Gravity complexes as a focus of seafloor fluid seepage: the Rio Grande Cone, SE Brazil.

Seafloor methane emissions can affect Earth's climate and ocean chemistry. Vast quantities of methane formed by microbial decomposition of organic matter are locked within gas hydrate and free gas on continental slopes, particularly in large areas with high sediment accumulations such as deep-sea fans. The release of methane in slope environments has frequently been associated with dissociation of gas hydrates near the edge of the gas hydrate stability zone on the upper slope, with discharges in greater water depths less understood. Here we show, using data from the Rio Grande Cone (western South Atlantic), that the intrinsic, gravity-induced downslope collapse of thick slope sediment accumulations creates structures that serve as pathways for gas migration, unlocking methane and causing seafloor emissions via giant gas flares in the water column. The observed emissions in the study region (up to 310 Mg year-1) are three times greater than estimates for the entire US North Atlantic margin and reveal the importance of collapsing sediment accumulations for ocean carbon cycling. Similar outgassing systems on the Amazon and Niger fans suggest that gravity tectonics on passive margins is a common yet overlooked mechanism driving massive seafloor methane emissions in sediment-laden continental slopes.

Phase I pilot study of the effects of trovafloxacin (CP-99,219) on the pharmacokinetics of theophylline in healthy men.

This study examined the effect of trovafloxacin (CP-99,219) on the pharmacokinetics and pharmacodynamics of a single dose of theophylline, when administered to steady-state concentrations. Twelve healthy, nonsmoking male volunteers participated. A 450-mg dose of theophylline was administered at 7:00 AM on day 1. On day 4, volunteers received 300 mg of trovafloxacin (CP-99,219) daily in the morning for 7 days. The 450-mg dose of theophylline was repeated on day 8 at 7:00 AM concomitantly with 300 mg of trovafloxacin. Theophylline concentrations in plasma and trovafloxacin in serum were determined using reverse-phase high-performance liquid chromatography. There was no significant difference between the geometric mean values for Cmax of theophylline, 6.42 micrograms/mL and 6.00 micrograms mL on days 1 and 8, respectively. A change (P = 0.032) in the geometric mean of the area under the concentration-time curve extrapolated to infinity (AUC0-infinity) for theophylline was noted for trovafloxacin was administered. Mean terminal phase elimination rate constants (Kes) were reduced (P = 0.001) by 13% after administration of trovafloxacin from day 1 to day 8. In general, changes in theophylline clearance of less than 20% are unlikely to be of clinical significance. In this study, oral administration of trovafloxacin in 300 mg doses to achieve steady-state concentration resulted in an 8.4% increase in the extent of systemic exposure (AUC0-infinity) to theophylline. Assuming that this AUC change is based on oral clearance and not absorption, one would not expect to see clinically significant changes in the pharmacokinetics of theophylline. No pharmacodynamic changes resulted from the pharmacokinetic changes of theophylline.

A blast of gas in the latest Paleocene: simulating first-order effects of massive dissociation of oceanic methane hydrate.

Carbonate and organic matter deposited during the latest Paleocene thermal maximum is characterized by a remarkable -2.5% excursion in delta 13C that occurred over approximately 10(4) yr and returned to near initial values in an exponential pattern over approximately 2 x 10(5) yr. It has been hypothesized that this excursion signifies transfer of 1.4 to 2.8 x 10(18) g of CH4 from oceanic hydrates to the combined ocean-atmosphere inorganic carbon reservoir. A scenario with 1.12 x 10(18) g of CH4 is numerically simulated here within the framework of the present-day global carbon cycle to test the plausibility of the hypothesis. We find that (1) the delta 13C of the deep ocean, shallow ocean, and atmosphere decreases by -2.3% over 10(4) yr and returns to initial values in an exponential pattern over approximately 2 x 10(5) yr; (2) the depth of the lysocline shoals by up to 400 m over 10(4) yr, and this rise is most pronounced in one ocean region; and (3) global surface temperature increases by approximately 2 degrees C over 10(4) yr and returns to initial values over approximately 2 x 10(6) yr. The first effect is quantitatively consistent with the geologic record; the latter two effects are qualitatively consistent with observations. Thus, significant CH4 release from oceanic hydrates is a plausible explanation for observed carbon cycle perturbations during the thermal maximum. This conclusion is of broad interest because the flux of CH4 invoked during the maximum is of similar magnitude to that released to the atmosphere from present-day anthropogenic CH4 sources.

Angioedema and urticaria associated with omeprazole confirmed by drug rechallenge.

Omeprazole is a substituted benzimidazole that has gained widespread use in the treatment of acidic and peptic ulcer disease. Adverse events with the drug are rare and involve mainly the gastrointestinal and central nervous systems. Skin inflammation, urticaria, pruritus, alopecia, and dry skin have been reported in 0.5-1.5% of patients. To date, no published report has linked angioedema with omeprazole. We report a case of a 34-year-old woman with cellulitis, ulcerative erosive esophagitis, and gastric and duodenal ulcers who developed several hypersensitivity reactions characterized by shortness of breath, wheezing, cough, mild angioedema, and total body urticaria and pruritus. These symptoms correlated with the addition of omeprazole to her regimen and the timing of its administration. A previous case report prompted a rechallenge with enteric-coated omeprazole granules removed from the capsule shell. Recurrence of the adverse events suggested an allergy to the drug itself and not the capsule. Angioedema can be a life-threatening allergic reaction requiring immediate treatment. Rechallenge using omeprazole with or without the capsule shell should be done only in a hospital setting where prompt action can be taken in the event of an emergency.

Cyclosporine-induced beta-adrenergic receptor down-regulation in bovine pulmonary artery smooth muscle cells: a pilot study.

We attempted to determine the effects of cyclosporine on beta-adrenergic receptors in bovine pulmonary artery smooth muscle cells. Bovine pulmonary artery smooth muscle cells were exposed to cyclosporine at a concentration of 100 ng/ml in culture media for 5 days, and control bovine pulmonary artery smooth muscle cells were exposed to only culture media for the same 5-day period. Beta-adrenergic receptors were measured as total binding capacity (Bmax) by nonlinear least squares fit of the specific binding curve. In a separate experiment beta1- versus beta2-adrenergic receptor subtypes were identified by computer modeling (LIGAND) of 17-19 point CGP20712A-125ICYP competition curves. Cyclosporine significantly (p=0.02) decreased bovine pulmonary artery smooth muscle beta-adrenergic receptor density by 54%+/-7%. The Bmax for control versus treated cells was 38.9+/-18 versus 17.7+/-12 fmol/mg protein, respectively. Subtype determination of beta-receptors revealed 70% or more beta2- and 30% or less beta1-adrenergic receptors. Cyclosporine caused a 54% reduction in overall beta-adrenergic receptor density in bovine pulmonary artery smooth muscle cells. The reduction in Bmax is suspected not to be a result of selective down-regulation of beta1-adrenergic receptors alone. We believe that cyclosporine may also contribute to a decrease in beta2-adrenergic receptors.

Effect of nebulized albuterol on serum potassium and cardiac rhythm in patients with asthma or chronic obstructive pulmonary disease.

STUDY OBJECTIVE: To evaluate the metabolic and cardiopulmonary effects of nebulized albuterol in patients suffering moderate to severe exacerbations of asthma or chronic obstructive pulmonary disease. DESIGN: Open-label, prospective study. SETTING: The emergency department of a university medical center. PATIENTS: Ten patients with moderate to severe exacerbation of asthma. INTERVENTIONS: Each patient received nebulized albuterol 2.5 mg for approximately 10 minutes. MEASUREMENTS AND MAIN RESULTS: Serum potassium, heart rate and rhythm, blood pressure, and pulmonary function were measured before treatment and every 15 minutes for 2 hours after treatment. Serum potassium concentrations decreased significantly (p < 0.05) within 75 minutes after initiation of treatment, from a baseline value of 4.5 +/- 0.6 mEq/L (range 3.5-5.5 mEq/L) to 3.7 +/- 0.5 mEq/L (range 2.8-4.4 mEq/L) at the end of the collection period (120 minutes). Forced expiratory volume in 1 second significantly increased over time in patients with asthma (p < 0.05). No statistically significant changes in blood pressure, heart rate, or corrected QT intervals occurred. Pre-emergency department use of a beta 2-agonist by metered-dose inhaler was not associated with a decreased serum potassium on admission. CONCLUSIONS: Nebulized beta 2-agonists are generally efficacious and safe in patients with acute bronchospasms. However, close monitoring of serum electrolytes, heart rate, and rhythm in patients at risk (elderly, those with pre-existing cardiac disease) is advised before these individuals receive repeat doses by continuous aerosol administration.

A pilot study of estrogen's effects on bronchial myocyte adhesion molecule expression.

We examined the effects of estrogen on tumor necrosis factor alpha (TNF-alpha)-induced expression of intracellular adhesion molecule (ICAM-1) and vascular adhesion molecule (VCAM-1) in cultured human bronchial smooth muscle cells (BSMC). Experiments were performed in triplicate in T-75 tissue culture flasks containing normal human BSMC. Four experiments were carried out: untreated BSMC cells (control); TNF-alpha 1000 U/ml stimulation of BSMC; forskolin 5 microM before TNF-alpha stimulation of BSMC; and estradiol 30 microM before TNF-alpha stimulation of BSMC. Cyclic adenosine monophosphate was measured by a commercially available radioimmunoassay kit. Cell expression of ICAM-1 and VCAM-1 was quantified by flow cytometry Incubation of cells with TNF-alpha 1000 U/ml for 24 hours elicited a 27-fold increase in basal expression of ICAM-1 and a 2-fold increase in VCAM-1 (p>0.05). Incubation of BSMC with forskolin 5 microM, for 1 hour before TNF-alpha, decreased TNF-alpha-induced expression of ICAM-1 by 62% and VCAM-1 slightly by 17%. The BSMC incubated with estradiol 30 microM, 1 hour before TNF-alpha, decreased TNF-alpha-induced expression of ICAM-1 by 21%; VCAM-1 remained unchanged (p>0.05). We found a trend toward inhibition of TNF-alpha-stimulated ICAM-1 expression in cultured BSMC with pretreatment with estradiol. However, due to large variability within the cell culture model, statistical significance was not reached.

In vitro and in vivo effects of genistein on murine alveolar macrophage TNF alpha production.

The present study was performed to determine whether genistein could inhibit in vivo LPS-induced alveolar macrophage TNFalpha production and thus reduce the alveolar neutrophil influx following LPS. In vitro incubation with genistein completely inhibited LPS-induced TNFalpha production by alveolar macrophages (AM) from BALB/c mice. Subsequently mice were pretreated with intraperitoneal genistein or vehicle, then received nasal LPS to induce an alveolitis. Genistein was then administered every eight hours for five days following LPS. At 24 hours after LPS, the bronchoalveolar lavage (BAL) TNFalpha and ex vivo TNFalpha production from AM, were lower in the genistein treated animals. As well, total BAL white blood cell (WBC) count was reduced in the genistein as compared to the vehicle-only group. The percent neutrophils and the resolution of neutrophils were similar between genistein and vehicle groups. Therefore, genistein was able to decrease AM TNFalpha production, and was associated with a decrease in BAL WBC count post-LPS.

Implementation of a criteria-based antimicrobial formulary system.

The development of a criteria-based antimicrobial formulary system for use in a 432-bed university-based tertiary-care hospital is described. A subcommittee of the hospital's pharmacy and therapeutics committee developed prescribing criteria for antimicrobials thought to have a specific place in the treatment of various infections. The criteria were based primarily on patient needs, but when two therapies were thought to have similar effectiveness and similar toxicity profiles, cost became the deciding factor in drug selection. Educational packets were designed to assist physicians in prescribing criteria-based antimicrobials. An antimicrobial order form was also developed. The program was implemented after an extensive orientation and education period; data on antimicrobial use were collected for the first year of the program. Hospitalwide compliance with the criteria was 89%, although compliance in certain departments was poorer. The database was formulated to be both service- and physician-specific for the purposes of reporting and education.

Pharmacokinetics of flunisolide administered via metered dose inhaler with and without a spacer device and following oral administration.

BACKGROUND: After inhalation of a glucocorticoid from a meter dose inhaler (MDI), a certain portion of the delivered dose is deposited in the lungs, and the remainder is deposited in the oropharynx. OBJECTIVE: To examine the absolute bioavailability of flunisolide given orally via metered dose inhaler, and metered dose inhaler with a commercially available spacer device as well as to determine the fraction of drug deposited in the lungs following inhalation. METHODS: Twenty-four healthy volunteers were enrolled in the study; twenty-two completed the study. The IRB approved the study protocol, and informed consent was obtained. Volunteers received four treatments: treatment A (MDI), 1.0 mg inhaled flunisolide; treatment B (MDI-S), 1.0 mg inhaled flunisolide with a spacer device; treatment C, 1.0 mg of orally administered flunisolide with 240 mL of water; and treatment D, 1.0 mg intravenous flunisolide by IV push in the antecubital vein over 60 seconds. Plasma and urine flunisolide were quantified by HPLC/mass spectrometry/mass spectrometry. RESULTS: Flunisolide is a corticosteroid with low oral bioavailability (6.7%), which was found to be lower than previously reported. Similar AUCs were observed between the MDI and MDI-S groups, but by using mass balance equations, it appears that more flunisolide was delivered to the lungs in the MDI-S group (410 microg versus 280 microg). Oropharyngeal deposition was an important difference between the two inhaler groups. Approximately an 11-fold reduction in the oropharyngeal deposition of flunisolide through use of the spacer device was observed. CONCLUSIONS: Use of a spacer device improved pulmonary delivery of flunisolide by almost 50% and significantly decreased the oropharyngeal exposure to drug.