10 minutes before spinal cord injury using a modified aneurysm clip at C7-T1 and continued for 30 minutes thereafter. RESULTS: In the uninjured animals, L-NOARG was associated with a dose-dependent increase in mean arterial pressure of 20 to 80% above baseline (P = 0.0001), together with a dose-related decrease in SCBF (P = 0.0373). In the injured animals, L-NOARG was associated with a 48% increase in mean arterial pressure. With L-NOARG, the changes in SCBF from baseline after injury were similar to those of noninjured controls (n = 25) and significantly less than injury controls (n = 18) or those receiving phenylephrine (n = 8). CONCLUSION: NO synthase inhibitors, by reducing available NO, cause systemic vasoconstriction and a decrease in SCBF in the uninjured spinal cord. In the injured spinal cord, the administration of L-NOARG results in a redistribution of blood flow with an augmentation in posttraumatic SCBF at the injury site.

Managing data quality through automation.

Traditional definitions of data quality deal primarily with individual data sets and the data collection process. Today's standards for ensuring data quality have not changed with respect to the desired results, but have simply been expanded to take advantage of modern technology. Computers are used to acquire, review, store, analyze, and report data. Because each of these steps can be automated, the need for human intervention and manual review is minimized. As a result, the potential for invalid data to reach the data analysis stage has increased significantly. To reduce this potential, efforts must be devoted to developing automated procedures that cover every conceivable validation possibility. Relationships between data and data sets must be well defined [1], and data base support that facilitates ready access to the data for the purpose of analysis must be provided. For small data sets, automation may therefore be impractical; but for large, interrelated data sets, automation is highly desirable. Computer automation has therefore expanded the traditional concept of ensuring data quality to include a complex array of interrelated tasks that must be properly managed to achieve the desired results.

Human blood preservation: effect on in vitro protein binding.

In vitro plasma protein binding for phenytoin, meperidine, and bretylium tosylate was affected by the type of preserved human blood used for its estimation. Fresh heparinized plasma and serum gave equivalent fractions bound at the concentrations studied for all three drugs. However, the in vitro plasma binding of phenytoin and meperidine decreased 9-50% when estimated in fresh citrated plasma or commercially available lyophylized human serum at the concentration levels investigated. The fraction of bretylium tosylate bound to plasma protein decreased 30-40% when estimated in fresh citrated plasma but was unchanged when estimated in the lyophylized human serum.

Urinary metabolites of 3a,4,5,6,7,7a-hexahydro-3-(1-methyl-5-nitro-1H-imidazol-2-yl)-1,2-benzisoxazole in the dog.

The antiprotozoal drug 3a,4,5,6,7,7a-hexahydro-3-(1-methyl-5-nitro-1H-imidazol-2-yl)-1,2-benzisoxazole (I), which exhibits activity against trypanosomiasis, is also antibacterial in vivo. Since the urine from a dog dosed with I showed a broader spectrum of antibacterial activity than I itself, metabolites from this urine were isolated and partially characterized. The metabolites were mono- and dihydroxy-substituted species with the hydroxyl groups on carbons 4--7 of the hexahydrobenzisoxazole ring. These observations led to the synthesis of several such hydroxy derivatives of I, and their properties fully supported the proposed positions of metabolic hydroxylation. One synthetic compound, the 6,7-cis-dihydroxy compound, exhibited higher antibacterial activity against Salmonella schottmuelleri in mice and greater trypanocidal activity in vivo against Trypanosoma cruzi (Brazil strain) than I.

The enhancement of beta-lactam antibiotic therapy by novobiocin.

Novobiocin demonstrates an effect similar to that of probenecid (the "probenecid effect") in enhancing the therapeutic efficacy of antibiotics excreted mainly by the renal tubules. The ability of cefoxitin, cephalexin, cephalothin and penicillin G to protect mice against infection with Salmonella schottmuelleri was enhanced 2- to 3-fold when the animals were given oral doses of either probenecid or of novobiocin. The efficacy of cephaloridine, excreted mainly by glomerular filtration, was not enhanced by either probenecid or by novobiocin.

Thienamycin, a new beta-lactam antibiotic. I. Discovery, taxonomy, isolation and physical properties.

A new beta-lactam antibiotic, named thienamycin, was discovered in culture broths of Streptomyces MA4297. The producing organism, subsequently determined to be a hitherto unrecognized species, is designated Streptomyces cattleya (NRRL 8057). The antibiotic was isolated by adsorption on Dowex 50, passage through Dowex 1, further chromatography on Dowex 50 and Bio-Gel P2, and final purification and desalting on XAD-2. Thienamycin is zwitterionic, has the elemental composition C11H16N2O4S (M.W. = 272.18) and possesses a distinctive UV absorption (lambda max = 297 nm, epsilon = 7,900). Its beta-lactam is unusually sensitive to hydrolysis above pH8 and to reaction with nucleophiles such as hydroxylamine, cysteine and, to a lesser degree, the primary amine of the antibiotic itself. The latter reaction results in accelerated inactivation at high antibiotic concentrations.

Pharmacokinetics of rosiglitazone in patients with end-stage renal disease.

The pharmacokinetics and tolerability of a single 8-mg oral dose of rosiglitazone, an anti-diabetic agent, were compared in 10 long-term haemodialysis patients and 10 healthy volunteers. Haemodialysis patients received rosiglitazone 4 h after haemodialysis (non-dialysis day) and 3 h before haemodialysis (dialysis day). Haemodialysis did not influence rosiglitazone pharmacokinetics, and dialytic clearance was low (0.10 1/h). The mean area under the concentration-time curve (AUC(0-infinity)), the maximum observed plasma concentration (Cmax) and the half-life for rosiglitazone were similar in haemodialysis patients (non-dialysis day) and healthy individuals (2192 +/- 598 ng.h/ml versus 2388 +/- 494 ng.h/ml, 338 +/- 114 ng/ml versus 373 +/- 95 ng/ml, and 3.70 +/- 0.75 h versus 3.81 +/- 0.86 h, respectively). AUC(0-infinity) and Cmax were not markedly influenced by haemodialysis. Rosiglitazone dose adjustments are not warranted in patients with type 2 diabetes with end-stage renal failure on haemodialysis.

Rapid GC method for quantitation of nifedipine in serum using electron capture detection.

For studying the pharmacokinetics of nifedipine after single doses, a rapid, specific, reliable gas chromatographic assay procedure for nifedipine in serum is developed. Using a single-step solvent extraction or a bonded-phase column extraction and electron capture detection, an assay sensitivity of 10 to 25 ng/ml can be achieved using 0.25 ml of serum. The assay quantitates intact nifedipine and separates it reproducibly from its nitro- and nitrosopyridine derivatives.

A systematic approach to examining the patient with nail disease.

The majority of patients who present to the clinician for podiatric care do so because of complaints involving the nail and its surrounding structures. All too often the clinician's examination of the nail is incomplete and in many instances completely overlooked. The authors present a systematic approach to the examination of the patient who presents with nail pathology.